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Coysh T, Jaunmuktane Z, Hosszu LLP, Majbour N, Zhang F, Campbell T, Darwent L, Matus MB, Chan E, Holm-Mercer L, Mok TH, Wadsworth JDF, Bieschke J, Nithi K, Brandner S, Smith C, Esiri M, Collinge J, Mead S. PRNP E146G mutation inherited prion disease: distinctive clinical, pathological and fluid biomarker features. J Neurol 2025; 272:299. [PMID: 40156621 PMCID: PMC11954691 DOI: 10.1007/s00415-025-13022-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 03/03/2025] [Accepted: 03/08/2025] [Indexed: 04/01/2025]
Abstract
Inherited prion diseases (IPDs) are phenotypically diverse neurodegenerative conditions caused by mutations in the prion protein gene (PRNP). We describe IPD due to a novel PRNP E146G mutation in a 50-year-old man presenting with slowly progressive dysarthria, prominent myoclonus especially in the lower limbs, and less prominent gait ataxia, pyramidal and extrapyramidal signs. Cognitive impairment was not overt at disease onset. MRI revealed cerebellar atrophy and white matter hyperintensities. His 46-year-old sister carries the mutation and has subtle gait ataxia and dysarthria. Both patients exhibit a distinctive fluid biomarker profile: in CSF S100B is > twofold upper limit of normal, total tau is moderately elevated, and neurofilament light chain, 14-3-3 and RT-QuIC are negative; in plasma there is marked elevation of GFAP but repeatedly normal neurofilament light chain. The proband's father died aged 55 following an 8-year dementing illness with similar presentation. Post-mortem revealed cerebellar cortical atrophy and profuse large PrP amyloid plaques across cerebral and cerebellar grey matter. Immunoblotting identified low molecular weight protease-resistant PrP fragments. E146G mutation IPD broadly fits into the historical Gerstmann-Sträussler-Scheinker disease spectrum but, based on deep clinical phenotyping of this initial pedigree, we highlight some distinctive features, which may aid in identification of this disease.
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Affiliation(s)
- Thomas Coysh
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Zane Jaunmuktane
- Department of Neuropathology, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Laszlo L P Hosszu
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Nour Majbour
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Fuquan Zhang
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Tracy Campbell
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Lee Darwent
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Marcelo Barria Matus
- National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Edgar Chan
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Leah Holm-Mercer
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Tze How Mok
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Jonathan D F Wadsworth
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Jan Bieschke
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Kannan Nithi
- Department of Neurology, Northampton General Hospital NHS Trust, Cliftonville, Northampton, NN1 5BD, UK
| | - Sebastian Brandner
- Department of Neuropathology, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Colin Smith
- National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Margaret Esiri
- Department of Neuropathology, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
| | - John Collinge
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK
| | - Simon Mead
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
- National Prion Clinic, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
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Irie KI, Honda H, Tateishi T, Mori S, Yamamoto A, Morimitsu M, Shinsuke K, Moritaka T, Kurata S, Kumazoe H, Shijo M, Sasagasako N, Taniwaki T. Dopaminergic neurodegeneration in Gerstmann-Sträussler-Scheinker (P102L) disease: insights from imaging and pathological examination. Front Neurol 2024; 15:1452709. [PMID: 39376689 PMCID: PMC11456421 DOI: 10.3389/fneur.2024.1452709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 09/06/2024] [Indexed: 10/09/2024] Open
Abstract
Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. This study investigated five cases of GSS P102L [GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene] with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. Additionally, reduced DAT immunostaining was observed in the putamen compared with a control. While previous studies have identified reduced DAT-SPECT and positron emission tomography uptake in Creutzfeldt-Jakob disease and fatal familial insomnia owing to nigrostriatal neurodegeneration induced by abnormal prion protein deposition, similar phenomena in GSS P102L have not been reported. This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing.
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Affiliation(s)
- Ken-Ichi Irie
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Neuropathology Center, NHO Omuta Hospital, Fukuoka, Japan
| | - Hiroyuki Honda
- Neuropathology Center, NHO Omuta Hospital, Fukuoka, Japan
| | - Takahisa Tateishi
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Shinichiro Mori
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
- Neuropathology Center, NHO Omuta Hospital, Fukuoka, Japan
| | - Akifumi Yamamoto
- Division of Neurology, Department of Neurology, Neuro Muscular Center, NHO Omuta Hospital, Fukuoka, Japan
| | - Makoto Morimitsu
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kikuchi Shinsuke
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Taiga Moritaka
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Seiji Kurata
- Department of Radiology, Kurume University School of Medicine, Kurume, Japan
| | | | - Masahiro Shijo
- Neuropathology Center, NHO Omuta Hospital, Fukuoka, Japan
- Department of Neurology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan
| | - Naokazu Sasagasako
- Division of Neurology, Department of Neurology, Neuro Muscular Center, NHO Omuta Hospital, Fukuoka, Japan
| | - Takayuki Taniwaki
- Division of Respirology, Neurology and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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Ono N, Suzuyama K, Minagawa H, Uwatoko K, Yoshikawa M, Ide T, Mitsuoka M, Honda K, Hirai T, Otsuka T, Kai K, Honda H, Kitamoto T, Irie H, Yukitake M, Koike H. Involvement of the nigrostriatal system in Gerstman-Sträussler-Scheinker disease with the PRNP-P102L mutation. J Neurol Sci 2024; 464:123166. [PMID: 39128159 DOI: 10.1016/j.jns.2024.123166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/07/2024] [Accepted: 08/04/2024] [Indexed: 08/13/2024]
Abstract
INTRODUCTION Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal-dominant inherited prion disease most often associated with the human prion protein gene (PRNP)-P102L mutation. Although patients manifest considerable phenotypic heterogeneity, the involvement of the nigrostriatal system has not been well-studied. METHODS We performed dopamine transporter single-photon emission computed tomography (DAT-SPECT) using 123I-ioflupane to investigate the nigrostriatal system function in nine patients with the PRNP-P102L mutation. We also examined the pathological findings in another patient whose predominant feature was ataxia and who died 5 years after disease onset. RESULTS Striatum uptake of 123I-ioflupane indicated by specific binding ratio (SBR) values was significantly reduced in two patients. The DAT-SPECT examination was performed 6 months after disease onset in one of these patients who manifested rapidly developing cognitive decline mimicking Creutzfeldt-Jakob disease. DAT-SPECT was also performed 9 years after disease onset in another patient who manifested the conventional features of GSS involving ataxia and dementia in the initial phase but showed akinetic mutism at the examination time. Another patient examined 2 years after disease onset who predominantly manifested ataxia showed marginally abnormal SBR values. An autopsy case showed moderate neuronal loss in the substantia nigra, and the degree of neuronal loss was similar in most other parts of the brain. CONCLUSION Nigrostriatal system involvement may occur in patients with GSS associated with the PRNP-P102L mutation, even though parkinsonism is not the predominant feature.
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Affiliation(s)
- Natsuki Ono
- Department of Neurology, Imari Arita Kyoritsu Hospital, Arita, Japan; Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; Department of Neurology, Kouhoukai Takagi Hospital, Okawa, Japan
| | - Kohei Suzuyama
- Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Hiromu Minagawa
- Department of Neurology, Kouhoukai Takagi Hospital, Okawa, Japan
| | - Kiku Uwatoko
- Department of Neurology, Kouhoukai Takagi Hospital, Okawa, Japan
| | - Masaaki Yoshikawa
- Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Toshihiro Ide
- Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Miyuki Mitsuoka
- Department of Radiology, Saga University Hospital, Saga, Japan
| | - Kazuo Honda
- Department of Radiology, Kouhoukai Takagi Hospital, Okawa, Japan
| | - Tetsuyoshi Hirai
- Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Takateru Otsuka
- Department of Radiology, Kouhoukai Takagi Hospital, Okawa, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga, Japan
| | - Hiroyuki Honda
- Neuropathology Center, NHO, Omuta Hospital, Omuta, Japan
| | - Tetsuyuki Kitamoto
- Department of Neurological Science, Tohoku University School of Medicine, Sendai, Japan
| | - Hiroyuki Irie
- Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan
| | | | - Haruki Koike
- Division of Neurology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.
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Chen Z, Kong Y, Zhang J, Zou WQ, Wu L. Genetic and pathological features encipher the phenotypic heterogeneity of Gerstmann-Sträussler-Scheinker disease. Neurobiol Dis 2024; 195:106497. [PMID: 38583641 DOI: 10.1016/j.nbd.2024.106497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 02/29/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024] Open
Abstract
OBJECTIVES To elucidate and compare the genetic, clinical, ancillary diagnostic, and pathological characteristics across different Gerstmann-Sträussler-Scheinker disease (GSS) phenotypes and explore the underlying causes of the phenotypic heterogeneities. METHODS The genetic, clinical, ancillary diagnostic, and pathological profiles of GSS patients reported in the literature were obtained and analyzed. Additionally, 3 patients with genetically confirmed GSS from our unit were included. Based on clinical presentation, patients were classified into typical GSS, Creutzfeldt-Jakob disease (CJD)-like GSS, GSS with dementia, and other categories. RESULTS A total of 329 GSS cases were included with a 1.13:1 female-to-male ratio, median onset age 44, and median duration 4 years. Of the 294 categorized patients, 50.7% had typical GSS, 24.8% showed CJD-like GSS, and 16.3% presented with GSS with dementia. Clinical classification varied significantly based on genotype, with P102L more common in typical GSS and A117V prevalent in CJD-like GSS. Polymorphism at codon 129 has no effect on GSS phenotype, but the 129 M allele acts as a protective factor in GSS patients in Asia and North America. Moderate to severe spongiform degeneration and the presence of PK-resistant small fragments migrating at <11 kDa on electrophoretic gels along with PrP27-30 fragments were more prevalent in CJD-like GSS phenotype, while hyperphosphorylated tau protein co-deposition tends to be characteristic of typical GSS and GSS with dementia. CONCLUSION This study reveals GSS's intricate nature, showing significant variations in clinical presentations, diagnostic findings, and pathological features. Mutation sites and pathological changes play crucial roles in determining the GSS clinical heterogeneity.
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Affiliation(s)
- Zhongyun Chen
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yu Kong
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Jing Zhang
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Wen-Quan Zou
- Department of Neurology, Institute of Neurology, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China.
| | - Liyong Wu
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
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Suzuyama K, Eriguchi M, Minagawa H, Honda H, Kai K, Kitamoto T, Hara H. Accumulation Area of a Japanese PRNP P102L Variant Associated With Gerstmann-Sträussler-Scheinker Disease: The Ariake PRNP P102L Variant. J Clin Neurol 2024; 20:321-329. [PMID: 38171504 PMCID: PMC11076189 DOI: 10.3988/jcn.2023.0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/25/2023] [Accepted: 07/31/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND AND PURPOSE The coast of Kyushu Island on Ariake Sea in Japan is known to be an accumulation area for patients with a proline-to-leucine substitution mutation at residue 102 (P102L) of the human prion protein gene (PRNP), which is associated with Gerstmann-Sträussler-Scheinker disease. We designated this geographical distribution as the "Ariake PRNP P102L variant." The purpose of this study was to characterize the clinical features of this variant. METHODS We enrolled patients with the PRNP P102L variant who were followed up at the Saga University Hospital from April 2002 to November 2019. The clinical information of patients were obtained from medical records, including clinical histories, brain magnetic resonance imaging (MRI), and electroencephalography (EEG). A brain autopsy was performed on one of the participants. RESULTS We enrolled 24 patients from 19 family lines, including 12 males. The mean age at symptom onset was 60.6 years (range, 41-77 years). The incidence rate of the Ariake PRNP P102L variant was 3.32/1,000,000 people per year in Saga city. The initial symptoms were ataxia (ataxic gait or dysarthria) in 19 patients (79.2%), cognitive impairment in 3 (12.5%), and leg paresthesia in 2 (8.3%). The median survival time from symptom onset among the 18 fatal cases was 63 months (range, 23-105 months). Brain MRI revealed no localized cerebellar atrophy, but sparse diffusion-weighted imaging abnormalities were detected in 16.7% of the patients. No periodic sharp-wave complexes were identified in EEG. Neuropathological investigations revealed uni- and multicentric prion protein (PrP) plaques in the cerebral cortex, putamen, thalamus, and cerebellum of one patient. Western blot analysis revealed 8-kDa proteinase-K-resistant PrP. CONCLUSIONS This is the first report of the accumulation area of a PRNP P102L variant on the coast of Ariake Sea. The Ariake PRNP P102L variant can be characterized by a relatively long disease duration with sparse abnormalities in brain MRI and EEG relative to previous reports. Detailed interviews to obtain information on the birthplace and the family history of related symptoms are important to diagnosing a PRNP P102L variant.
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Affiliation(s)
- Kohei Suzuyama
- Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan.
| | - Makoto Eriguchi
- Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan
| | - Hiromu Minagawa
- Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan
| | - Hiroyuki Honda
- Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Neurology, Neuro Muscular Center, National Hospital Organization Omuta National Hospital, Omuta, Japan
| | - Keita Kai
- Department of Pathology, Saga University Hospital, Saga, Japan
| | - Tetsuyuki Kitamoto
- Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideo Hara
- Division of Neurology, Department of Internal Medicine, Saga University Faculty of Medicine, Saga, Japan
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Stephen CD, de Gusmao CM, Srinivasan SR, Olsen A, Freua F, Kok F, Montes Garcia Barbosa R, Chen JY(H, Appleby BS, Prior T, Frosch MP, Schmahmann JD. Gerstmann-Sträussler-Scheinker Disease Presenting as Late-Onset Slowly Progressive Spinocerebellar Ataxia, and Comparative Case Series with Neuropathology. Mov Disord Clin Pract 2024; 11:411-423. [PMID: 38258626 PMCID: PMC10982592 DOI: 10.1002/mdc3.13976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Genetic prion diseases, including Gerstmann-Sträussler-Scheinker disease (GSS), are extremely rare, fatal neurodegenerative disorders, often associated with progressive ataxia and cognitive/neuropsychiatric symptoms. GSS typically presents as a rapidly progressive cerebellar ataxia, associated with cognitive decline. Late-onset cases are rare. OBJECTIVE To compare a novel GSS phenotype with six other cases and present pathological findings from a single case. METHODS Case series of seven GSS patients, one proceeding to autopsy. RESULTS Case 1 developed slowly progressive gait difficulties at age 71, mimicking a spinocerebellar ataxia, with a family history of balance problems in old age. Genome sequencing revealed a heterozygous c.392G > A (p.G131E) pathogenic variant and a c.395A > G resulting in p.129 M/V polymorphism in the PRNP gene. Probability analyses considering family history, phenotype, and a similar previously reported point mutation (p.G131V) suggest p.G131E as a new pathogenic variant. Clinical features and imaging of this case are compared with those six additional cases harboring p.P102L mutations. Autopsy findings of a case are described and were consistent with the prion pathology of GSS. CONCLUSIONS We describe a patient with GSS with a novel p.G131E mutation in the PRNP gene, presenting with a late-onset, slowly progressive phenotype, mimicking a spinocerebellar ataxia, and six additional cases with the typical P102L mutation.
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Affiliation(s)
- Christopher D. Stephen
- Ataxia Center, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Cognitive Behavioral Neurology Unit, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Claudio Melo de Gusmao
- Movement Disorders Division, Department of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Department of NeurologyUniversity of São PauloSão PauloBrazil
| | - Sharan R. Srinivasan
- Movement Disorders Division, Department of NeurologyUniversity of MichiganAnn ArborMichiganUSA
| | - Abby Olsen
- Movement Disorders Division, Department of NeurologyUniversity of Pittsburgh and UPMCPittsburghPennsylvaniaUSA
| | - Fernando Freua
- Movement Disorders Division, Department of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Fernando Kok
- Movement Disorders Division, Department of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Renata Montes Garcia Barbosa
- Movement Disorders Division, Department of NeurologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Jin Yun (Helen) Chen
- Neurogenetics Unit, Department of Neurology, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- C.S. Kubik Laboratory of Neuropathology, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Brian S. Appleby
- The National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Thomas Prior
- The National Prion Disease Pathology Surveillance CenterCase Western Reserve UniversityClevelandOhioUSA
| | - Matthew P. Frosch
- C.S. Kubik Laboratory of Neuropathology, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Jeremy D. Schmahmann
- Ataxia Center, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Cognitive Behavioral Neurology Unit, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Laboratory for Neuroanatomy and Cerebellar Neurobiology, Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
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Bridwell RE, Barlow JA, Jacobson AR, Curell A, Long B. Hereditary Creutzfeldt-Jakob Disease: A Case Presentation of a Rare Stroke Mimic. Cureus 2024; 16:e55559. [PMID: 38576698 PMCID: PMC10993755 DOI: 10.7759/cureus.55559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2024] [Indexed: 04/06/2024] Open
Abstract
Acute ischemic cerebrovascular accident (CVA) is a time-sensitive emergent diagnosis, requiring rapid diagnosis and consideration of thrombolytic administration. However, a myriad of cerebrovascular mimics creates a diagnostic challenge. A rare CVA mimic is Creutzfeldt-Jakob disease (CJD), a rapidly progressive fatal dementia due to protein misfolding. Magnetic resonance imaging (MRI) and neurology consultation for electroencephalogram (EEG) and specialized cerebrospinal fluid (CSF) studies are diagnostic while the patient is alive. All forms are fatal within months, and diagnosis can be confirmed on postmortem brain testing. While incredibly uncommon, emergency clinicians should consider this diagnosis in the proper patient to advocate for specialized CSF testing and potential palliative care consultation.
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Affiliation(s)
- Rachel E Bridwell
- Emergency Medicine, Madigan Army Medical Center, Joint Base Lewis-McChord, USA
| | | | | | - Angela Curell
- Anesthesiology, University of Cincinnati Medical Center, Cincinnati, USA
| | - Brit Long
- Emergency Medicine, Brooke Army Medical Center, Fort Sam Houston, USA
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Chen Z, Guo J, Ran N, Zhong Y, Yang F, Sun H. A family with mental disorder as the first symptom finally confirmed with Gerstmann-Sträussler-Scheinker disease with P102L mutation in PRNP gene - case report. Prion 2023; 17:37-43. [PMID: 36847171 PMCID: PMC9980613 DOI: 10.1080/19336896.2023.2180255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 01/11/2023] [Indexed: 02/24/2023] Open
Abstract
Gerstmann-Sträussler-Scheinker (GSS) disease is an autosomal dominant neurodegenerative disease, and it is characterized by progressive cerebellar ataxia. Up to now, GSS cases with the p.P102L mutation have mainly been reported in Caucasian, but rarely in Asian populations. A 54-year-old female patient presented with an unstable gait in the hospital. Last year, she was unable to walk steadily and occasionally choked, could not even walk independently gradually. After taking her medical history, we found that she was misdiagnosed with schizophrenia before the gait problems. The patient's father showed similar symptoms and was diagnosed with brain atrophy at the age of 56, but her daughter showed no similar symptoms at present. On arrival at the Neurology Department, the patient's vital signs and laboratory examinations showed no abnormality. As the proband presented with cerebellar ataxia and had an obvious family history, we were sure that she had hereditary cerebellar ataxia. Then, patient's brain MRI showed an abnormal signal in the right parietal cortex and bilateral small ischaemic lesions in the frontal lobe. A gene panel (including 142 ataxia-related genes) was performed, and a heterozygous mutation PRNP Exon2 c.305C>T p. (Pro102Leu) was identified. Her daughter had the same heterozygous mutation. The patient was diagnosed with GSS with mental disorders as initial symptoms. After 2 months of TCM treatment, the patient's walking instability decreased, and her emotional fluctuations were less than before. In conclusion, we have reported a rare case of GSS in Sichuan, China, and the family with mental disorder as the first symptom was finally confirmed with GSS PRNP P102L mutation.
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Affiliation(s)
- Zeran Chen
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611137, China
| | - Junjun Guo
- Pediatric, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Ningjing Ran
- Neurology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Yujia Zhong
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Sichuan, 611137, China
| | - Fang Yang
- Neurology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
| | - Honghui Sun
- Neurology Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610075, China
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Safadi D, Cohen OS, Chapman J, Rosenmann H, Nitsan Z, Kahan E, Appel S, Alkrenawi M. The epidemiological and clinical characteristics of patients with young-onset genetic Creutzfeldt-Jakob disease. Neurol Res 2023; 45:854-857. [PMID: 37165675 DOI: 10.1080/01616412.2023.2212210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 05/01/2023] [Indexed: 05/12/2023]
Abstract
OBJECTIVES The onset of Creutzfeldt-Jakob disease (CJD) is usually around the age of 60, but younger patients have been described as well. Our study characterizes the demographic and clinical features of young-onset CJD patients. METHODS The CJD Israeli National Database was reviewed, and the patients were divided into groups of young (<40-year-old) (Y|) and older disease onset (>40-year-old) (O). Each group was further divided into sporadic (sCJD) and genetic (gCJD) patients. Clinical and demographic parameters were compared between the groups. RESULTS The study included 731 patients (Y- 18 patients, O- 713 patients). MRI showed classical features more often in the older population (O-76.9%, Y-36%, p = 0.006). Rapidly progressive dementia as a presenting feature was more common in the older group (O = 58%, Y = 27.7%, p = 0.019) whereas cerebellar onset (gait instability, dysarthria) was more common in the younger group (O = 6.7%, Y = 27.7%, p = 0.036)). Among gCJD patients, rapidly progressive dementia was commonly seen in older patients (O = 54%, Y = 21% p = 0.008) whereas cerebellar symptoms were seen in young patients (O = 7%, Y = 30% p = 0.01) Typical MRI findings were seen in 37% of young people compared to 87% of older patients (p = 0.002). No significant differences were between young and older patients in the sCJD group. CONCLUSION Young-onset gCJD patients have unique disease features including less typical brain MRI changes, a lower prevalence of dementia, and a higher prevalence of cerebellar signs at disease onset.
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Affiliation(s)
- Daniel Safadi
- Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
| | - Oren S Cohen
- Department of Neurology, Assaf Harofeh Medical Center, Tsrifin, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Joab Chapman
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Department of Neurology, The Sagol Neuroscience Center, and Chaim Sheba Medical Center, Ramat gan
| | - Hanna Rosenmann
- Department of Neurology,The Agnes Ginges Center for Human Neurogenetics, Hadassa Hebrew University Medical Center, Jerusalem, Israel
| | - Zeev Nitsan
- Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
- Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
| | - Esther Kahan
- Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
- Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheva, Israel
| | - Shmuel Appel
- Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
| | - Marwan Alkrenawi
- Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
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Chen L, Xu Y, Fang MJ, Shi YG, Zhang J, Zhang LL, Wang Y, Han YZ, Hu JY, Yang RM, Yu XE. Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation. Front Neurol 2023; 14:1187813. [PMID: 37602242 PMCID: PMC10435367 DOI: 10.3389/fneur.2023.1187813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 07/13/2023] [Indexed: 08/22/2023] Open
Abstract
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xu-en Yu
- Department of Neurology, The Affiliated Hospital of Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
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11
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Kishida H, Ueda N, Tanaka F. The advances in the early and accurate diagnosis of Creutzfeldt-Jakob disease and other prion diseases: where are we today? Expert Rev Neurother 2023; 23:803-817. [PMID: 37581576 DOI: 10.1080/14737175.2023.2246653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 08/07/2023] [Indexed: 08/16/2023]
Abstract
INTRODUCTION Before the introduction of MRI diffusion-weighted images (DWI), the diagnosis of Creutzfeldt-Jakob disease (CJD) relied upon nonspecific findings including clinical symptoms, EEG abnormalities, and elevated levels of cerebrospinal fluid 14-3-3 protein. Subsequently, the use of DWI has improved diagnostic accuracy, but it sometimes remains difficult to differentiate CJD from encephalitis, epilepsy, and other dementing disorders. The revised diagnostic criteria include real-time quaking-induced conversion (RT-QuIC), detecting small amounts of CJD-specific prion protein, and clinically sensitive DWI. Combining these techniques has further improved diagnostic accuracy, enabling earlier diagnosis. AREAS COVERED Herein, the authors review the recent advances in diagnostic methods and revised diagnostic criteria for sporadic CJD. They also discuss other prion diseases, such as variant CJD and chronic wasting disease, where the emergence of new types is a concern. EXPERT OPINION Despite improvements in diagnostic methods and criteria, some subtypes of prion disease are still difficult to diagnose, and even the diagnosis using the most innovative RT-QuIC test remains a challenge in terms of accuracy and standardization. However, these revised criteria can be adapted to the emergence of new types of prion diseases. It is essential to continue careful surveillance and update information on the latest prion disease phenotypes.
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Affiliation(s)
- Hitaru Kishida
- Department of Neurology, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
| | - Naohisa Ueda
- Department of Neurology, Yokohama City University Medical Center, Yokohama, Kanagawa, Japan
| | - Fumiaki Tanaka
- Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
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12
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Jagota P, Lim S, Pal PK, Lee J, Kukkle PL, Fujioka S, Shang H, Phokaewvarangkul O, Bhidayasiri R, Mohamed Ibrahim N, Ugawa Y, Aldaajani Z, Jeon B, Diesta C, Shambetova C, Lin C. Genetic Movement Disorders Commonly Seen in Asians. Mov Disord Clin Pract 2023; 10:878-895. [PMID: 37332644 PMCID: PMC10272919 DOI: 10.1002/mdc3.13737] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 02/27/2023] [Accepted: 03/21/2023] [Indexed: 11/21/2023] Open
Abstract
The increasing availability of molecular genetic testing has changed the landscape of both genetic research and clinical practice. Not only is the pace of discovery of novel disease-causing genes accelerating but also the phenotypic spectra associated with previously known genes are expanding. These advancements lead to the awareness that some genetic movement disorders may cluster in certain ethnic populations and genetic pleiotropy may result in unique clinical presentations in specific ethnic groups. Thus, the characteristics, genetics and risk factors of movement disorders may differ between populations. Recognition of a particular clinical phenotype, combined with information about the ethnic origin of patients could lead to early and correct diagnosis and assist the development of future personalized medicine for patients with these disorders. Here, the Movement Disorders in Asia Task Force sought to review genetic movement disorders that are commonly seen in Asia, including Wilson's disease, spinocerebellar ataxias (SCA) types 12, 31, and 36, Gerstmann-Sträussler-Scheinker disease, PLA2G6-related parkinsonism, adult-onset neuronal intranuclear inclusion disease (NIID), and paroxysmal kinesigenic dyskinesia. We also review common disorders seen worldwide with specific mutations or presentations that occur frequently in Asians.
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Affiliation(s)
- Priya Jagota
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Shen‐Yang Lim
- Division of Neurology, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
- The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Pramod Kumar Pal
- Department of NeurologyNational Institute of Mental Health & Neurosciences (NIMHANS)BengaluruIndia
| | - Jee‐Young Lee
- Department of NeurologySeoul Metropolitan Government‐Seoul National University Boramae Medical Center & Seoul National University College of MedicineSeoulRepublic of Korea
| | - Prashanth Lingappa Kukkle
- Center for Parkinson's Disease and Movement DisordersManipal HospitalBangaloreIndia
- Parkinson's Disease and Movement Disorders ClinicBangaloreIndia
| | - Shinsuke Fujioka
- Department of Neurology, Fukuoka University, Faculty of MedicineFukuokaJapan
| | - Huifang Shang
- Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Diseases CenterWest China Hospital, Sichuan UniversityChengduChina
| | - Onanong Phokaewvarangkul
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
| | - Roongroj Bhidayasiri
- Chulalongkorn Centre of Excellence for Parkinson's Disease and Related Disorders, Department of Medicine, Faculty of MedicineChulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross SocietyBangkokThailand
- The Academy of Science, The Royal Society of ThailandBangkokThailand
| | - Norlinah Mohamed Ibrahim
- Neurology Unit, Department of Medicine, Faculty of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Yoshikazu Ugawa
- Deprtment of Human Neurophysiology, Faculty of MedicineFukushima Medical UniversityFukushimaJapan
| | - Zakiyah Aldaajani
- Neurology Unit, King Fahad Military Medical ComplexDhahranSaudi Arabia
| | - Beomseok Jeon
- Department of NeurologySeoul National University College of MedicineSeoulRepublic of Korea
- Movement Disorder CenterSeoul National University HospitalSeoulRepublic of Korea
| | - Cid Diesta
- Section of Neurology, Department of NeuroscienceMakati Medical Center, NCRMakatiPhilippines
| | | | - Chin‐Hsien Lin
- Department of NeurologyNational Taiwan University HospitalTaipeiTaiwan
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13
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Mok TH, Nihat A, Majbour N, Sequeira D, Holm-Mercer L, Coysh T, Darwent L, Batchelor M, Groveman BR, Orr CD, Hughson AG, Heslegrave A, Laban R, Veleva E, Paterson RW, Keshavan A, Schott JM, Swift IJ, Heller C, Rohrer JD, Gerhard A, Butler C, Rowe JB, Masellis M, Chapman M, Lunn MP, Bieschke J, Jackson GS, Zetterberg H, Caughey B, Rudge P, Collinge J, Mead S. Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease. Brain 2023; 146:2570-2583. [PMID: 36975162 PMCID: PMC10232278 DOI: 10.1093/brain/awad101] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/17/2023] [Accepted: 03/13/2023] [Indexed: 03/29/2023] Open
Abstract
Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.
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Affiliation(s)
- Tze How Mok
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Akin Nihat
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Nour Majbour
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
| | - Danielle Sequeira
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Leah Holm-Mercer
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Thomas Coysh
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Lee Darwent
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
| | - Mark Batchelor
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
| | - Bradley R Groveman
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Christina D Orr
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Andrew G Hughson
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Amanda Heslegrave
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
| | - Rhiannon Laban
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
| | - Elena Veleva
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
| | - Ross W Paterson
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Ashvini Keshavan
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Jonathan M Schott
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Imogen J Swift
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Carolin Heller
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Jonathan D Rohrer
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Dementia Research Centre, Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, London WC1N 3AR, UK
| | - Alexander Gerhard
- Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester M13 9PL, UK
- Department of Geriatric Medicine, Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, 45147 Essen, Germany
- Department of Nuclear Medicine, Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen, 45147 Essen, Germany
| | - Christopher Butler
- Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford OX3 9DU, UK
| | - James B Rowe
- Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust and Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, Cambridge CB2 7EF, UK
| | - Mario Masellis
- Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5, Canada
| | - Miles Chapman
- Neuroimmunology and CSF Laboratory, University College London Hospitals NHS Trust National Hospital of Neurology and Neurosurgery, London WC1N 3BG, UK
| | - Michael P Lunn
- Neuroimmunology and CSF Laboratory, University College London Hospitals NHS Trust National Hospital of Neurology and Neurosurgery, London WC1N 3BG, UK
| | - Jan Bieschke
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
| | - Graham S Jackson
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
| | - Henrik Zetterberg
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
- United Kingdom Dementia Research Institute at University College London, London WC1E 6BT, UK
- Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, S-43180 Mölndal, Sweden
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, S-431 80 Mölndal, Sweden
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
- Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792-2420, USA
| | - Byron Caughey
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | - Peter Rudge
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - John Collinge
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
| | - Simon Mead
- Medical Research Council Prion Unit at University College London, UCL Institute of Prion Diseases, London W1W 7FF, UK
- NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London WC1N 3BG, UK
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Pérez-Carbonell L, Sarto J, Gaig C, Muñoz-Lopetegi A, Ruiz-García R, Naranjo L, Augé JM, Perissinotti A, Santamaria J, Iranzo A, Sánchez-Valle R. Sleep in Gerstmann-Straüssler-Scheinker disease. Sleep Med 2023; 108:11-15. [PMID: 37302168 DOI: 10.1016/j.sleep.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND Gerstmann-Sträussler-Scheinker (GSS) is a rare prion disease with heterogeneous clinical presentation. Although sleep-related abnormalities are prominent and well-known in other prion diseases such as fatal familial insomnia and Creutzfeldt-Jakob disease, information on sleep is limited in GSS. METHODS We evaluated sleep in three genetically confirmed GSS cases using clinical history, sleep scales and video-polysomnography. In addition, patients underwent neurological assessment, neurological scales, neuropsychological testing, lumbar puncture, brain MRI and brain 18F-FDG-PET. RESULTS Two patients reported sleep maintenance insomnia attributed to leg stiffness and back pain while the remaining patient did not report sleep problems. Video-polysomnography showed normal sleep staging in all of them. Findings such as reduced sleep efficiency in two patients, a confusional arousal in one patient, obstructive apneas in one patient, and periodic legs movements in sleep in two patients were observed. CONCLUSIONS In contrast to fatal familial insomnia, the normal sleep staging in GSS may suggest dissimilar involvement of the neuronal structures that regulate sleep. We found non-specific sleep alterations in GSS such as obstructive apneas and periodic leg movements in sleep which are of unknown origin and of uncertain clinical relevance. Studies including a larger number of patients, serial sleep evaluations and incorporating neuropathological assessment will further help to understand sleep in GSS.
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Affiliation(s)
- Laura Pérez-Carbonell
- Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain
| | - Jordi Sarto
- Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
| | - Carles Gaig
- Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain
| | - Amaia Muñoz-Lopetegi
- Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain
| | - Raquel Ruiz-García
- Immunology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
| | - Laura Naranjo
- Immunology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
| | - Josep María Augé
- Immunology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain
| | - Andrés Perissinotti
- Nuclear Medicine Service, Hospital Clínic Barcelona, Biomedical Research Networking Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), ISCIII, Barcelona, Spain
| | - Joan Santamaria
- Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain
| | - Alex Iranzo
- Sleep Disorders Center, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, CIBERNED: CB06/05/0018-ISCIII, Barcelona, Spain.
| | - Raquel Sánchez-Valle
- Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic Barcelona, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
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15
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Rudenskaya GE, Konovalov FA, Illarioshkin SN, Shchagina OA. [Gerstmann-Sträussler disease: a familial case with common PRNP mutation and atypical features]. Zh Nevrol Psikhiatr Im S S Korsakova 2023; 123:138-143. [PMID: 36843471 DOI: 10.17116/jnevro2023123021138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP. Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.
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Affiliation(s)
| | - F A Konovalov
- Genomed Ltd, Moscow, Russia.,Laboratory of Clinical Bioinformatics, Moscow, Russia
| | | | - O A Shchagina
- Research Centre for Medical Genetics, Moscow, Russia
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16
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Nuzhnyi EP, Abramycheva NY, Fedotova EY, Illarioshkin SN. Gerstmann–Sträussler–Scheinker syndrome with early-onset spinocerebellar ataxia phenotype. NEUROLOGY, NEUROPSYCHIATRY, PSYCHOSOMATICS 2022. [DOI: 10.14412/2074-2711-2022-6-63-66] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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17
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Corbie R, Campbell T, Darwent L, Rudge P, Collinge J, Mead S. Estimation of the number of inherited prion disease mutation carriers in the UK. Eur J Hum Genet 2022; 30:1167-1170. [PMID: 35754056 PMCID: PMC9553982 DOI: 10.1038/s41431-022-01132-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/26/2022] [Accepted: 06/09/2022] [Indexed: 12/15/2022] Open
Abstract
Inherited prion diseases (IPD) are a set of rare neurodegenerative diseases that are always caused by mutation of the prion protein gene (PRNP). These are highly heterogeneous in clinical presentation and best described by the specific gene mutation, but traditionally include the canonical syndromes familial Creutzfeldt-Jakob disease, Gerstamann-Straussler-Scheinker syndrome, and fatal familial insomnia. In the UK, care of IPD patients and clinical PRNP sequencing have been carried out almost exclusively by the National Prion Clinic and affiliated laboratories since the disease gene was discovered in 1989. Using data obtained over 30 years (1990-2019), this study aimed to provide a greater understanding of the genetic prevalence of IPD using multiple complementary methods. A key source of bias in rare disorders is ascertainment, so we included an analysis based on capture-recapture techniques that may help to minimise ascertainment bias. 225 patients, with 21 different IPD mutations were identified, varying in frequency (with 8/21 mutations comprising over 90% observed cases), derived from 116 kindreds and 151 3-generation families. We estimated a total of 303 UK families (95% CI = 222, 384) segregate IPD mutations, 1091 (95% CI = 720, 1461) UK mutation carriers and a lifetime risk of approximately 1 in 60,000. Simpler methods of measuring prevalence based on extrapolation from the annual incidence of disease, and large scale genomic studies, result in similar estimates of prevalence. These estimates may be of value for planning preventive trials of therapeutics in IPD mutation carriers, prevention of prion disease transmission and provision of specialist services.
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Affiliation(s)
- Rosie Corbie
- grid.52996.310000 0000 8937 2257National Prion Clinic, University College London (UCL) Hospitals NHS Foundation Trust, London, UK
| | - Tracy Campbell
- grid.421964.c0000 0004 0606 3301MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF UK
| | - Lee Darwent
- grid.421964.c0000 0004 0606 3301MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF UK
| | - Peter Rudge
- grid.52996.310000 0000 8937 2257National Prion Clinic, University College London (UCL) Hospitals NHS Foundation Trust, London, UK ,grid.421964.c0000 0004 0606 3301MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF UK
| | - John Collinge
- grid.52996.310000 0000 8937 2257National Prion Clinic, University College London (UCL) Hospitals NHS Foundation Trust, London, UK ,grid.421964.c0000 0004 0606 3301MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF UK
| | - Simon Mead
- National Prion Clinic, University College London (UCL) Hospitals NHS Foundation Trust, London, UK. .,MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
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18
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Manka SW, Wenborn A, Collinge J, Wadsworth JDF. Prion strains viewed through the lens of cryo-EM. Cell Tissue Res 2022; 392:167-178. [PMID: 36028585 PMCID: PMC10113314 DOI: 10.1007/s00441-022-03676-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/18/2022] [Indexed: 12/14/2022]
Abstract
Mammalian prions are lethal transmissible pathogens that cause fatal neurodegenerative diseases in humans and animals. They consist of fibrils of misfolded, host-encoded prion protein (PrP) which propagate through templated protein polymerisation. Prion strains produce distinct clinicopathological phenotypes in the same host and appear to be encoded by distinct misfolded PrP conformations and assembly states. Despite fundamental advances in our understanding of prion biology, key knowledge gaps remain. These include precise delineation of prion replication mechanisms, detailed explanation of the molecular basis of prion strains and inter-species transmission barriers, and the structural definition of neurotoxic PrP species. Central to addressing these questions is the determination of prion structure. While high-resolution definition of ex vivo prion fibrils once seemed unlikely, recent advances in cryo-electron microscopy (cryo-EM) and computational methods for 3D reconstruction of amyloids have now made this possible. Recently, near-atomic resolution structures of highly infectious, ex vivo prion fibrils from hamster 263K and mouse RML prion strains were reported. The fibrils have a comparable parallel in-register intermolecular β-sheet (PIRIBS) architecture that now provides a structural foundation for understanding prion strain diversity in mammals. Here, we review these new findings and discuss directions for future research.
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Affiliation(s)
- Szymon W Manka
- MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK
| | - Adam Wenborn
- MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK
| | - John Collinge
- MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK.
| | - Jonathan D F Wadsworth
- MRC Prion Unit at UCL, Institute of Prion Diseases, University College London, 33 Cleveland Street, London, W1W 7FF, UK.
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19
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Nihat A, Mok TH, Odd H, Thompson AGB, Caine D, McNiven K, O'Donnell V, Tesfamichael S, Rudge P, Collinge J, Mead S. Development of novel clinical examination scales for the measurement of disease severity in Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 2022; 93:404-412. [PMID: 35022318 PMCID: PMC8921594 DOI: 10.1136/jnnp-2021-327722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 12/01/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To use a robust statistical methodology to develop and validate clinical rating scales quantifying longitudinal motor and cognitive dysfunction in sporadic Creutzfeldt-Jakob disease (sCJD) at the bedside. METHODS Rasch analysis was used to iteratively construct interval scales measuring composite cognitive and motor dysfunction from pooled bedside neurocognitive examinations collected as part of the prospective National Prion Monitoring Cohort study, October 2008-December 2016.A longitudinal clinical examination dataset constructed from 528 patients with sCJD, comprising 1030 Motor Scale and 757 Cognitive Scale scores over 130 patient-years of study, was used to demonstrate scale utility. RESULTS The Rasch-derived Motor Scale consists of 8 items, including assessments reliant on pyramidal, extrapyramidal and cerebellar systems. The Cognitive Scale comprises 6 items, and includes measures of executive function, language, visual perception and memory. Both scales are unidimensional, perform independently of age or gender and have excellent inter-rater reliability. They can be completed in minutes at the bedside, as part of a normal neurocognitive examination. A composite Examination Scale can be derived by averaging both scores. Several scale uses, in measuring longitudinal change, prognosis and phenotypic heterogeneity are illustrated. CONCLUSIONS These two novel sCJD Motor and Cognitive Scales and the composite Examination Scale should prove useful to objectively measure phenotypic and clinical change in future clinical trials and for patient stratification. This statistical approach can help to overcome obstacles to assessing clinical change in rapidly progressive, multisystem conditions with limited longitudinal follow-up.
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Affiliation(s)
- Akin Nihat
- UCL Institute of Prion Diseases, MRC Prion Unit at UCL, London, UK.,National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Tze How Mok
- UCL Institute of Prion Diseases, MRC Prion Unit at UCL, London, UK.,National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Hans Odd
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Andrew Geoffrey Bourne Thompson
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Diana Caine
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Kirsty McNiven
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Veronica O'Donnell
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Selam Tesfamichael
- National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Peter Rudge
- UCL Institute of Prion Diseases, MRC Prion Unit at UCL, London, UK.,National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - John Collinge
- UCL Institute of Prion Diseases, MRC Prion Unit at UCL, London, UK.,National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
| | - Simon Mead
- UCL Institute of Prion Diseases, MRC Prion Unit at UCL, London, UK .,National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, National Prion Clinic, London, UK
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20
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Schmitz M, Villar-Piqué A, Hermann P, Escaramís G, Calero M, Chen C, Kruse N, Cramm M, Golanska E, Sikorska B, Liberski PP, Pocchiari M, Lange P, Stehmann C, Sarros S, Martí E, Baldeiras I, Santana I, Žáková D, Mitrová E, Dong XP, Collins S, Poleggi A, Ladogana A, Mollenhauer B, Kovacs GG, Geschwind MD, Sánchez-Valle R, Zerr I, Llorens F. Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases. Brain 2022; 145:700-712. [PMID: 35288744 PMCID: PMC9014756 DOI: 10.1093/brain/awab350] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/29/2021] [Accepted: 08/10/2021] [Indexed: 12/14/2022] Open
Abstract
Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt–Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt–Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt–Jakob disease-E200K, Gerstmann–Sträussler–Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
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Affiliation(s)
- Matthias Schmitz
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Anna Villar-Piqué
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III (ISCIII), L'Hospitalet de Llobregat, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Spain
| | - Peter Hermann
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany
| | - Geòrgia Escaramís
- CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain.,Department of Biomedical Sciences, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Miguel Calero
- Alzheimer Disease Research Unit, CIEN Foundation, Queen Sofia Foundation Alzheimer Center Madrid, Madrid, Spain.,Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Madrid, Spain
| | - Cao Chen
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Niels Kruse
- Institute for Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - Maria Cramm
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany
| | - Ewa Golanska
- Department of Molecular Pathology and Neuropathology Medical University of Lodz, Poland
| | - Beata Sikorska
- Department of Molecular Pathology and Neuropathology Medical University of Lodz, Poland
| | - Pawel P Liberski
- Department of Molecular Pathology and Neuropathology Medical University of Lodz, Poland
| | | | - Peter Lange
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany
| | - Christiane Stehmann
- Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Shannon Sarros
- Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
| | - Eulàlia Martí
- CIBER in Epidemiology and Public Health (CIBERESP), Barcelona, Spain.,Department of Biomedical Sciences, Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Inês Baldeiras
- Laboratory of Neurochemistry, Coimbra University Hospital, Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal
| | - Isabel Santana
- Laboratory of Neurochemistry, Coimbra University Hospital, Coimbra, Portugal.,Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal
| | - Dana Žáková
- Department of Prion Diseases, Slovak Medical University Bratislava, Bratislava, Slovakia
| | - Eva Mitrová
- Department of Prion Diseases, Slovak Medical University Bratislava, Bratislava, Slovakia
| | - Xiao-Ping Dong
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Steven Collins
- Australian National Creutzfeldt-Jakob Disease Registry, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia.,Department of Medicine (RMH), The University of Melbourne, Melbourne, Australia
| | - Anna Poleggi
- Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Anna Ladogana
- Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Brit Mollenhauer
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.,Paracelsus-Elena Klinik, Center for Parkinsonism and Movement Disorders, Kassel, Germany
| | - Gabor G Kovacs
- Neuropathology and Prion Disease Reference Center, Department of Forensic and Insurance Medicine, Semmelweis University, Budapest, Hungary.,Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria.,Tanz Centre for Research in Neurodegenerative Disease (CRND) and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
| | - Michael D Geschwind
- Department of Neurology, Memory and Aging Center, University of California, San Francisco (UCSF), San Francisco, CA, USA
| | - Raquel Sánchez-Valle
- Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Inga Zerr
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
| | - Franc Llorens
- Department of Neurology, Clinical Dementia Center and National Reference Center for CJD Surveillance, University Medical School, Göttingen, Germany.,Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III (ISCIII), L'Hospitalet de Llobregat, Spain.,Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Spain
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21
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Abstract
The cellular isoform of prion protein, designated PrPC, is a membrane glycoprotein expressed most abundantly in the brain, particularly by neurons, and its conformational conversion into the abnormally folded, amyloidogenic isoform, PrPSc, is an underlying mechanism in the pathogenesis of prion diseases, a group of neurodegenerative disorders in humans and animals. Most cases of these diseases are sporadic and their aetiologies are unknown. We recently found that a neurotropic strain of influenza A virus (IAV/WSN) caused the conversion of PrPC into PrPSc and the subsequent formation of infectious prions in mouse neuroblastoma cells after infection. These results show that IAV/WSN is the first non-prion pathogen capable of inducing the conversion of PrPC into PrPSc and propagating infectious prions in cultured neuronal cells, and also provide the intriguing possibility that IAV infection in neurons might be a cause of or be associated with sporadic prion diseases. Here, we present our findings of the IAV/WSN-induced conversion of PrPC into PrPSc and subsequent propagation of infectious prions, and also discuss the biological significance of the conversion of PrPC into PrPSc in virus infections.
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Affiliation(s)
- Suehiro Sakaguchi
- Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, Tokushima 770-8503, Japan
| | - Hideyuki Hara
- Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, Tokushima 770-8503, Japan
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22
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A Japanese family with P102L Gerstmann-Sträussler-Scheinker disease with a variant Creutzfeldt-Jakob disease-like phenotype among the siblings: A case report. eNeurologicalSci 2021; 25:100380. [PMID: 34841096 PMCID: PMC8607161 DOI: 10.1016/j.ensci.2021.100380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/12/2021] [Accepted: 11/10/2021] [Indexed: 12/03/2022] Open
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23
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Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion. Int J Mol Sci 2021; 22:ijms222212439. [PMID: 34830321 PMCID: PMC8624980 DOI: 10.3390/ijms222212439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/14/2021] [Accepted: 11/16/2021] [Indexed: 01/04/2023] Open
Abstract
Conformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrPC into PrPSc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrPC into PrPSc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrPC into PrPSc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrPC into PrPSc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrPC into PrPSc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrPC to convert into PrPSc after prion infection.
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24
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Carta M, Aguzzi A. Molecular foundations of prion strain diversity. Curr Opin Neurobiol 2021; 72:22-31. [PMID: 34416480 DOI: 10.1016/j.conb.2021.07.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/09/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
Despite being caused by a single protein, prion diseases are strikingly heterogenous. Individual prion variants, known as strains, possess distinct biochemical properties, form aggregates with characteristic morphologies and preferentially seed certain brain regions, causing markedly different disease phenotypes. Strain diversity is determined by protein structure, post-translational modifications and the presence of extracellular matrix components, with single amino acid substitutions or altered protein glycosylation exerting dramatic effects. Here, we review recent advances in the study of prion strains and discuss how a deeper knowledge of the molecular origins of strain heterogeneity is providing a foundation for the development of anti-prion therapeutics.
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Affiliation(s)
- Manfredi Carta
- Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland
| | - Adriano Aguzzi
- Institute of Neuropathology, University Hospital of Zurich, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
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25
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Cao L, Feng H, Huang X, Yi J, Zhou Y. Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as cervical spondylotic myelopathy: A case report with 5-year follow-up. Medicine (Baltimore) 2021; 100:e25687. [PMID: 33879752 PMCID: PMC8078271 DOI: 10.1097/md.0000000000025687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 04/08/2021] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare autosomal dominant disease caused by a mutation in the prion protein gene (PRNP) that is not well known among neurologists and is therefore easily misdiagnosed. PATIENT CONCERNS : A 49-year-old man was admitted for the first time because of an unsteady walk with mogilalia for 1 year. He underwent a cervical discectomy and a plate-screw fixation 6 months prior, although postoperative gait instability did not improve. DIAGNOSIS Whole exome sequencing identified a pathogenic and heterozygous mutation in the PRNP 4 years after onset. The patient was eventually diagnosed with GSS. INTERVENTIONS Symptomatic treatment to improve cerebrocirculation and cerebrometabolism was provided. OUTCOMES The neurological decline continued. The Mini-Mental State Examination and modified Rankin Scale scores changed from 19 to 11 and 2 to 5, respectively. Progressive cerebral and cerebellar atrophy on magnetic resonance imaging was observed. LESSONS Cerebral and cerebellar atrophy are neuroimaging features symptomatic of GSS that become more apparent as the disease progresses. This atrophy is positively correlated with the severity of symptoms and reduced quality of life. Neurologists treating middle-aged patients with progressive ataxia, cognitive impairment or dysarthria, and brain atrophy need to consider the possibility of GSS.
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Affiliation(s)
- Liming Cao
- Department of Neurology, The First Affiliated Hospital of Shenzhen University
- Department of Neurology, The Third Affiliated Hospital of Shenzhen University
| | - Hongye Feng
- Department of Neurology, The First Affiliated Hospital of Shenzhen University
- Department of Neurology, Shenzhen Second People's Hospital
| | - Xuming Huang
- Department of Gastroenterology, Shiyan People's Hospital, Shenzhen, China
| | - Jiamei Yi
- Department of Neurology, The Third Affiliated Hospital of Shenzhen University
| | - Yanxia Zhou
- Department of Neurology, The First Affiliated Hospital of Shenzhen University
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26
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Mole J, Mead S, Rudge P, Nihat A, Mok T, Collinge J, Caine D. Cognitive decline heralds onset of symptomatic inherited prion disease. Brain 2021; 144:989-998. [PMID: 33844831 DOI: 10.1093/brain/awaa409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/03/2020] [Accepted: 09/21/2020] [Indexed: 11/14/2022] Open
Abstract
The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n = 27), onset of subjective symptoms without positive clinical findings (n = 8) and symptomatic with positive clinical findings (n = 24). In the longitudinal analysis, we analysed data from 24 patients who were presymptomatic at the time of recruitment and were followed up over a period of up to 17 years, of whom 16 remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but similar set of tests (Trail Making Test part A, Stroop test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease. In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62-1.00), P = 0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.
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Affiliation(s)
- Joseph Mole
- Department of Neuropsychology, NHNN, University College London Hospitals NHS Foundation Trust, London, UK
- Queen Square Institute of Neurology, University College London, London, UK
| | - Simon Mead
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK
| | - Peter Rudge
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK
| | - Akin Nihat
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK
| | - Tzehow Mok
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK
| | - John Collinge
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK
| | - Diana Caine
- Department of Neuropsychology, NHNN, University College London Hospitals NHS Foundation Trust, London, UK
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
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Mbizvo GK, Ziso B, Larner AJ. Epilepsy and prion diseases: A narrative review. Epilepsy Behav 2021; 115:107630. [PMID: 33309427 DOI: 10.1016/j.yebeh.2020.107630] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 11/03/2020] [Accepted: 11/06/2020] [Indexed: 12/26/2022]
Abstract
Epileptic seizures have been described as one feature of prion diseases, but are an unusual clinical presentation. The aim of this narrative Review was to summarize current knowledge of epileptic seizures in the various forms of prion diseases, from a clinical perspective. Examination of the published literature identified no systematic studies; the evidence base is largely anecdotal, consisting mainly of case studies and small case series. Hence, uncertainty prevails as to seizure frequency, semiology, treatment, and pathogenesis in prion diseases. Seizures probably occur in around 10% of sporadic cases but less frequently in iatrogenic and familial forms, with the possible exception of the E200K mutation. The literature suggests a predominance of focal motor and nonconvulsive status epilepticus. Electroencephalographic accompaniments include periodic lateralized or generalized periodic epileptiform discharges (PLEDs, GPEDs), sometimes predating the more typical periodic sharp wave complexes. There are no convincing accounts of successful antiepileptic drug therapy. The underlying mechanisms of epileptogenesis in prion diseases may include loss of cellular prion protein function (PrPc) and aggregation of abnormally folded prion protein (PrPSc). The need for systematic studies and clinical trials to expand the evidence base surrounding epilepsy and prion diseases is evident.
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Affiliation(s)
- Gashirai K Mbizvo
- Cognitive Function Clinic, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
| | - Besa Ziso
- Cognitive Function Clinic, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom
| | - Andrew J Larner
- Cognitive Function Clinic, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom
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Watson N, Brandel JP, Green A, Hermann P, Ladogana A, Lindsay T, Mackenzie J, Pocchiari M, Smith C, Zerr I, Pal S. The importance of ongoing international surveillance for Creutzfeldt-Jakob disease. Nat Rev Neurol 2021; 17:362-379. [PMID: 33972773 PMCID: PMC8109225 DOI: 10.1038/s41582-021-00488-7] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2021] [Indexed: 02/04/2023]
Abstract
Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal and transmissible neurodegenerative disease associated with the accumulation of misfolded prion protein in the CNS. International CJD surveillance programmes have been active since the emergence, in the mid-1990s, of variant CJD (vCJD), a disease linked to bovine spongiform encephalopathy. Control measures have now successfully contained bovine spongiform encephalopathy and the incidence of vCJD has declined, leading to questions about the requirement for ongoing surveillance. However, several lines of evidence have raised concerns that further cases of vCJD could emerge as a result of prolonged incubation and/or secondary transmission. Emerging evidence from peripheral tissue distribution studies employing high-sensitivity assays suggests that all forms of human prion disease carry a theoretical risk of iatrogenic transmission. Finally, emerging diseases, such as chronic wasting disease and camel prion disease, pose further risks to public health. In this Review, we provide an up-to-date overview of the transmission of prion diseases in human populations and argue that CJD surveillance remains vital both from a public health perspective and to support essential research into disease pathophysiology, enhanced diagnostic tests and much-needed treatments.
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Affiliation(s)
- Neil Watson
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Jean-Philippe Brandel
- grid.411439.a0000 0001 2150 9058Cellule Nationale de référence des MCJ, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Alison Green
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Peter Hermann
- grid.411984.10000 0001 0482 5331National Reference Centre for TSE, Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany
| | - Anna Ladogana
- grid.416651.10000 0000 9120 6856Registry of Creutzfeldt-Jakob Disease, Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Terri Lindsay
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Janet Mackenzie
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Maurizio Pocchiari
- grid.416651.10000 0000 9120 6856Registry of Creutzfeldt-Jakob Disease, Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy
| | - Colin Smith
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Inga Zerr
- grid.411984.10000 0001 0482 5331National Reference Centre for TSE, Department of Neurology, University Medical Centre Göttingen, Göttingen, Germany
| | - Suvankar Pal
- grid.4305.20000 0004 1936 7988National CJD Research & Surveillance Unit, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
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Jankovska N, Olejar T, Matej R. Extracellular Amyloid Deposits in Alzheimer's and Creutzfeldt-Jakob Disease: Similar Behavior of Different Proteins? Int J Mol Sci 2020; 22:E7. [PMID: 33374972 PMCID: PMC7792617 DOI: 10.3390/ijms22010007] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer's disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term "amyloid" refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer's disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.
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Affiliation(s)
- Nikol Jankovska
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
| | - Tomas Olejar
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
| | - Radoslav Matej
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, 100 00 Prague, Czech Republic; (T.O.); (R.M.)
- Department of Pathology, First Faculty of Medicine, Charles University, and General University Hospital, 100 00 Prague, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, and University Hospital Kralovske Vinohrady, 100 00 Prague, Czech Republic
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Jones E, Mead S. Genetic risk factors for Creutzfeldt-Jakob disease. Neurobiol Dis 2020; 142:104973. [PMID: 32565065 DOI: 10.1016/j.nbd.2020.104973] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/18/2020] [Accepted: 06/13/2020] [Indexed: 10/24/2022] Open
Abstract
Prion diseases are a group of fatal neurodegenerative disorders of mammals that share a central role for prion protein (PrP, gene PRNP) in their pathogenesis. Prions are infectious agents that account for the observed transmission of prion diseases between humans and animals in certain circumstances. The prion mechanism invokes a misfolded and multimeric assembly of PrP (a prion) that grows by templating of the normal protein and propagates by fission. Aside from the medical and public health notoriety of acquired prion diseases, the conditions have attracted interest as it has been realized that common neurodegenerative disorders share so-called prion-like mechanisms. In this article we will expand on recent evidence for new genetic loci that alter the risk of human prion disease. The most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD), is characterized by the seemingly spontaneous appearance of prions in the brain. Genetic variation within PRNP is associated with all types of prion diseases, in particular, heterozygous genotypes at codons 129 and 219 have long been known to be strong protective factors against sCJD. A large number of rare mutations have been described in PRNP that cause autosomal dominant inherited prion diseases. Two loci recently identified by genome-wide association study increase sCJD risk, including variants in or near to STX6 and GAL3ST1. STX6 encodes syntaxin-6, a component of SNARE complexes with cellular roles that include the fusion of intracellular vesicles with target membranes. GAL3ST1 encodes cerebroside sulfotransferase, the only enzyme that sulfates sphingolipids to make sulfatides, a major lipid component of myelin. We discuss how these roles may modify the pathogenesis of prion diseases and their relevance for other neurodegenerative disorders.
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Affiliation(s)
- Emma Jones
- MRC Prion Unit at University College London (UCL), UCL Institute of Prion Diseases, 33 Cleveland Street, W1W 7FF, United Kingdom
| | - Simon Mead
- MRC Prion Unit at University College London (UCL), UCL Institute of Prion Diseases, 33 Cleveland Street, W1W 7FF, United Kingdom.
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Identification of Prion Disease-Related Somatic Mutations in the Prion Protein Gene ( PRNP) in Cancer Patients. Cells 2020; 9:cells9061480. [PMID: 32560489 PMCID: PMC7349074 DOI: 10.3390/cells9061480] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/13/2020] [Accepted: 06/15/2020] [Indexed: 12/14/2022] Open
Abstract
Prion diseases are caused by misfolded prion protein (PrPSc) and are accompanied by spongiform vacuolation of brain lesions. Approximately three centuries have passed since prion diseases were first discovered around the world; however, the exact role of certain factors affecting the causative agent of prion diseases is still debatable. In recent studies, somatic mutations were assumed to be cause of several diseases. Thus, we postulated that genetically unstable cancer tissue may cause somatic mutations in the prion protein gene (PRNP), which could trigger the onset of prion diseases. To identify somatic mutations in the PRNP gene in cancer tissues, we analyzed somatic mutations in the PRNP gene in cancer patients using the Cancer Genome Atlas (TCGA) database. In addition, to evaluate whether the somatic mutations in the PRNP gene in cancer patients had a damaging effect, we performed in silico analysis using PolyPhen-2, PANTHER, PROVEAN, and AMYCO. We identified a total of 48 somatic mutations in the PRNP gene, including 8 somatic mutations that are known pathogenic mutations of prion diseases. We identified significantly different distributions among the types of cancer, the mutation counts, and the ages of diagnosis between the total cancer patient population and cancer patients carrying somatic mutations in the PRNP gene. Strikingly, although invasive breast carcinoma and glioblastoma accounted for a high percentage of the total cancer patient population (9.9% and 5.4%, respectively), somatic mutations in the PRNP gene have not been identified in these two cancer types. We suggested the possibility that somatic mutations of the PRNP gene in glioblastoma can be masked by a diagnosis of prion disease. In addition, we found four aggregation-prone somatic mutations, these being L125F, E146Q, R151C, and K204N. To the best of our knowledge, this is the first specific analysis of the somatic mutations in the PRNP gene in cancer patients.
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Asante EA, Linehan JM, Tomlinson A, Jakubcova T, Hamdan S, Grimshaw A, Smidak M, Jeelani A, Nihat A, Mead S, Brandner S, Wadsworth JDF, Collinge J. Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS. PLoS Biol 2020; 18:e3000725. [PMID: 32516343 PMCID: PMC7282622 DOI: 10.1371/journal.pbio.3000725] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 05/06/2020] [Indexed: 12/02/2022] Open
Abstract
Inherited prion diseases are caused by autosomal dominant coding mutations in the human prion protein (PrP) gene (PRNP) and account for about 15% of human prion disease cases worldwide. The proposed mechanism is that the mutation predisposes to conformational change in the expressed protein, leading to the generation of disease-related multichain PrP assemblies that propagate by seeded protein misfolding. Despite considerable experimental support for this hypothesis, to-date spontaneous formation of disease-relevant, transmissible PrP assemblies in transgenic models expressing only mutant human PrP has not been demonstrated. Here, we report findings from transgenic mice that express human PrP 117V on a mouse PrP null background (117VV Tg30 mice), which model the PRNP A117V mutation causing inherited prion disease (IPD) including Gerstmann-Sträussler-Scheinker (GSS) disease phenotypes in humans. By studying brain samples from uninoculated groups of mice, we discovered that some mice (≥475 days old) spontaneously generated abnormal PrP assemblies, which after inoculation into further groups of 117VV Tg30 mice, produced a molecular and neuropathological phenotype congruent with that seen after transmission of brain isolates from IPD A117V patients to the same mice. To the best of our knowledge, the 117VV Tg30 mouse line is the first transgenic model expressing only mutant human PrP to show spontaneous generation of transmissible PrP assemblies that directly mirror those generated in an inherited prion disease in humans. Transgenic mice expressing the human prion protein containing a mutation linked to the inherited prion disease Gerstmann-Sträussler-Scheinker disease develop spontaneous neuropathology. This represents the first human prion protein transgenic model to show spontaneous generation of transmissible prion assemblies that directly mirror those generated in humans.
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Affiliation(s)
- Emmanuel A. Asante
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
- * E-mail: (EAA); (JDFW); (JC)
| | | | - Andrew Tomlinson
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Tatiana Jakubcova
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Shyma Hamdan
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Andrew Grimshaw
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Michelle Smidak
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Asif Jeelani
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Akin Nihat
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Simon Mead
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
| | - Sebastian Brandner
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and Division of Neuropathology, the National Hospital For Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, London United Kingdom
| | - Jonathan D. F. Wadsworth
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
- * E-mail: (EAA); (JDFW); (JC)
| | - John Collinge
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, United Kingdom
- * E-mail: (EAA); (JDFW); (JC)
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Shortening heparan sulfate chains prolongs survival and reduces parenchymal plaques in prion disease caused by mobile, ADAM10-cleaved prions. Acta Neuropathol 2020; 139:527-546. [PMID: 31673874 DOI: 10.1007/s00401-019-02085-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 10/10/2019] [Accepted: 10/13/2019] [Indexed: 12/18/2022]
Abstract
Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1+/-) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography-mass spectrometry (LC-MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC-MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.
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Mok TH, Mead S. Preclinical biomarkers of prion infection and neurodegeneration. Curr Opin Neurobiol 2020; 61:82-88. [PMID: 32109717 DOI: 10.1016/j.conb.2020.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/09/2020] [Accepted: 01/21/2020] [Indexed: 12/01/2022]
Abstract
Therapeutic strategies and study designs for neurodegenerative diseases have started to explore the potential of preventive treatment in healthy people, emphasising characterisation of biomarkers capable of indicating proximity to clinical onset. This need is even more pressing for individuals at risk of prion disease given its rarity which virtually precludes the probability of recruiting enough numbers for well powered preventive trials based on clinical endpoints. Experimental mouse inoculation studies have revealed a rapid exponential rise in infectious titres followed by a relative plateau of considerable duration before clinical onset. This clinically silent incubation period represents a potential window of opportunity for the adaptation of ultrasensitive prion seeding assays to define the onset of prion infection, and for neurodegenerative biomarker discovery through similarly sensitive digital immunoassay platforms.
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Affiliation(s)
- Tze How Mok
- National Prion Clinic, Box 98, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London W1W 7FF, United Kingdom
| | - Simon Mead
- National Prion Clinic, Box 98, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG, United Kingdom; MRC Prion Unit at UCL, Institute of Prion Diseases, Courtauld Building, 33 Cleveland Street, London W1W 7FF, United Kingdom.
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Paucar M. Reader response: Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings. Neurology 2020; 94:186. [DOI: 10.1212/wnl.0000000000008848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Park YH, Kang MJ, Suh J, An SS, Kim S. Author response: Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings. Neurology 2020; 94:186. [DOI: 10.1212/wnl.0000000000008849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2019] [Indexed: 11/15/2022] Open
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Rudge P, Jaunmuktane Z, Hyare H, Ellis M, Koltzenburg M, Collinge J, Brandner S, Mead S. Early neurophysiological biomarkers and spinal cord pathology in inherited prion disease. Brain 2020; 142:760-770. [PMID: 30698738 PMCID: PMC6391599 DOI: 10.1093/brain/awy358] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/07/2018] [Accepted: 11/26/2018] [Indexed: 11/29/2022] Open
Abstract
A common presentation of inherited prion disease is Gerstmann-Sträussler-Scheinker syndrome, typically presenting with gait ataxia and painful dysaesthesiae in the legs evolving over 2–5 years. The most frequent molecular genetic diagnosis is a P102L mutation of the prion protein gene (PRNP). There is no explanation for why this clinical syndrome is so distinct from Creutzfeldt-Jakob disease, and biomarkers of the early stages of disease have not been developed. Here we aimed, first, at determining if quantitative neurophysiological assessments could predict clinical diagnosis or disability and monitor progression and, second, to determine the neuropathological basis of the initial clinical and neurophysiological findings. We investigated subjects known to carry the P102L mutation in the longitudinal observational UK National Prion Monitoring Cohort study, with serial assessments of clinical features, peripheral nerve conduction, H and F components, threshold tracking and histamine flare and itch response and neuropathological examination in some of those who died. Twenty-three subjects were studied over a period of up to 12 years, including 65 neurophysiological assessments at the same department. Six were symptomatic throughout and six became symptomatic during the study. Neurophysiological abnormalities were restricted to the lower limbs. In symptomatic patients around the time of, or shortly after, symptom onset the H-reflex was lost. Lower limb thermal thresholds were at floor/ceiling in some at presentation, in others thresholds progressively deteriorated. Itch sensation to histamine injection was lost in most symptomatic patients. In six patients with initial assessments in the asymptomatic stage of the disease, a progressive deterioration in the ability to detect warm temperatures in the feet was observed prior to clinical diagnosis and the onset of disability. All of these six patients developed objective abnormalities of either warm or cold sensation prior to the onset of significant symptoms or clinical diagnosis. Autopsy examination in five patients (including two not followed clinically) showed prion protein in the substantia gelatinosa, spinothalamic tracts, posterior columns and nuclei and in the neuropil surrounding anterior horn cells. In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. Neuro-physiological measures become abnormal around the time of symptom onset, prior to diagnosis, and may be of value for improved early diagnosis and for recruitment and monitoring of progression in clinical trials.
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Affiliation(s)
- Peter Rudge
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK.,MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland St. London, UK
| | - Zane Jaunmuktane
- Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, London, UK
| | - Harpreet Hyare
- University College London NHS Foundation Trust, Queen Square, London, UK
| | - Matthew Ellis
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
| | - Martin Koltzenburg
- University College London NHS Foundation Trust, Queen Square, London, UK
| | - John Collinge
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK.,MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland St. London, UK
| | - Sebastian Brandner
- Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London NHS Foundation Trust, Queen Square, London, UK.,Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK
| | - Simon Mead
- National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH), London, UK.,MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland St. London, UK
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Kang MJ, Suh J, An SS, Kim S, Park YH. Pearls & Oy-sters: Challenging diagnosis of Gerstmann-Sträussler-Scheinker disease: Clinical and imaging findings. Neurology 2019; 92:101-103. [PMID: 30617168 DOI: 10.1212/wnl.0000000000006730] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Min Ju Kang
- From the Department of Neurology (M.J.K., J.S., S.K., Y.H.P.), Seoul National University College of Medicine and Seoul National University Bundang Hospital; and Department of Bionanotechnology (S.S.A.), Gachon University, Republic of Korea
| | - Jeewon Suh
- From the Department of Neurology (M.J.K., J.S., S.K., Y.H.P.), Seoul National University College of Medicine and Seoul National University Bundang Hospital; and Department of Bionanotechnology (S.S.A.), Gachon University, Republic of Korea
| | - Seong Soo An
- From the Department of Neurology (M.J.K., J.S., S.K., Y.H.P.), Seoul National University College of Medicine and Seoul National University Bundang Hospital; and Department of Bionanotechnology (S.S.A.), Gachon University, Republic of Korea
| | - SangYun Kim
- From the Department of Neurology (M.J.K., J.S., S.K., Y.H.P.), Seoul National University College of Medicine and Seoul National University Bundang Hospital; and Department of Bionanotechnology (S.S.A.), Gachon University, Republic of Korea
| | - Young Ho Park
- From the Department of Neurology (M.J.K., J.S., S.K., Y.H.P.), Seoul National University College of Medicine and Seoul National University Bundang Hospital; and Department of Bionanotechnology (S.S.A.), Gachon University, Republic of Korea.
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Clinical Laboratory Tests Used To Aid in Diagnosis of Human Prion Disease. J Clin Microbiol 2019; 57:JCM.00769-19. [PMID: 31366689 DOI: 10.1128/jcm.00769-19] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains the gold-standard diagnostic tool, antemortem laboratory testing can be performed to aid in the diagnosis of prion disease. This review is meant to help laboratory directors and physicians in their interpretation of test results. Laboratory assays to detect both nonspecific biomarkers of prion disease and prion-specific biomarkers can be used. The levels of nonspecific biomarkers in cerebrospinal fluid (CSF) are elevated when rapid neurodegeneration is occurring in the patient, and these markers include 14-3-3, tau, neuron-specific enolase, S100B, and alpha-synuclein. These markers have various sensitivities and specificities but are overall limited, as the levels of any of these analytes can be elevated in nonprion disease that is causing rapid damage of brain tissue. Prion-specific assays used in clinical laboratory testing are currently limited to two options. The first option is second-generation real-time quaking-induced conversion (RT-QuIC) performed on CSF, and the second option is Western blotting of a brain biopsy specimen used to detect protease-resistant prion protein. Although both tests have exquisite specificity, RT-QuIC has a sensitivity of 92 to 97.2% in symptomatic individuals, compared to the brain biopsy Western blot sensitivity of 20 to 60%. RT-QuIC was added to the Centers for Disease Control and Prevention's diagnostic criteria for prion disease in 2018. Other caveats of laboratory testing need to be considered, as sporadic, genetic, and acquired forms of prion disease have different clinical and laboratory presentations, and these caveats are discussed. Laboratory testing plays an important role in the diagnosis of prion disease, which is often challenging to diagnose.
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Abstract
Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene (PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non-PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.
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Affiliation(s)
- Simon Mead
- Medical Research Council Prion Unit at UCL, Institute of Prion Diseases, University College London, London W1W 7FF, United Kingdom;
| | - Sarah Lloyd
- Medical Research Council Prion Unit at UCL, Institute of Prion Diseases, University College London, London W1W 7FF, United Kingdom;
| | - John Collinge
- Medical Research Council Prion Unit at UCL, Institute of Prion Diseases, University College London, London W1W 7FF, United Kingdom;
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Tesar A, Matej R, Kukal J, Johanidesova S, Rektorova I, Vyhnalek M, Keller J, Eliasova I, Parobkova E, Smetakova M, Musova Z, Rusina R. Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome. Ann Neurol 2019; 86:643-652. [PMID: 31397917 DOI: 10.1002/ana.25579] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 08/05/2019] [Accepted: 08/07/2019] [Indexed: 12/22/2022]
Abstract
Gerstmann-Sträussler-Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real-time quaking-induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643-652.
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Affiliation(s)
- Adam Tesar
- The Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University, and General University Hospital, Prague
| | - Radoslav Matej
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, and Thomayer Hospital, Prague.,Department of Pathology, First Faculty of Medicine, Charles University, and General University Hospital, Prague.,Department of Pathology, Third Faculty of Medicine, Charles University, and Kralovske Vinohrady University Hospital, Prague
| | - Jaromir Kukal
- Faculty of Nuclear Sciences and Physical Engineering, Czech Technical University, Prague
| | - Silvie Johanidesova
- Department of Neurology, Third Faculty of Medicine, Charles University, and Thomayer Hospital, Prague
| | - Irena Rektorova
- Applied Neuroscience Research Group, Central European Institute of Technology, Masaryk University, Brno.,Department of Neurology, Faculty of Medicine, Masaryk University, and Saint Anne's University Hospital, Brno
| | - Martin Vyhnalek
- Department of Neurology, Second Faculty of Medicine, Charles University, and Motol University Hospital, Prague.,International Clinical Research Center, St Anne's University Hospital Brno, Brno
| | - Jiri Keller
- The Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University, and General University Hospital, Prague.,Department of Radiology, Na Homolce Hospital, Prague
| | - Ilona Eliasova
- Applied Neuroscience Research Group, Central European Institute of Technology, Masaryk University, Brno.,Department of Neurology, Faculty of Medicine, Masaryk University, and Saint Anne's University Hospital, Brno
| | - Eva Parobkova
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, and Thomayer Hospital, Prague.,Department of Pathology, Third Faculty of Medicine, Charles University, and Kralovske Vinohrady University Hospital, Prague
| | - Magdalena Smetakova
- Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University, and Thomayer Hospital, Prague.,Department of Pathology, Third Faculty of Medicine, Charles University, and Kralovske Vinohrady University Hospital, Prague
| | - Zuzana Musova
- Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University, and Motol University Hospital, Prague, Czech Republic
| | - Robert Rusina
- The Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University, and General University Hospital, Prague.,Department of Neurology, Third Faculty of Medicine, Charles University, and Thomayer Hospital, Prague
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42
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Minikel EV, Vallabh SM, Orseth MC, Brandel JP, Haïk S, Laplanche JL, Zerr I, Parchi P, Capellari S, Safar J, Kenny J, Fong JC, Takada LT, Ponto C, Hermann P, Knipper T, Stehmann C, Kitamoto T, Ae R, Hamaguchi T, Sanjo N, Tsukamoto T, Mizusawa H, Collins SJ, Chiesa R, Roiter I, de Pedro-Cuesta J, Calero M, Geschwind MD, Yamada M, Nakamura Y, Mead S. Age at onset in genetic prion disease and the design of preventive clinical trials. Neurology 2019; 93:e125-e134. [PMID: 31171647 DOI: 10.1212/wnl.0000000000007745] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 02/21/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE To determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease. METHODS We assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials. RESULTS Genetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. CONCLUSION The characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
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Affiliation(s)
- Eric Vallabh Minikel
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK.
| | - Sonia M Vallabh
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Margaret C Orseth
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Jean-Philippe Brandel
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Stéphane Haïk
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Jean-Louis Laplanche
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Inga Zerr
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Piero Parchi
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Sabina Capellari
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Jiri Safar
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Janna Kenny
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Jamie C Fong
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Leonel T Takada
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Claudia Ponto
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Peter Hermann
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Tobias Knipper
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Christiane Stehmann
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Tetsuyuki Kitamoto
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Ryusuke Ae
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Tsuyoshi Hamaguchi
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Nobuo Sanjo
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Tadashi Tsukamoto
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Hidehiro Mizusawa
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Steven J Collins
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Roberto Chiesa
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Ignazio Roiter
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Jesús de Pedro-Cuesta
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Miguel Calero
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Michael D Geschwind
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Masahito Yamada
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Yosikazu Nakamura
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
| | - Simon Mead
- From Broad Institute of MIT and Harvard (E.V.M., S.M.V.), Cambridge; Analytical and Translational Genetics Unit (E.V.M.), Massachusetts General Hospital; Program in Biological and Biomedical Sciences (E.V.M., S.M.V.), Harvard Medical School, Boston; Prion Alliance (E.V.M., S.M.V.), Cambridge; Harvard Business School (M.C.O.), Boston, MA; Institut du Cerveau et de la Moelle Épinière (J.-P.B., S.H.), ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Université; Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob (J.-P.B., S.H., J.-L.P.), Assistance Publique-Hôpitaux de Paris, France; National Reference Center for TSE (I.Z., C.P., P.H., T.K.), Georg-August University, Göttingen, Germany; IRCCS-Istituto delle Scienze Neurologiche di Bologna (P.P., S.C.); Departments of Experimental, Diagnostic and Specialty Medicine (P.P.) and Biomedical and Neuromotor Sciences (S.C.), University of Bologna, Italy; National Prion Disease Pathology Surveillance Center (J.S.), Case Western Reserve University, Cleveland, OH; MRC Prion Unit at UCL (J.K., S.M.), Institute of Prion Diseases, University College London, UK; Memory and Aging Center (J.C.F., L.T.T., M.D.G.), University of California San Francisco; Australian National CJD Registry (C.S., S.J.C.), University of Melbourne, Parkville, Australia; Department of Neurological Science (T.K.), Tohoku University Graduate School of Medicine, Sendai; Department of Public Health (R.A., Y.N.), Jichi Medical University, Shimotsuke; Department of Neurology and Neurobiology of Aging (T.H., M.Y.), Kanazawa University Graduate School of Medical Sciences, Kanazawa; Department of Neurology and Neurological Science (N.S.), Tokyo Medical and Dental University; National Center of Neurology and Psychiatry (T.T., H.M.), Kodaira, Japan; Laboratory of Prion Neurobiology (R.C.), Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan; AULSS2 Ca' Foncello Hospital (I.R.), Treviso, Italy; Spanish National Reference Center for CJD (J.d.P.-C., M.C.), Instituto de Salud Carlos III and CIBERNED, Madrid, Spain; and NHS National Prion Clinic (S.M.), National Hospital for Neurology and Neurosurgery, UCL Hospitals NHS Foundation Trust, London, WC1N 3BG, UK
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Wang J, Xiao K, Zhou W, Shi Q, Dong XP. Analysis of 12 Chinese Patients with Proline-to-Leucine Mutation at Codon 102-Associated Gerstmann-Sträussler-Scheinker Disease. J Clin Neurol 2019; 15:184-190. [PMID: 30877692 PMCID: PMC6444146 DOI: 10.3988/jcn.2019.15.2.184] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 11/20/2018] [Accepted: 11/21/2018] [Indexed: 01/14/2023] Open
Abstract
Background and Purpose Gerstmann-Sträussler-Scheinker disease (GSS) with a proline-to-leucine mutation at codon 102 (P102L) in the PRNP gene is the most frequently reported GSS subtype worldwide. This study aimed to determine the epidemiological, clinical, genetic, and laboratory characteristics of 12 Chinese patients with P102L-associated GSS (henceforth P102L GSS). Methods The enrolled P102L GSS cases were analyzed according to the diagnostic criteria for Creutzfeldt-Jakob disease (CJD) issued by the China National Health Commission. Results The median onset age was 50 years (range 34 to 67 years) and sex ratio was 1:2 (males:females). Most patients displayed more than one foremost symptom. Movement symptoms were frequently reported (9 of the 12 cases), followed by rapidly progressing dementia (7 cases), mental problems (5 cases), and slowly progressing dementia (2 cases). Almost all cases displayed more sporadic CJD (sCJD)-associated neurological symptoms and signs as time progressed. Five (45.5%) of 11 cases were cerebrospinal fluid 14-3-3 positive, and 2 (25%) of 8 cases exhibited periodic sharp wave complexes in electroencephalograms. MRI abnormalities were detected in all 11 of the scanned patients. Methionine homozygous genotype at codon 129 (M129M) and glutamic acid homozygous at codon 219 (E219E) homozygosity was present in 11 cases, while 1 case was M129M homozygous and glutamic acid/lysine heterozygous at codon 219 (E219K) heterozygous. Ten of the 12 cases recalled a disease-related family history during the clinical interviews. The median survival from symptom onset of the seven dead cases was 16 months (range 10 to 44 months). Patients showing the sCJD phenotype (rapidly progressing dementia) appeared to be associated with a shorter survival time. Conclusions The indistinguishable clinical features of P102L GSS patients with sCJD, especially in the early stage, support the importance of PRNP testing for diagnosing GSS.
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Affiliation(s)
- Jing Wang
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Kang Xiao
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Wei Zhou
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Qi Shi
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiao Ping Dong
- State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.,Center of Global Public Health, Chinese Center for Disease Control and Prevention, Beijing, China.
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Zhao MM, Feng LS, Hou S, Shen PP, Cui L, Feng JC. Gerstmann-Sträussler-Scheinker disease: A case report. World J Clin Cases 2019; 7:389-395. [PMID: 30746381 PMCID: PMC6369391 DOI: 10.12998/wjcc.v7.i3.389] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/24/2018] [Accepted: 12/30/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease that is clinically characterized by the early onset of progressive cerebellar ataxia. The incidence of GSS is extremely low and it is particularly rare in China. Therefore, clinicians may easily confuse this disease with other diseases that also cause ataxia, resulting in its under-diagnosis or misdiagnosis.
CASE SUMMARY Here, we report the first case of genetically diagnosed GSS disease in Northeast China. The patient exhibited typical ataxia and dysarthria 2.5 years after symptom onset. However, magnetic resonance imaging of the brain and spinal cord revealed a normal anatomy. Screening results for the spinocerebellar ataxia gene were also negative. We thus proposed to expand the scope of genetic screening to include over 200 mutations that can cause ataxia. A final diagnosis of GSS was presented and the patient was followed for more than 3.5 years, during which we noted imaging abnormalities. The patient gradually exhibited decorticate posturing and convulsions. We recommended administration of oral sodium valproate, which resolved the convulsions.
CONCLUSION Patients with inherited ataxia should be considered for a diagnosis of GSS via genetic testing at an early disease stage.
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Affiliation(s)
- Ming-Ming Zhao
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Liang-Shu Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Shuai Hou
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Ping-Ping Shen
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li Cui
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jia-Chun Feng
- Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Nicolas G, Veltman JA. The role of de novo mutations in adult-onset neurodegenerative disorders. Acta Neuropathol 2019; 137:183-207. [PMID: 30478624 PMCID: PMC6513904 DOI: 10.1007/s00401-018-1939-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 12/13/2022]
Abstract
The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient-parent trios allows a hypothesis-free study of the role of de novo mutations in AOND and the discovery of novel disease genes. Another hypothesis that may explain a proportion of sporadic AOND cases is the occurrence of a de novo mutation after the fertilization of the oocyte (post-zygotic mutation) or even as a late-somatic mutation, restricted to the brain. Such somatic mutation hypothesis, that can be tested with the use of novel sequencing technologies, is fully compatible with the seeding and spreading mechanisms of the pathological proteins identified in most of these disorders. We review here the current knowledge and future perspectives on de novo mutations in known and novel candidate genes identified in the most common AONDs such as Alzheimer's disease, Parkinson's disease, the frontotemporal lobar degeneration spectrum and Prion disorders. Also, we review the first lessons learned from recent genomic studies of control and diseased brains and the challenges which remain to be addressed.
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Affiliation(s)
- Gaël Nicolas
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, 22, Boulevard Gambetta, 76000, 76031, Rouen Cedex, France.
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Joris A Veltman
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
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Terry C, Harniman RL, Sells J, Wenborn A, Joiner S, Saibil HR, Miles MJ, Collinge J, Wadsworth JDF. Structural features distinguishing infectious ex vivo mammalian prions from non-infectious fibrillar assemblies generated in vitro. Sci Rep 2019; 9:376. [PMID: 30675000 PMCID: PMC6344479 DOI: 10.1038/s41598-018-36700-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 11/23/2018] [Indexed: 01/19/2023] Open
Abstract
Seeded polymerisation of proteins forming amyloid fibres and their spread in tissues has been implicated in the pathogenesis of multiple neurodegenerative diseases: so called "prion-like" mechanisms. While ex vivo mammalian prions, composed of multichain assemblies of misfolded host-encoded prion protein (PrP), act as lethal infectious agents, PrP amyloid fibrils produced in vitro generally do not. The high-resolution structure of authentic infectious prions and the structural basis of prion strain diversity remain unknown. Here we use cryo-electron microscopy and atomic force microscopy to examine the structure of highly infectious PrP rods isolated from mouse brain in comparison to non-infectious recombinant PrP fibrils generated in vitro. Non-infectious recombinant PrP fibrils are 10 nm wide single fibres, with a double helical repeating substructure displaying small variations in adhesive force interactions across their width. In contrast, infectious PrP rods are 20 nm wide and contain two fibres, each with a double helical repeating substructure, separated by a central gap of 8-10 nm in width. This gap contains an irregularly structured material whose adhesive force properties are strikingly different to that of the fibres, suggestive of a distinct composition. The structure of the infectious PrP rods, which cause lethal neurodegeneration, readily differentiates them from all other protein assemblies so far characterised in other neurodegenerative diseases.
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Affiliation(s)
- Cassandra Terry
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- London Metropolitan University, North Campus, Holloway Road, London, N7 8DB, UK
| | | | - Jessica Sells
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
- King's Centre for Stem Cells & Regenerative Medicine, King's College London, Guy's Campus, London, SE1 9RT, UK
| | - Adam Wenborn
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Susan Joiner
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK
| | - Helen R Saibil
- Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK
| | - Mervyn J Miles
- School of Physics, H.H. Wills Physics Laboratory, University of Bristol, Tyndall Avenue, Bristol, BS8 1TL, UK
| | - John Collinge
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
| | - Jonathan D F Wadsworth
- MRC Prion Unit at UCL, UCL Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
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Ishizawa K, Mitsufuji T, Shioda K, Kobayashi A, Komori T, Nakazato Y, Kitamoto T, Araki N, Yamamoto T, Sasaki A. An autopsy report of three kindred in a Gerstmann-Sträussler-Scheinker disease P105L family with a special reference to prion protein, tau, and beta-amyloid. Brain Behav 2018; 8:e01117. [PMID: 30240140 PMCID: PMC6192393 DOI: 10.1002/brb3.1117] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 07/04/2018] [Accepted: 07/18/2018] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Gerstmann-Sträussler-Scheinker disease P105L (GSS105) is a rare variant of GSS caused by a point mutation of the prion protein (PrP) gene at codon 105 (proline to leucine substitution). It is clinically characterized by spastic paraparesis and dementia and histopathologically defined by PrP-plaques in the brain. This report describes a clinicopathological analysis of three autopsied kindred from a Japanese GSS105 family, plus a topological analysis of PrP, hyperphosphorylated tau (p-tau), and beta-amyloid (Aβ). METHODS Using paraffin-embedded sections, we applied histology and single- and multiple-labeling immunohistochemistry for PrP, p-tau, and Aβ to the three cases. Comparative semi-quantitative analyses of tissue injuries and PrP-plaques were also employed. RESULTS Case 1 (45 years old (yo)) and Case 2 (56 yo) are sisters, and Case 3 (49 yo) is the son of Case 2. Case 1 and Case 2 presented with spastic paraparesis followed by dementia, whereas Case 3 presented, not with spastic paraparesis, but with psychiatric symptoms. In Case 1 and Case 2, the brain showed tissue injuries with many PrP-plaques in the cerebral cortices, and the pyramidal tract showed myelin loss/pallor. In Case 3, the brain was least degenerated with a number of PrP-plaques; however, the pyramidal tract remained intact. In addition, p-tau was deposited in all cases, where p-tau was present in or around PrP-plaques. By double-labeling immunohistochemistry, the colocalization of p-tau with PrP-plaques was confirmed. Moreover in Case 2, Aβ was deposited in the cerebral cortices. Interestingly, not only p-tau but also Aβ was colocalized with PrP-plaques. In all cases, both three repeat tau and four repeat tau were associated with PrP-plaques. CONCLUSIONS The clinicopathological diversity of GSS105, which is possible even in the same family, was ascertained. Not only p-tau but also Aβ could be induced by PrP ("secondary degeneration"), facilitating the kaleidoscopic symptoms of GSS.
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Affiliation(s)
- Keisuke Ishizawa
- Department of NeurologySaitama Medical UniversitySaitamaJapan
- Department of PathologySaitama Medical UniversitySaitamaJapan
| | | | - Kei Shioda
- Department of PathologySaitama Medical UniversitySaitamaJapan
| | - Atsushi Kobayashi
- Hokkaido University Graduate School of Veterinary MedicineHokkaidoJapan
| | - Takashi Komori
- Department of PathologyTokyo Metropolitan Neurological HospitalTokyoJapan
| | | | - Tetsuyuki Kitamoto
- Division of CJD Science and Technology, Department of Prion Research, Center for Translational and Advanced Animal Research on Human DiseasesTohoku University Graduate School of MedicineMiyagiJapan
| | - Nobuo Araki
- Department of NeurologySaitama Medical UniversitySaitamaJapan
| | | | - Atsushi Sasaki
- Department of PathologySaitama Medical UniversitySaitamaJapan
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Abstract
Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene (PRNP) have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia. Mutations in PRNP can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features. They may also show varying ancillary testing results and neuropathological findings. Although the majority of gPrDs have a rapid progression with a short survival time of a few months, many also present as ataxic or parkinsonian disorders, which have a slower decline over a few to several years. A few very rare mutations manifest as neuropsychiatric disorders, with systemic symptoms that include gastrointestinal disorders and neuropathy; these forms can progress over years to decades. In this review, we classify gPrDs as rapid, slow, or mixed types based on their typical rate of progression and duration, and we review the broad spectrum of phenotypes manifested by these diseases.
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Affiliation(s)
- Mee-Ohk Kim
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Leonel T Takada
- Cognitive and Behavioral Neurology Unit, Department of Neurology, University of São Paulo, São Paulo, 05403-900, Brazil
| | - Katherine Wong
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Sven A Forner
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Michael D Geschwind
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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49
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Abstract
Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene (PRNP) have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia. Mutations in PRNP can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features. They may also show varying ancillary testing results and neuropathological findings. Although the majority of gPrDs have a rapid progression with a short survival time of a few months, many also present as ataxic or parkinsonian disorders, which have a slower decline over a few to several years. A few very rare mutations manifest as neuropsychiatric disorders, with systemic symptoms that include gastrointestinal disorders and neuropathy; these forms can progress over years to decades. In this review, we classify gPrDs as rapid, slow, or mixed types based on their typical rate of progression and duration, and we review the broad spectrum of phenotypes manifested by these diseases.
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Affiliation(s)
- Mee-Ohk Kim
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Leonel T Takada
- Cognitive and Behavioral Neurology Unit, Department of Neurology, University of São Paulo, São Paulo, 05403-900, Brazil
| | - Katherine Wong
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Sven A Forner
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
| | - Michael D Geschwind
- Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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50
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Matamoros-Angles A, Gayosso LM, Richaud-Patin Y, di Domenico A, Vergara C, Hervera A, Sousa A, Fernández-Borges N, Consiglio A, Gavín R, López de Maturana R, Ferrer I, López de Munain A, Raya Á, Castilla J, Sánchez-Pernaute R, Del Río JA. iPS Cell Cultures from a Gerstmann-Sträussler-Scheinker Patient with the Y218N PRNP Mutation Recapitulate tau Pathology. Mol Neurobiol 2018; 55:3033-3048. [PMID: 28466265 PMCID: PMC5842509 DOI: 10.1007/s12035-017-0506-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 03/21/2017] [Indexed: 01/20/2023]
Abstract
Gerstmann-Sträussler-Scheinker (GSS) syndrome is a fatal autosomal dominant neurodegenerative prionopathy clinically characterized by ataxia, spastic paraparesis, extrapyramidal signs and dementia. In some GSS familiar cases carrying point mutations in the PRNP gene, patients also showed comorbid tauopathy leading to mixed pathologies. In this study we developed an induced pluripotent stem (iPS) cell model derived from fibroblasts of a GSS patient harboring the Y218N PRNP mutation, as well as an age-matched healthy control. This particular PRNP mutation is unique with very few described cases. One of the cases presented neurofibrillary degeneration with relevant Tau hyperphosphorylation. Y218N iPS-derived cultures showed relevant astrogliosis, increased phospho-Tau, altered microtubule-associated transport and cell death. However, they failed to generate proteinase K-resistant prion. In this study we set out to test, for the first time, whether iPS cell-derived neurons could be used to investigate the appearance of disease-related phenotypes (i.e, tauopathy) identified in the GSS patient.
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Affiliation(s)
- Andreu Matamoros-Angles
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Lucía Mayela Gayosso
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain
| | - Yvonne Richaud-Patin
- Centre de Medicina Regenerativa de Barcelona, c/ Dr. Aiguader 88, 08003, Barcelona, Spain
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid, Spain
| | - Angelique di Domenico
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
| | - Cristina Vergara
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Laboratory of Histology, Neuroanatomy and Neuropathology (CP 620), ULB Neuroscience Institute. Université Libre de Bruxelles, Faculty of Medicine, Brussels, Belgium
| | - Arnau Hervera
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | - Amaya Sousa
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain
| | - Natalia Fernández-Borges
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain
- CISA-INIA, Center for Animal Health Research, Madrid, Spain
| | - Antonella Consiglio
- Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Rosalina Gavín
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
| | | | - Isidro Ferrer
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain
- Dept. Patologia i Terapèutica Experimental, Universitat de Barcelona, Barcelona, Spain
| | - Adolfo López de Munain
- Instituto Biodonostia-Hospital Universitario Donostia, San Sebastian, Gipuzkoa, Spain
- Neurosciences Department, University of the Basque Country UPV-EHU, Bilbao, Spain
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), San Sebastian, Gipuzkoa, Spain
| | - Ángel Raya
- Centre de Medicina Regenerativa de Barcelona, c/ Dr. Aiguader 88, 08003, Barcelona, Spain.
- Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBERBBN), Madrid, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| | - Joaquín Castilla
- Proteomics unit (Prion lab), CIC bioGUNE, Parque tecnológico de Bizkaia, 48160, Derio, Bizkaia, Spain.
- IKERBASQUE, Basque Foundation for Science, Bilbao, Bizkaia, Spain.
| | - Rosario Sánchez-Pernaute
- Stem cells and neural repair laboratory, Fundación Inbiomed, San Sebastian, Gipuzkoa, Spain.
- Andalusian Initiative for Advanced Therapies, Junta de Andalusia, Seville, Spain.
| | - José Antonio Del Río
- Institute for Bioengineering of Catalonia (IBEC), Parc Científic de Barcelona, Baldiri Reixac 15-21, E-08028, Barcelona, Spain.
- Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain.
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
- Institute of Neuroscience, University of Barcelona, Barcelona, Spain.
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