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Plavelil N, Appu AP, Gopal KC, Mondal A, Perkins N, Mukherjee AB. Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model. Neurobiol Dis 2025; 209:106890. [PMID: 40158736 PMCID: PMC12018121 DOI: 10.1016/j.nbd.2025.106890] [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: 02/20/2025] [Revised: 03/20/2025] [Accepted: 03/27/2025] [Indexed: 04/02/2025] Open
Abstract
Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-palmitoylation, a reversable posttranslational modification by saturated fatty acids (generally palmitate) facilitates endosomal trafficking of many proteins, especially in the brain. While palmitoyl-acyltransferases (called ZDHHCs) catalyze S-palmitoylation, depalmitoylation is mediated by palmitoyl-protein thioesterases (PPTs). We previously reported that in Cln1-/- mice, which mimic human CLN1-disease, endoplasmic reticulum (ER)-stress leads to unfolded protein response (UPR) contributing to neurodegeneration. However, the mechanism underlying ER-stress has remained elusive. The anterograde (ER to Golgi) protein-trafficking is mediated via COPII (coat protein complex II) vesicles, whereas the retrograde transport (Golgi to ER) is mediated by COPI vesicles. We hypothesized that dysregulated anterograde protein-trafficking causing stagnation of proteins in the ER leads to ER-stress in Cln1-/- mice. We found that the levels of five COPII vesicle-associated proteins (i.e. Sar1, Sec23, Sec24, Sec13 and Sec31) are significantly higher in the ER-fractions of cortical tissues from Cln1-/- mice compared with those from their WT littermates. Remarkably, all COPII proteins, except Sec13, undergo S-palmitoylation. Moreover, CLN8, a Batten disease-protein, requires dynamic S-palmitoylation (palmitoylation-depalmitoylation) for ER-Golgi trafficking. Intriguingly, Ppt1-deficiency in Cln1-/- mice impairs ER-Golgi trafficking of Cln8-protein along with several other COPII-associated proteins. We propose that impaired anterograde trafficking causes excessive accumulation of proteins in the ER causing ER-stress and UPR contributing to neurodegeneration in CLN1 disease.
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Affiliation(s)
- Nisha Plavelil
- Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America.
| | - Abhilash P Appu
- Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America
| | - K C Gopal
- Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America
| | - Avisek Mondal
- Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America
| | - Neil Perkins
- Biostatistics and Bioinformatics Branch (HNT72), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, United States of America
| | - Anil B Mukherjee
- Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America.
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Chaoul V, Saab S, Shmoury O, Alam R, Al Aridi L, Makhoul NJ, Soueid J, Boustany RM. Expanded Phenotype of the Cln6nclf Mouse Model. Cells 2025; 14:661. [PMID: 40358187 PMCID: PMC12071971 DOI: 10.3390/cells14090661] [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: 02/28/2025] [Revised: 03/28/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and motor decline, seizures, and early death. An in-depth characterization of a naturally occurring Cln6 mutant mouse (Cln6nclf) is presented, with implications for translational research. The expanded phenotype provides data showing early death, vision loss, and motor deficits in male and female Cln6nclf mice. Diminished visual acuity in Cln6nclf mice was noted at 28 weeks of age, but the pathological loss of retinal layers began as early as 2 weeks or postnatal day 14 (P14). Apoptosis was confirmed by TUNEL staining in the Cln6nclf mouse brain at P8 and in the retina at P12. A peak in glial fibrillary acidic protein (GFAP) expression was established as a normal developmental phenomenon in the wild-type and Cln6nclf mouse brain cerebellum and the CA2-CA3 regions of the hippocampus at P8. In Cln6nclf mice, GFAP levels were elevated at P12 in the cerebellum and hippocampus. In the retina, a developmental peak in gliosis was absent, with increased astrogliosis noted at P6 and P8 in female and male Cln6nclf mice, respectively. This highlights the lack of a sex-dependent response in wild-type mice. These novel data position the Cln6nclf mouse model as a useful tool for screening potential therapeutics for human CLN6 disease.
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Affiliation(s)
- Victoria Chaoul
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Sara Saab
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Omar Shmoury
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Ramy Alam
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Lynn Al Aridi
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Nadine J. Makhoul
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
| | - Jihane Soueid
- Department of Anatomy, Cell Biology and Physiological Sciences, American Unibersity of Beirut, Beirut 1107 2020, Lebanon;
| | - Rose-Mary Boustany
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon; (V.C.); (S.S.); (O.S.); (R.A.); (L.A.A.); (N.J.M.)
- Division of Pediatric Neurology, Faculty of Medicine, American University of Beirut, Beirut 1107 2020, Lebanon
- Neurogenetics Program and Pediatric Neurology, Departments of Pediatrics, Adolescent Medicine and Biochemistry, American University of Beirut, Beirut 1107 2020, Lebanon
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3
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Bauchat A, Polishchuk V, Fabrizio VA, Brondon JE, Page KM, Driscoll TA, Martin PL, Mahadeo KM, Kurtzberg J, Prasad VK. Safety and feasibility of umbilical cord blood transplantation in children with neuronal ceroid lipofuscinosis: a retrospective study. Stem Cells Transl Med 2025; 14:szae080. [PMID: 39471475 PMCID: PMC11821899 DOI: 10.1093/stcltm/szae080] [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: 05/31/2024] [Accepted: 09/17/2024] [Indexed: 11/01/2024] Open
Abstract
Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.
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Affiliation(s)
- Andrea Bauchat
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
| | - Veronika Polishchuk
- Division of Pediatric Hematology, Oncology, and Stem Cell Transplant, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 E Chicago Ave, Chicago, IL 60611, United States
| | - Vanessa A Fabrizio
- Colorado Children’s Hospital, Anschutz Medical Campus, University of Colorado, 13123 E 16th Ave, Aurora, CO 80045, United States
| | | | - Kristin M Page
- Department of Pediatrics and Medicine, Medical College of Wisconsin, 8915 W Connell Ct, Milwaukee, WI 53226, United States
| | - Timothy A Driscoll
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
| | - Paul L Martin
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
| | - Kris M Mahadeo
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
| | - Joanne Kurtzberg
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
| | - Vinod K Prasad
- Division of Pediatric Transplant and Cellular Therapy, Duke University, 2400 Pratt Street, Box 102502, Durham, NC 27705, United States
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Thuppanattumadam Ananthasubramanian S, Padmanabha H, Ravindranadh CM, Kenchiah R, Bhatia S, Santhoshkumar R, Kumar TS, Sukrutha R, Arunachal G, Karthik K, Nagappa M, Nashi S, Mahale R, Viswananthan LG, Pooja M, Nagaraj AR, Ravi Shekar J, Yasha TC, Mahadevan A, Sinha S. Genetic spectrum of neuronal ceroid lipofuscinosis & its genotype-phenotype correlation -A single centre experience of 56 cases. J Neurol Sci 2025; 468:123338. [PMID: 39675099 DOI: 10.1016/j.jns.2024.123338] [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: 10/19/2024] [Revised: 11/30/2024] [Accepted: 12/01/2024] [Indexed: 12/17/2024]
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses (NCLs) are progressive, autosomal recessive lysosomal storage disorders primarily affecting children, marked by seizures, cognitive decline, motor regression, and visual impairment. Limited genetic data exist for South Asian populations, with most studies relying on enzymatic assays or electron microscopy. This study explores the genetic spectrum of NCL and genotype-phenotype correlations in a cohort from South India. METHODS A retrospective analysis was conducted on 56 genetically confirmed NCL patients diagnosed between January 2018 and June 2024 at a specialized neurological center in South India. Genetic analysis using next-generation sequencing (NGS) were performed, with variants classified as per ACMG guidelines. Clinical, electroencephalographic (EEG), imaging, and electron microscopy (EM) findings were reviewed, and genotype-phenotype correlations were analyzed. RESULTS The cohort (33 males, 23 females) had a median age of onset of 36 months and a median disease duration of 65.5 months. Eight genetic subtypes were identified, with predominant mutations in TPP1 (19.64%), CLN6, MFSD8, and CLN8 (16.07% each). Seizures (75%), regression of milestones (87.5%), visual impairment (33.9%), and ataxia (57.1%) were common. EEG abnormalities were found in 76.3%, MRI revealed cerebellar atrophy in 89.13%, and thalamic T2 hypo-intensity in 91.3%. EM showed curvilinear and fingerprint profiles. Of the identified variants, 31 were previously reported, while 29 were novel. CONCLUSION This is the largest single-center NCL cohort in South Asia, highlighting a diverse genetic spectrum and significant novel variants, underscoring the importance of genetic testing for diagnosis and future therapies.
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Affiliation(s)
| | - Hansashree Padmanabha
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - C M Ravindranadh
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Raghavendra Kenchiah
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Saloni Bhatia
- Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Rashmi Santhoshkumar
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Tumulu Seetam Kumar
- Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Ramya Sukrutha
- Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Gautham Arunachal
- Department of Human Genetics, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - K Karthik
- Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Madhu Nagappa
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Saraswati Nashi
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Rohan Mahale
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - L G Viswananthan
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - M Pooja
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - A R Nagaraj
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - J Ravi Shekar
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - T C Yasha
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Anita Mahadevan
- Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore 560029, India.
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Tong J, Gao J, Qi Y, Gao Z, Wang Q, Liu Y, Yuan T, Ren M, Yang G, Li Z, Li J, Sun H, Zhao X, Leung YY, Mu Y, Xu J, Lu C, Peng S, Ge L. GABA AR-PPT1 palmitoylation homeostasis controls synaptic transmission and circuitry oscillation. Transl Psychiatry 2024; 14:488. [PMID: 39695089 DOI: 10.1038/s41398-024-03206-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024] Open
Abstract
The infantile neuronal ceroid lipofuscinosis, also called CLN1 disease, is a fatal neurodegenerative disease caused by mutations in the CLN1 gene encoding palmitoyl protein thioesterase 1 (PPT1). Identifying the depalmitoylation substrates of PPT1 is crucial for understanding CLN1 disease. In this study, we found that GABAAR, the critical synaptic protein essential for inhibitory neurotransmission, is a substrate of PPT1. PPT1 depalmitoylates GABAAR α1 subunit at Cystein-260, while binding to Cystein-165 and -179. Mutations of PPT1 or its GABAAR α1 subunit binding site enhanced inhibitory synaptic transmission and strengthened oscillations powers but disrupted phase coupling in CA1 region and impaired learning and memory in 1- to 2-months-old PPT1-deficient and Gabra1em1 mice. Our study highlights the critical role of PPT1 in maintaining GABAAR palmitoylation homeostasis and reveals a previously unknown molecular pathway in CLN1 diseases induced by PPT1 mutations.
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Affiliation(s)
- Jia Tong
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Jingjing Gao
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
- School of Pharmacy, Lanzhou University, Lanzhou, China
| | - Yawei Qi
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Ziyan Gao
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Qianqian Wang
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Yang Liu
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Tiangang Yuan
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Minglong Ren
- Institute of Brain Functional Genomics, East China Normal University, Shanghai, China
| | - Guixia Yang
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Zhaoyue Li
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Jin Li
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Hongyuan Sun
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Xing Zhao
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Yeung-Yeung Leung
- Division of Brain Sciences, Imperial College Faculty of Medicine, Du Cane Road, London, UK
| | - Yonghui Mu
- Basic Medical College, Xinxiang Medical University, Xinxiang, He'nan, China
| | - Jiamin Xu
- Institute of Brain Functional Genomics, East China Normal University, Shanghai, China
| | - Chengbiao Lu
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China.
- He'nan International Joint Laboratory for Non-invasive Neural Modulation, Department of Physiology and Pathology, School of Basic Medical Science, Xinxiang Medical University, Xinxiang, He'nan, China.
| | - Shiyong Peng
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China.
| | - Lihao Ge
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, He'nan, China.
- Institute of Psychiatry and Neuroscience, Xinxiang Medical University, Xinxiang, He'nan, China.
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Han J, Chear S, Talbot J, Swier V, Booth C, Reuben-Thomas C, Dalvi S, Weimer JM, Hewitt AW, Cook AL, Singh R. Genetic and Cellular Basis of Impaired Phagocytosis and Photoreceptor Degeneration in CLN3 Disease. Invest Ophthalmol Vis Sci 2024; 65:23. [PMID: 39535788 PMCID: PMC11563035 DOI: 10.1167/iovs.65.13.23] [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: 06/13/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Purpose CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease induced pluripotent stem cell-RPE cells show defective phagocytosis of photoreceptor outer segment (POS). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect. Methods Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3Δ7-8/Δ7-8 (CLN3) Yucatan miniswine was also used to study the impact of CLN3Δ7-8/Δ7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3Δ7-8/Δ7-8 and wild-type miniswine eyes were carried out at 6, 36, or 48 months of age. Results CLN3Δ7-8/Δ7-8 RPE (CLN3 RPE) displayed decreased POS binding and consequently decreased uptake of POS compared with isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3Δ7-8/Δ7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36 months of age and was followed by almost complete loss of photoreceptors at 48 months of age. Conclusions CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.
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Affiliation(s)
- Jimin Han
- Department of Ophthalmology, University of Rochester, Rochester, New York, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, United States
- Center for Visual Science, University of Rochester, Rochester, New York, United States
| | - Sueanne Chear
- Wicking Dementia Research and Education Centre, University of Tasmania, Tasmania, Australia
| | - Jana Talbot
- Wicking Dementia Research and Education Centre, University of Tasmania, Tasmania, Australia
| | - Vicki Swier
- Pediatrics & Rare Diseases Group; Sanford Research, Sioux Falls, South Dakota, United States
| | - Clarissa Booth
- Pediatrics & Rare Diseases Group; Sanford Research, Sioux Falls, South Dakota, United States
| | - Cheyenne Reuben-Thomas
- Department of Ophthalmology, University of Rochester, Rochester, New York, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, United States
- Center for Visual Science, University of Rochester, Rochester, New York, United States
| | - Sonal Dalvi
- Department of Ophthalmology, University of Rochester, Rochester, New York, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, United States
- Center for Visual Science, University of Rochester, Rochester, New York, United States
| | - Jill M. Weimer
- Pediatrics & Rare Diseases Group; Sanford Research, Sioux Falls, South Dakota, United States
- Department of Pediatrics; Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, United States
| | - Alex W. Hewitt
- Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | - Anthony L. Cook
- Wicking Dementia Research and Education Centre, University of Tasmania, Tasmania, Australia
| | - Ruchira Singh
- Department of Ophthalmology, University of Rochester, Rochester, New York, United States
- Department of Biomedical Genetics, University of Rochester, Rochester, New York, United States
- Center for Visual Science, University of Rochester, Rochester, New York, United States
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7
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Yasa S, Butz ES, Colombo A, Chandrachud U, Montore L, Tschirner S, Prestel M, Sheridan SD, Müller SA, Groh J, Lichtenthaler SF, Tahirovic S, Cotman SL. Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover. Commun Biol 2024; 7:1373. [PMID: 39438652 PMCID: PMC11496662 DOI: 10.1038/s42003-024-07057-w] [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: 03/13/2024] [Accepted: 10/11/2024] [Indexed: 10/25/2024] Open
Abstract
Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3∆ex7/8 mice, a genetically accurate disease model. Loss of CLN3 function in microglia leads to lysosomal storage material accumulation and abnormal morphology of subcellular organelles. Moreover, pathological proteomic signatures are indicative of defects in lysosomal function and abnormal lipid metabolism. Consistent with these findings, CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Accordingly, we also observe impaired myelin integrity in aged Cln3∆ex7/8 mouse brain. Autophagy inducers and cholesterol-lowering drugs correct the observed microglial phenotypes. Taken together, these data implicate a cell-autonomous defect in CLN3-deficient microglia that impacts their ability to support neuronal cell health, suggesting microglial targeted therapies should be considered for CLN3 disease.
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Affiliation(s)
- Seda Yasa
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Neurology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Neurology, Harvard Medical School, Boston, MA, USA
- Medical and Population Genetics Program, the Broad Institute of M.I.T. and Harvard, Cambridge, MA, USA
| | - Elisabeth S Butz
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Neurology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
| | - Alessio Colombo
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Uma Chandrachud
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Luca Montore
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
| | - Sarah Tschirner
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Matthias Prestel
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Steven D Sheridan
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Stephan A Müller
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Janos Groh
- Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany
| | - Stefan F Lichtenthaler
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Sabina Tahirovic
- German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
| | - Susan L Cotman
- Center for Genomic Medicine, Massachusetts General Hospital Research Institute, Boston, MA, USA.
- Department of Neurology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
- Department of Neurology, Harvard Medical School, Boston, MA, USA.
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8
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Bellamy KKL, Skedsmo FS, Hultman J, Jansen JH, Lingaas F. Neuronal ceroid lipofuscinosis in a Schapendoes dog is caused by a missense variant in CLN6. Anim Genet 2024; 55:612-620. [PMID: 38866396 DOI: 10.1111/age.13457] [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: 05/03/2024] [Revised: 05/03/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024]
Abstract
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative disorders that occur in humans, dogs, and several other species. NCL is characterised clinically by progressive deterioration of cognitive and motor function, epileptic seizures, and visual impairment. Most forms present early in life and eventually lead to premature death. Typical pathological changes include neuronal accumulation of autofluorescent, periodic acid-Schiff- and Sudan black B-positive lipopigments, as well as marked loss of neurons in the central nervous system. Here, we describe a 19-month-old Schapendoes dog, where clinical signs were indicative of lysosomal storage disease, which was corroborated by pathological findings consistent with NCL. Whole genome sequencing of the affected dog and both parents, followed by variant calling and visual inspection of known NCL genes, identified a missense variant in CLN6 (c.386T>C). The variant is located in a highly conserved region of the gene and predicted to be harmful, which supports a causal relationship. The identification of this novel CLN6 variant enables pre-breeding DNA-testing to prevent future cases of NCL6 in the Schapendoes breed, and presents a potential natural model for NCL6 in humans.
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Affiliation(s)
| | - Fredrik S Skedsmo
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Josefin Hultman
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Johan Høgset Jansen
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
| | - Frode Lingaas
- Department of Preclinical Sciences and Pathology, Faculty of Veterinary Medicine, Norwegian University of Life Sciences, Ås, Norway
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9
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Dobloug S, Kjellström U, Anderson G, Gardner E, Mole SE, Sheth J, Puschmann A. Maculopathy and adult-onset ataxia in patients with biallelic MFSD8 variants. Mol Genet Genomic Med 2024; 12:e2505. [PMID: 39108195 PMCID: PMC11303817 DOI: 10.1002/mgg3.2505] [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: 05/16/2024] [Revised: 07/17/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Biallelic variants in the major facilitator superfamily domain containing 8 gene (MFSD8) are associated with distinct clinical presentations that range from typical late-infantile neuronal ceroid lipofuscinosis type 7 (CLN7 disease) to isolated adult-onset retinal dystrophy. Classic late-infantile CLN7 disease is a severe, rare neurological disorder with an age of onset typically between 2 and 6 years, presenting with seizures and/or cognitive regression. Its clinical course is progressive, leading to premature death, and often includes visual loss due to severe retinal dystrophy. In rare cases, pathogenic variants in MFSD8 can be associated with isolated non-syndromic macular dystrophy with variable age at onset, in which the disease process predominantly or exclusively affects the cones of the macula and where there are no neurological or neuropsychiatric manifestations. METHODS Here we present longitudinal studies on four adult-onset patients who were biallelic for four MFSD8 variants. RESULTS Two unrelated patients who presented with adult-onset ataxia and had macular dystrophy on examination were homozygous for a novel variant in MFSD8 NM_152778.4: c.935T>C p.(Ile312Thr). Two other patients presented in adulthood with visual symptoms, and one of these developed mild to moderate cerebellar ataxia years after the onset of visual symptoms. CONCLUSIONS Our observations expand the knowledge on biallelic pathogenic MFSD8 variants and confirm that these are associated with a spectrum of more heterogeneous clinical phenotypes. In MFSD8-related disease, adult-onset recessive ataxia can be the presenting manifestation or may occur in combination with retinal dystrophy.
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Affiliation(s)
- Sigurd Dobloug
- Department of NeurologyHelsingborg General HospitalHelsingborgSweden
- Department for Clinical Sciences, Lund, NeurologyLund UniversityLundSweden
| | | | - Glenn Anderson
- Department of HistopathologyGreat Ormond Street HospitalLondonUK
| | - Emily Gardner
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUK
| | - Sara E. Mole
- Great Ormond Street Institute of Child HealthUniversity College LondonLondonUK
| | - Jayesh Sheth
- Foundation for Research in Genetics and EndocrinologyInstitute of Human GeneticsAhmedabadIndia
| | - Andreas Puschmann
- Lund University, Skåne University Hospital, NeurologyLundSweden
- SciLifeLabLund UniversityLundSweden
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10
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Han J, Chear S, Talbot J, Swier V, Booth C, Reuben-Thomas C, Dalvi S, Weimer JM, Hewitt AW, Cook AL, Singh R. Genetic and cellular basis of impaired phagocytosis and photoreceptor degeneration in CLN3 disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.09.597388. [PMID: 38895469 PMCID: PMC11185776 DOI: 10.1101/2024.06.09.597388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Purpose CLN3 Batten disease (also known as Juvenile Neuronal Ceroid Lipofuscinosis; JNCL) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease iPSC-RPE cells show defective phagocytosis of photoreceptor outer segments (POSs). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect. Methods Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3 Δ 7-8/ Δ 7-8 ( CLN3 ) Yucatan miniswine was also used to study the impact of CLN3 Δ 7-8/ Δ 7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3 Δ 7/8 and wild-type miniswine eyes were carried out at 6-, 36-, or 48-month age. Results CLN3 Δ 7-8/ Δ 7-8 RPE ( CLN3 RPE) displayed reduced POS binding and consequently decreased uptake of POS compared to isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3 Δ 7-8/ Δ 7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36 months-of-age and was followed by almost complete loss of photoreceptors at 48 months of age. Conclusions CLN3 Δ 7-8/ Δ 7-8 mutation (that affects up to 85% patients) affects both RPE and POSs and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.
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11
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K P, Madhana PN, Eswaramoorthy R, Ramasamy M. A computational approach to analyzing the functional and structural impacts of Tripeptidyl-Peptidase 1 missense mutations in neuronal ceroid lipofuscinosis. Metab Brain Dis 2024; 39:545-558. [PMID: 38185715 DOI: 10.1007/s11011-024-01341-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 12/18/2023] [Indexed: 01/09/2024]
Abstract
Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD). Fifty-six missense mutants were enumerated with computational methods to perceive the significant mutants (G475R and G501C) and correlated with clinical and literature data. A structure-based screening method was initiated to understand protein-ligand interaction and dynamic simulation. The docking procedure was performed for the native (3EDY) and mutant (G473R and G501C) structures with Gemfibrozil (gem), which lowers the lipid level, decreases the triglycerides amount in the blood circulation, and controls hyperlipidemia. The Native had an interaction score of -5.57 kcal/mol, and the mutants had respective average binding scores of -6.24 (G473R) and - 5.17 (G501C) kcal/mol. Finally, molecular dynamics simulation showed that G473R and G501C mutants had better flexible and stable orientation in all trajectory analyses. Therefore, this work gives an extended understanding of both functional and structural levels of influence for the mutant form that leads to NCL disorder.
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Affiliation(s)
- Priyanka K
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, TamilNadu, 600116, India
| | - Priya N Madhana
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, TamilNadu, 600116, India
| | - Rajalakshmanan Eswaramoorthy
- Department of Prosthodontics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, TamilNadu, India
| | - Magesh Ramasamy
- Department of Biotechnology, Sri Ramachandra Institute of Higher Education and Research (DU), Porur, Chennai, TamilNadu, 600116, India.
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12
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Martínez-Rubio D, Hinarejos I, Argente-Escrig H, Marco-Marín C, Lozano MA, Gorría-Redondo N, Lupo V, Martí-Carrera I, Miranda C, Vázquez-López M, García-Pérez A, Marco-Hernández AV, Tomás-Vila M, Aguilera-Albesa S, Espinós C. Genetic Heterogeneity Underlying Phenotypes with Early-Onset Cerebellar Atrophy. Int J Mol Sci 2023; 24:16400. [PMID: 38003592 PMCID: PMC10671053 DOI: 10.3390/ijms242216400] [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: 09/14/2023] [Revised: 11/01/2023] [Accepted: 11/09/2023] [Indexed: 11/26/2023] Open
Abstract
Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.
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Affiliation(s)
- Dolores Martínez-Rubio
- Rare Neurodegenerative Diseases Laboratory, Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), 46012 València, Spain
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 València, Spain
| | - Isabel Hinarejos
- Rare Neurodegenerative Diseases Laboratory, Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), 46012 València, Spain
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 València, Spain
| | | | - Clara Marco-Marín
- Structural Enzymopathology Unit, Instituto de Biomedicina de Valencia (IBV), Consejo Superior de Investigaciones Científicas (CSIC), 46022 València, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain
| | - María Ana Lozano
- Rare Neurodegenerative Diseases Laboratory, Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), 46012 València, Spain
| | - Nerea Gorría-Redondo
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
| | - Vincenzo Lupo
- Rare Neurodegenerative Diseases Laboratory, Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), 46012 València, Spain
| | - Itxaso Martí-Carrera
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario Donostia, 20014 Donostia, Spain
| | - Concepción Miranda
- Paediatric Neurology Unit, Department of Paediatrics, Hospital General Universitario Gregorio Marañón, 28027 Madrid, Spain
| | - María Vázquez-López
- Paediatric Neurology Unit, Department of Paediatrics, Hospital General Universitario Gregorio Marañón, 28027 Madrid, Spain
| | - Asunción García-Pérez
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario Fundación Alcorcón, Alcorcón, 28922 Madrid, Spain
| | - Ana Victoria Marco-Hernández
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitari Doctor, Peset, 46017 València, Spain
| | - Miguel Tomás-Vila
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitari i Politècnic La Fe, 46026 València, Spain
| | - Sergio Aguilera-Albesa
- Paediatric Neurology Unit, Department of Paediatrics, Hospital Universitario de Navarra, Navarrabiomed, 31008 Pamplona, Spain
| | - Carmen Espinós
- Rare Neurodegenerative Diseases Laboratory, Valencia Biomedical Research Foundation, Centro de Investigación Príncipe Felipe (CIPF), 46012 València, Spain
- Joint Unit CIPF-IIS La Fe Rare Diseases, 46012 València, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain
- Biotechnology Department, Universitat Politècnica de València, 46022 València, Spain
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13
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Bernardi S, Gemignani F, Marchese M. The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis. Neurobiol Dis 2023; 185:106258. [PMID: 37573956 PMCID: PMC10480493 DOI: 10.1016/j.nbd.2023.106258] [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: 05/25/2023] [Revised: 08/01/2023] [Accepted: 08/11/2023] [Indexed: 08/15/2023] Open
Abstract
The progressive myoclonic epilepsies (PMEs) are a group of rare neurodegenerative diseases characterized by myoclonus, epileptic seizures, and progressive neurological deterioration with cerebellar involvement. They include storage diseases like Gaucher disease, Lafora disease, and forms of neuronal ceroid lipofuscinosis (NCL). To date, 13 NCLs have been reported (CLN1-CLN8, CLN10-CLN14), associated with mutations in different genes. These forms, which affect both children and adults, are characterized by seizures, cognitive and motor impairments, and in most cases visual loss. In NCLs, as in other PMEs, central nervous system (CNS) neurodegeneration is widespread and involves different subpopulations of neurons. One of the most affected regions is the cerebellar cortex, where motor and non-motor information is processed and transmitted to deep cerebellar nuclei through the axons of Purkinje cells (PCs). PCs, being GABAergic, have an inhibitory effect on their target neurons, and provide the only inhibitory output of the cerebellum. Degeneration of PCs has been linked to motor impairments and epileptic seizures. Seizures occur when some insult upsets the normal balance in the CNS between excitatory and inhibitory impulses, causing hyperexcitability. Here we review the role of PCs in epilepsy onset and progression following their PME-related loss. In particular, we focus on the involvement of PCs in seizure phenotype in NCLs, highlighting findings from case reports and studies of animal models in which epilepsy can be linked to PC loss.
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Affiliation(s)
- Sara Bernardi
- Department Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy; Department of Biology, University of Pisa, Pisa, Italy
| | | | - Maria Marchese
- Department Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.
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14
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Panjeshahi S, Karimzadeh P, Movafagh A, Ahmadabadi F, Rahimian E, Alijanpour S, Miryounesi M. Clinical and genetic characterization of neuronal ceroid lipofuscinoses (NCLs) in 29 Iranian patients: identification of 11 novel mutations. Hum Genet 2023; 142:1001-1016. [PMID: 37074398 DOI: 10.1007/s00439-023-02556-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 04/10/2023] [Indexed: 04/20/2023]
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative lysosomal storage diseases which are considered among the most frequent causes of dementia in childhood worldwide This study aimed to identify the gene variants, molecular etiologies, and clinical features in 23 unrelated Iranian families with NCL. In total, 29 patients with neuronal ceroid lipofuscinoses (NCLs), diagnosed based on clinical manifestations, MRI neuroimaging, and electroencephalography (EEG), were recruited for this study. Through whole-exome sequencing (WES), functional prediction, Sanger sequencing, and segregation analysis, we found that 12 patients (41.3%) with mutations in the CLN6 gene, 7 patients (24%) with the TPP1 (CLN2) gene variants, and 4 patients (13.7%) with mutations in the MFSD8 (CLN7) gene. Also, mutations in each of the CLN3 and CLN5 genes were detected in 2 cases and mutations of each PPT1 (CLN1) and CLN8 gene were observed in only 1 separate patient. We identified 18 different mutations, 11 (61%) of which are novel, never have been reported before, and the others have been previously described. The gene variants identified in this study expand the number of published clinical cases and the variant frequency spectrum of the neuronal ceroid lipofuscinoses (NCLs) genes; moreover, the identification of these variants supplies foundational clues for future NCL diagnosis and therapy.
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Affiliation(s)
- Samareh Panjeshahi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parvaneh Karimzadeh
- Pediatric Neurology Research Center, Pediatric Neurology Department, Mofid Children's Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Movafagh
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Ahmadabadi
- Pediatric Neurology Research Center, Pediatric Neurology Department, Mofid Children's Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Sahar Alijanpour
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Klein M, Hermey G. Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis? Neural Regen Res 2023; 18:1463-1471. [PMID: 36571343 PMCID: PMC10075119 DOI: 10.4103/1673-5374.361544] [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: 11/19/2022] Open
Abstract
Evidence from genetics and from analyzing cellular and animal models have converged to suggest links between neurodegenerative disorders of early and late life. Here, we summarize emerging links between the most common late life neurodegenerative disease, Alzheimer's disease, and the most common early life neurodegenerative diseases, neuronal ceroid lipofuscinoses. Genetic studies reported an overlap of clinically diagnosed Alzheimer's disease and mutations in genes known to cause neuronal ceroid lipofuscinoses. Accumulating data strongly suggest dysfunction of intracellular trafficking mechanisms and the autophagy-endolysosome system in both types of neurodegenerative disorders. This suggests shared cytopathological processes underlying these different types of neurodegenerative diseases. A better understanding of the common mechanisms underlying the different diseases is important as this might lead to the identification of novel targets for therapeutic concepts, the transfer of therapeutic strategies from one disease to the other and therapeutic approaches tailored to patients with specific mutations. Here, we review dysfunctions of the endolysosomal autophagy pathway in Alzheimer's disease and neuronal ceroid lipofuscinoses and summarize emerging etiologic and genetic overlaps.
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Affiliation(s)
- Marcel Klein
- Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Hermey
- Institute for Molecular and Cellular Cognition, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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16
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Placci M, Giannotti MI, Muro S. Polymer-based drug delivery systems under investigation for enzyme replacement and other therapies of lysosomal storage disorders. Adv Drug Deliv Rev 2023; 197:114683. [PMID: 36657645 PMCID: PMC10629597 DOI: 10.1016/j.addr.2022.114683] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/30/2022] [Accepted: 12/25/2022] [Indexed: 01/18/2023]
Abstract
Lysosomes play a central role in cellular homeostasis and alterations in this compartment associate with many diseases. The most studied example is that of lysosomal storage disorders (LSDs), a group of 60 + maladies due to genetic mutations affecting lysosomal components, mostly enzymes. This leads to aberrant intracellular storage of macromolecules, altering normal cell function and causing multiorgan syndromes, often fatal within the first years of life. Several treatment modalities are available for a dozen LSDs, mostly consisting of enzyme replacement therapy (ERT) strategies. Yet, poor biodistribution to main targets such as the central nervous system, musculoskeletal tissue, and others, as well as generation of blocking antibodies and adverse effects hinder effective LSD treatment. Drug delivery systems are being studied to surmount these obstacles, including polymeric constructs and nanoparticles that constitute the focus of this article. We provide an overview of the formulations being tested, the diseases they aim to treat, and the results observed from respective in vitro and in vivo studies. We also discuss the advantages and disadvantages of these strategies, the remaining gaps of knowledge regarding their performance, and important items to consider for their clinical translation. Overall, polymeric nanoconstructs hold considerable promise to advance treatment for LSDs.
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Affiliation(s)
- Marina Placci
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST), Barcelona 08028, Spain
| | - Marina I Giannotti
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST), Barcelona 08028, Spain; CIBER-BBN, ISCIII, Barcelona, Spain; Department of Materials Science and Physical Chemistry, University of Barcelona, Barcelona 08028, Spain
| | - Silvia Muro
- Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute for Science and Technology (BIST), Barcelona 08028, Spain; Institute of Catalonia for Research and Advanced Studies (ICREA), Barcelona 08010, Spain; Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD 20742, USA; Department of Chemical and Biomolecular Engineering, University of Maryland, College Park, MD 20742, USA.
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17
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Sakti DH, Cornish EE, Fraser CL, Nash BM, Sandercoe TM, Jones MM, Rowe NA, Jamieson RV, Johnson AM, Grigg JR. Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging. Doc Ophthalmol 2023; 146:241-256. [PMID: 36964447 PMCID: PMC10256658 DOI: 10.1007/s10633-023-09930-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 03/07/2023] [Indexed: 03/26/2023]
Abstract
BACKGROUND Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders with varying visual dysfunction. CLN3 is a subtype which commonly presents with visual decline. Visual symptomatology can be indistinct making early diagnosis difficult. This study reports ocular biomarkers of CLN3 patients to assist clinicians in early diagnosis, disease monitoring, and future therapy. METHODS Retrospective review of 5 confirmed CLN3 patients in our eye clinic. Best corrected visual acuity (BCVA), electroretinogram (ERG), ultra-widefield (UWF) fundus photography and fundus autofluorescence (FAF), and optical coherence tomography (OCT) studies were undertaken. RESULTS Five unrelated children, 4 females and 1 male, with median age of 6.2 years (4.6-11.7) at first assessment were investigated at the clinic from 2016 to 2021. Four homozygous and one heterozygous pathogenic CLN3 variants were found. Best corrected visual acuities (BCVAs) ranged from 0.18 to 0.88 logMAR at first presentation. Electronegative ERGs were identified in all patients. Bull's eye maculopathies found in all patients. Hyper-autofluorescence ring surrounding hypo-autofluorescence fovea on FAF was found. Foveal ellipsoid zone (EZ) disruptions were found in all patients with additional inner and outer retinal microcystic changes in one patient. Neurological problems noted included autism, anxiety, motor dyspraxia, behavioural issue, and psychomotor regression. CONCLUSIONS CLN3 patients presented at median age 6.2 years with visual decline. Early onset maculopathy with an electronegative ERG and variable cognitive and motor decline should prompt further investigations including neuropaediatric evaluation and genetic assessment for CLN3 disease. The structural parameters such as EZ and FAF will facilitate ocular monitoring.
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Affiliation(s)
- Dhimas H Sakti
- Save Sight Institute, Speciality of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney Eye Hospital Campus, 8 Macquarie St, Sydney, NSW, 2001, Australia
- Department of Ophthalmology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Elisa E Cornish
- Save Sight Institute, Speciality of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney Eye Hospital Campus, 8 Macquarie St, Sydney, NSW, 2001, Australia
- Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Clare L Fraser
- Save Sight Institute, Speciality of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney Eye Hospital Campus, 8 Macquarie St, Sydney, NSW, 2001, Australia
| | - Benjamin M Nash
- Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, The University of Sydney, Sydney, NSW, Australia
- Sydney Genome Diagnostics, Sydney Children's Hospital Network (Westmead), Sydney, Australia
| | - Trent M Sandercoe
- Department of Ophthalmology, Sydney Children's Hospital Network (Westmead), Sydney, Australia
| | - Michael M Jones
- Department of Ophthalmology, Sydney Children's Hospital Network (Westmead), Sydney, Australia
| | - Neil A Rowe
- Department of Ophthalmology, Sydney Children's Hospital Network (Westmead), Sydney, Australia
| | - Robyn V Jamieson
- Save Sight Institute, Speciality of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney Eye Hospital Campus, 8 Macquarie St, Sydney, NSW, 2001, Australia
- Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, The University of Sydney, Sydney, NSW, Australia
| | - Alexandra M Johnson
- Department of Neurology, Sydney Children's Hospital, University of New South Wales, Sydney, Australia
| | - John R Grigg
- Save Sight Institute, Speciality of Clinical Ophthalmology and Eye Health, Faculty of Medicine and Health, The University of Sydney, Sydney Eye Hospital Campus, 8 Macquarie St, Sydney, NSW, 2001, Australia.
- Eye Genetics Research Unit, The Children's Hospital at Westmead, Save Sight Institute, Children's Medical Research Institute, The University of Sydney, Sydney, NSW, Australia.
- Department of Ophthalmology, Sydney Children's Hospital Network (Westmead), Sydney, Australia.
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18
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Kolesnikova M, Lima de Carvalho JR, Oh JK, Soucy M, Demirkol A, Kim AH, Tsang SH, Breazzano MP. Phenotypic Variability of Retinal Disease Among a Cohort of Patients With Variants in the CLN Genes. Invest Ophthalmol Vis Sci 2023; 64:23. [PMID: 36912596 PMCID: PMC10019488 DOI: 10.1167/iovs.64.3.23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023] Open
Abstract
Purpose To describe the phenotype of CLN-associated retinal dystrophy in a subset of patients at the Columbia University Medical Center, United States, and the Hospital das Clínicas de Pernambuco, Brazil, in comparison to the published literature. Methods Eleven patients with confirmed biallelic variants in the CLN genes were evaluated via dilated fundus examination, clinical imaging, and full-field electroretinogram. A thorough literature search was conducted to determine previously published variants and associated phenotypes. Results Genetic testing confirmed the presence of variants in CLN3, CLN7/MFSD8, CLN8, and GRN/CLN11. Five novel variants were identified, and four novel phenotypes of previously published alleles were described. The phenotype differed among patients with variants in the same gene and sometimes among patients with the same allele. Conclusions Substantial phenotypic variability among variants in the CLN genes makes identification of genotype-phenotype or allele-phenotype correlations challenging. Further study is required to establish an extensive database for adequate patient counseling.
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Affiliation(s)
- Masha Kolesnikova
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, United States.,College of Medicine at the State University of New York at Downstate Medical Center, Brooklyn, New York, United States
| | - Jose Ronaldo Lima de Carvalho
- Department of Ophthalmology, Hospital das Clínicas de Pernambuco, Empresa Brasileira de Serviços Hospitalares, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - Jin Kyun Oh
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York-Presbyterian Hospital, New York, New York, United States
| | - Megan Soucy
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
| | - Aykut Demirkol
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, United States.,Usküdar University Vocational School of Health Services, Department of Opticianry, Istanbul, Turkey
| | - Angela H Kim
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, United States.,College of Medicine at the State University of New York at Downstate Medical Center, Brooklyn, New York, United States
| | - Stephen H Tsang
- Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, New York-Presbyterian Hospital, New York, New York, United States.,Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Medical Center, New York-Presbyterian Hospital, New York, New York, United States.,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, United States
| | - Mark P Breazzano
- Wilmer Eye Institute, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.,Retina-Vitreous Surgeons of Central New York, Liverpool, New York, United States.,Department of Ophthalmology & Visual Sciences, State University of New York Upstate Medical University, Syracuse, New York, United States
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19
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Sivananthan S, Lee L, Anderson G, Csanyi B, Williams R, Gissen P. Buffy Coat Score as a Biomarker of Treatment Response in Neuronal Ceroid Lipofuscinosis Type 2. Brain Sci 2023; 13:209. [PMID: 36831752 PMCID: PMC9954623 DOI: 10.3390/brainsci13020209] [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: 11/02/2022] [Revised: 01/19/2023] [Accepted: 01/22/2023] [Indexed: 01/28/2023] Open
Abstract
The introduction of intracerebroventricular (ICV) enzyme replacement therapy (ERT) for treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease has produced dramatic improvements in disease management. However, assessments of therapeutic effect for ICV ERT are limited to clinical observational measures, namely the CLN2 Clinical Rating Scale, a subjective measure of motor and language performance. There is a need for an objective biomarker to enable assessments of disease progression and response to treatment. To address this, we investigated whether the proportion of cells with abnormal storage inclusions on electron microscopic examination of peripheral blood buffy coats could act as a biomarker of disease activity in CLN2 disease. We conducted a prospective longitudinal analysis of six patients receiving ICV ERT. We demonstrated a substantial and continuing reduction in the proportion of abnormal cells over the course of treatment, whereas symptomatic scores revealed little or no change over time. Here, we proposed the use of the proportion of cells with abnormal storage as a biomarker of response to therapy in CLN2. In the future, as more tissue-specific biomarkers are developed, the buffy coats may form part of a panel of biomarkers in order to give a more holistic view of a complex disease.
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Affiliation(s)
- Siyamini Sivananthan
- Department of Inherited Metabolic Diseases, Great Ormond Street Hospital, London WC1N 1EH, UK
| | - Laura Lee
- Department of Inherited Metabolic Diseases, Great Ormond Street Hospital, London WC1N 1EH, UK
| | - Glenn Anderson
- Department of Inherited Metabolic Diseases, Great Ormond Street Hospital, London WC1N 1EH, UK
- Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
| | - Barbara Csanyi
- Department of Inherited Metabolic Diseases, Great Ormond Street Hospital, London WC1N 1EH, UK
| | - Ruth Williams
- Department of Children’s Neurosciences, Evelina London Children’s Hospital, London SE1 7EH, UK
| | - Paul Gissen
- Department of Inherited Metabolic Diseases, Great Ormond Street Hospital, London WC1N 1EH, UK
- Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London, London WC1N 1EH, UK
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20
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Linear Diagnostic Procedure Elicited by Clinical Genetics and Validated by mRNA Analysis in Neuronal Ceroid Lipofuscinosis 7 Associated with a Novel Non-Canonical Splice Site Variant in MFSD8. Genes (Basel) 2023; 14:genes14020245. [PMID: 36833170 PMCID: PMC9956376 DOI: 10.3390/genes14020245] [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: 12/09/2022] [Revised: 01/08/2023] [Accepted: 01/16/2023] [Indexed: 01/19/2023] Open
Abstract
Neuronal ceroid lipofuscinoses (CNL) are lysosomal storage diseases that represent the most common cause of dementia in children. To date, 13 autosomal recessive (AR) and 1 autosomal dominant (AD) gene have been characterized. Biallelic variants in MFSD8 cause CLN7 type, with nearly 50 pathogenic variants, mainly truncating and missense, reported so far. Splice site variants require functional validation. We detected a novel homozygous non-canonical splice-site variant in MFSD8 in a 5-year-old girl who presented with progressive neurocognitive impairment and microcephaly. The diagnostic procedure was elicited by clinical genetics first, and then confirmed by cDNA sequencing and brain imaging. Inferred by the common geographic origin of the parents, an autosomal recessive inheritance was hypothesized, and SNP-array was performed as the first-line genetic test. Only three AR genes lying within the observed 24 Mb regions of homozygosity were consistent with the clinical phenotype, including EXOSC9, SPATA5 and MFSD8. The cerebral and cerebellar atrophy detected in the meantime by MRI, along with the suspicion of accumulation of ceroid lipopigment in neurons, prompted us to perform targeted MFSD8 sequencing. Following the detection of a splice site variant of uncertain significance, skipping of exon 8 was demonstrated by cDNA sequencing, and the variant was redefined as pathogenic.
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21
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Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker. Neuroradiology 2022; 64:2059-2067. [PMID: 35699772 PMCID: PMC9474504 DOI: 10.1007/s00234-022-02988-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/25/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. METHODS One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. RESULTS The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r = - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r = - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r = - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p = < 0.0001). CONCLUSION Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies.
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22
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Jia W, Luo Y, Wang J, Yang Y, Yang W, Zhang X. Juvenile-Onset Kufs Disease in a Chinese Consanguineous Family due to CLN6 Mutation. NEURODEGENER DIS 2022; 21:126-131. [PMID: 35609511 DOI: 10.1159/000524784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/19/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To identify the genetic cause of two cases of Kufs disease in the same family. The two affected individuals exhibited different levels of severity under magnetic resonance imaging (MRI). METHODS Whole-exome sequencing was performed on affected individuals, and the candidate gene was confirmed by Sanger sequencing. Western blot analysis was used to evaluate the level of expression of CLN6 protein in 239T cells. RESULTS We identified a novel homozygous mutation of the CLN6 gene (c.14G>T, p.Arg5Leu) in a consanguineous Chinese family in which two people had Kufs disease. Both patients exhibited seizures and progressive psychomotor decline and mental deterioration without visual impairment. They had different ages of onset, although they carried the same missense mutation. The affected female showed pronounced abnormal MRI signal in the bilateral hippocampus while her younger brother only showed a very slight abnormal signal. Further study showed that this missense mutation could decrease the level of expression of CLN6 protein. CONCLUSIONS A novel homozygous mutation of the CLN6 gene was identified, and patients with the same mutation showed different ages of onset and different levels of severity under MRI. SIGNIFICANCE Our study established that the same CLN6 mutation could produce different phenotypes in patients, and it has expanded the mutational and phenotypical spectrum of the CLN6 gene.
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Affiliation(s)
- Weimin Jia
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Yalin Luo
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Jiuxiang Wang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Yue Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Wenming Yang
- Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Xianqin Zhang
- College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
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23
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Kaminiów K, Kozak S, Paprocka J. Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis. Int J Mol Sci 2022; 23:5729. [PMID: 35628533 PMCID: PMC9145894 DOI: 10.3390/ijms23105729] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/15/2022] [Accepted: 05/17/2022] [Indexed: 11/17/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. These genes encode a variety of proteins, whose functions have not been fully defined; most are lysosomal enzymes, transmembrane proteins of the lysosome, or other organelles. Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. Depending on the mutation, these symptoms can vary, with respect to the severity and onset of symptoms by age. Currently, all forms of NCL are fatal, and no curative treatments are available. Herein, we provide an overview to summarize the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis.
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Affiliation(s)
- Konrad Kaminiów
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.)
| | - Sylwia Kozak
- Students’ Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland; (K.K.); (S.K.)
| | - Justyna Paprocka
- Pediatric Neurology Department, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland
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24
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Rossini L, Durante C, Marzollo A, Biffi A. New Indications for Hematopoietic Stem Cell Gene Therapy in Lysosomal Storage Disorders. Front Oncol 2022; 12:885639. [PMID: 35646708 PMCID: PMC9136164 DOI: 10.3389/fonc.2022.885639] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/11/2022] [Indexed: 12/04/2022] Open
Abstract
Lysosomal storage disorders (LSDs) are a heterogenous group of disorders due to genetically determined deficits of lysosomal enzymes. The specific molecular mechanism and disease phenotype depends on the type of storage material. Several disorders affect the brain resulting in severe clinical manifestations that substantially impact the expectancy and quality of life. Current treatment modalities for LSDs include enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) from allogeneic healthy donors, but are available for a limited number of disorders and lack efficacy on several clinical manifestations. Hematopoietic stem cell gene therapy (HSC GT) based on integrating lentiviral vectors resulted in robust clinical benefit when administered to patients affected by Metachromatic Leukodystrophy, for whom it is now available as a registered medicinal product. More recently, HSC GT has also shown promising results in Hurler syndrome patients. Here, we discuss possible novel HSC GT indications that are currently under development. If these novel drugs will prove effective, they might represent a new standard of care for these disorders, but several challenges will need to be addresses, including defining and possibly expanding the patient population for whom HSC GT could be efficacious.
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Affiliation(s)
- Linda Rossini
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
| | - Caterina Durante
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
| | - Antonio Marzollo
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
- Fondazione Citta’ della Speranza, Istituto di Ricerca Pediatrica, Padua, Italy
| | - Alessandra Biffi
- Pediatric Hematology, Oncology and Stem Cell Transplant Division, Padua University Hospital, Padua, Italy
- Maternal and Child Health Department, Padua University, Padua, Italy
- *Correspondence: Alessandra Biffi,
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25
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Rus CM, Weissensteiner T, Pereira C, Susnea I, Danquah BD, Morales Torres G, Rocha ME, Cozma C, Saravanakumar D, Mannepalli S, Kandaswamy KK, Di Bucchianico S, Zimmermann R, Rolfs A, Bauer P, Beetz C. Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center. Orphanet J Rare Dis 2022; 17:179. [PMID: 35505348 PMCID: PMC9066917 DOI: 10.1186/s13023-022-02288-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 03/14/2022] [Indexed: 11/29/2022] Open
Abstract
Background Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.
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Affiliation(s)
- Corina-Marcela Rus
- Centogene GmbH, Am Strande 7, 18057, Rostock, Germany. .,Institute of Chemistry, University of Rostock, Dr.-Lorenz-Weg 2, 18059, Rostock, Germany.
| | | | | | | | | | | | | | - Claudia Cozma
- Centogene GmbH, Am Strande 7, 18057, Rostock, Germany
| | | | | | | | | | - Ralf Zimmermann
- Institute of Chemistry, University of Rostock, Dr.-Lorenz-Weg 2, 18059, Rostock, Germany.,Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany
| | - Arndt Rolfs
- Centogene GmbH, Am Strande 7, 18057, Rostock, Germany.,Arcensus GmbH, Goethestrasse 20, 18055, Rostock, Germany
| | - Peter Bauer
- Centogene GmbH, Am Strande 7, 18057, Rostock, Germany.,Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, University of Rostock, Rostock, Germany
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Poncet AF, Grunewald O, Vaclavik V, Meunier I, Drumare I, Pelletier V, Bocquet B, Todorova MG, Le Moing AG, Devos A, Schorderet DF, Jobic F, Defoort-Dhellemmes S, Dollfus H, Smirnov VM, Dhaenens CM. Contribution of Whole-Genome Sequencing and Transcript Analysis to Decipher Retinal Diseases Associated with MFSD8 Variants. Int J Mol Sci 2022; 23:ijms23084294. [PMID: 35457110 PMCID: PMC9032189 DOI: 10.3390/ijms23084294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/25/2022] [Accepted: 04/11/2022] [Indexed: 01/01/2023] Open
Abstract
Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients’ lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.
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Affiliation(s)
- Anaïs F. Poncet
- Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France; (A.F.P.); (O.G.); (A.D.)
| | - Olivier Grunewald
- Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France; (A.F.P.); (O.G.); (A.D.)
| | - Veronika Vaclavik
- University of Lausanne, Jules-Gonin Eye Hospital, 1004 Lausanne, Switzerland;
- Cantonal Hospital, Department of Ophthalmology, 1700 Fribourg, Switzerland
| | - Isabelle Meunier
- National Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, F-34000 Montpellier, France; (I.M.); (B.B.)
- Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, F-34000 Montpellier, France
| | - Isabelle Drumare
- Exploration de la Vision et Neuro-Ophtalmology, CHU de Lille, F-59000 Lille, France; (I.D.); (S.D.-D.); (V.M.S.)
| | - Valérie Pelletier
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologiques, Hopitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; (V.P.); (H.D.)
| | - Béatrice Bocquet
- National Reference Centre for Inherited Sensory Diseases, University of Montpellier, Montpellier University Hospital, Sensgene Care Network, ERN-EYE Network, F-34000 Montpellier, France; (I.M.); (B.B.)
- Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, F-34000 Montpellier, France
| | - Margarita G. Todorova
- Department of Ophthalmology, Cantonal Hospital, 9007 St. Gallen, Switzerland;
- Department of Ophthalmology, University of Zürich, 8091 Zürich, Switzerland
- Department of Ophthalmology, University of Basel, 4056 Basel, Switzerland
| | - Anne-Gaëlle Le Moing
- Department of Child Neurology, Amiens-Picardy University Hospital, F-80000 Amiens, France;
| | - Aurore Devos
- Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France; (A.F.P.); (O.G.); (A.D.)
| | - Daniel F. Schorderet
- Faculty of Biology and Medicine, University of Lausanne and Faculty of Life Sciences, Ecole Polytechnique Fédérale of Lausanne, 1004 Lausanne, Switzerland;
| | - Florence Jobic
- Unité de Génétique Médicale et Oncogénétique, Centre Hospitalier Universitaire Amiens Picardie, F-80000 Amiens, France;
| | - Sabine Defoort-Dhellemmes
- Exploration de la Vision et Neuro-Ophtalmology, CHU de Lille, F-59000 Lille, France; (I.D.); (S.D.-D.); (V.M.S.)
| | - Hélène Dollfus
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologiques, Hopitaux Universitaires de Strasbourg, F-67000 Strasbourg, France; (V.P.); (H.D.)
| | - Vasily M. Smirnov
- Exploration de la Vision et Neuro-Ophtalmology, CHU de Lille, F-59000 Lille, France; (I.D.); (S.D.-D.); (V.M.S.)
- Université de Lille, Faculté de Médecine, F-59000 Lille, France
| | - Claire-Marie Dhaenens
- Univ. Lille, Inserm, CHU Lille, U1172-LilNCog-Lille Neuroscience & Cognition, F-59000 Lille, France; (A.F.P.); (O.G.); (A.D.)
- Correspondence: ; Tel.: +33-320444953
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27
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Simonati A, Williams RE. Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview. Front Neurol 2022; 13:811686. [PMID: 35359645 PMCID: PMC8961688 DOI: 10.3389/fneur.2022.811686] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/11/2022] [Indexed: 01/04/2023] Open
Abstract
The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.
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Affiliation(s)
- Alessandro Simonati
- Departments of Surgery, Dentistry, Paediatrics, and Gynaecology, School of Medicine, University of Verona, Verona, Italy
- Department of Clinical Neuroscience, AOUI-VR, Verona, Italy
- *Correspondence: Alessandro Simonati
| | - Ruth E. Williams
- Department of Children's Neuroscience, Evelina London Children's Hospital, London, United Kingdom
- Ruth E. Williams
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Nickel M, Schulz A. Natural History Studies in NCL and Their Expanding Role in Drug Development: Experiences From CLN2 Disease and Relevance for Clinical Trials. Front Neurol 2022; 13:785841. [PMID: 35211079 PMCID: PMC8861081 DOI: 10.3389/fneur.2022.785841] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/10/2022] [Indexed: 11/18/2022] Open
Abstract
Conducting clinical trials in rare diseases is challenging. In trials that aim to use natural history control cohorts for evaluation of efficacy, lack of data on natural history of disease prolongs development of future therapies significantly. Therefore, collection of valid natural history data in clinical settings is needed to advance drug development. These data need to fulfill requirements on type of collection, quantifiable measures on the course of disease, verification and monitoring as well as compliance to strict data protection and sharing policies. Disease registries can be a source for patient data. Late-infantile CLN2 disease is characterized by rapid psychomotor decline and epilepsy. Natural-history data of 140 genotype-confirmed CLN2 patients from two independent, international cohorts were analyzed in a natural history study. Both datasets included quantitative ratings with disease-specific clinical scores. Among 41 patients for whom longitudinal assessments spanning an extended disease course were available within the DEM-CHILD DB (an international NCL disease patient database, NCT04613089), a rapid loss of motor and language abilities was documented in quantitative detail. Data showed that the course of disease in late-infantile CLN2 disease is highly predictable with regard to the loss of language and motor function and that the results were homogeneous across multiple and international sites. These data were accepted by EMA and FDA as valid natural-history controls for the evaluation of efficacy in experimental therapies for CLN2 disease and led to an expedited approval of intracerebroventricular enzyme replacement therapy with cerliponase alpha in May 2017.
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Affiliation(s)
- Miriam Nickel
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Angela Schulz
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Qiao Y, Gu Y, Cheng Y, Su Y, Lv N, Shang Q, Xing Q. Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7. Front Genet 2022; 13:807515. [PMID: 35154277 PMCID: PMC8826235 DOI: 10.3389/fgene.2022.807515] [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: 11/02/2021] [Accepted: 01/06/2022] [Indexed: 11/24/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are among the most common progressive encephalopathies of childhood. Neuronal ceroid lipofuscinosis 7 (CLN7), one of the late infantile-onset NCLs, is an autosomal recessive disorder caused by mutations in the MFSD8 gene on chromosome 4q28. Almost all reported mutations of MFSD8 in CLN7 patients were SNVs. However, we report a 4-year-old boy with CLN7 harboring compound heterozygous mutations in the MFSD8 gene, including one novel two-nucleotide deletion c.136_137delAT (p. M46Vfs*22) and one whole gene deletion of MFSD8 confirmed by Sanger sequencing, genomic quantitative PCR and CNV-seq. Therefore, for nonconsanguineous CLN7 patients with homozygous mutations in the MFSD8 gene, genetic counseling staff should focus on the possibility of whole gene deletion. This is one case report describing a whole gene deletion in a Chinese patient with CLN7, suggesting the diagnosis of CLN7 should be based on clinical suspicion and genetic testing.
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Affiliation(s)
- Yimeng Qiao
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Yang Gu
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Ye Cheng
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Yu Su
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Nan Lv
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Qing Shang
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Qinghe Xing
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China.,Shanghai Center for Women and Children's Health, Shanghai, China
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30
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Pavan M, Bassani D, Bolcato G, Bissaro M, Sturles M, Moro S. Computational strategies to identify new drug candidates against neuroinflammation. Curr Med Chem 2022; 29:4756-4775. [PMID: 35135446 DOI: 10.2174/0929867329666220208095122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/09/2021] [Accepted: 12/13/2021] [Indexed: 11/22/2022]
Abstract
The even more increasing application of computational approaches in these last decades has deeply modified the process of discovery and commercialization of new therapeutic entities. This is especially true in the field of neuroinflammation, in which both the peculiar anatomical localization and the presence of the blood-brain barrier makeit mandatory to finely tune the candidates' physicochemical properties from the early stages of the discovery pipeline. The aim of this review is therefore to provide a general overview to the readers about the topic of neuroinflammation, together with the most common computational strategies that can be exploited to discover and design small molecules controlling neuroinflammation, especially those based on the knowledge of the three-dimensional structure of the biological targets of therapeutic interest. The techniques used to describe the molecular recognition mechanisms, such as molecular docking and molecular dynamics, will therefore be eviscerated, highlighting their advantages and their limitations. Finally, we report several case studies in which computational methods have been applied in drug discovery on neuroinflammation, focusing on the last decade's research.
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Affiliation(s)
- Matteo Pavan
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Davide Bassani
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Giovanni Bolcato
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Maicol Bissaro
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Mattia Sturles
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
| | - Stefano Moro
- Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences University of Padova, via Marzolo 5, 35131 Padova, Italy
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Guelbert G, Guelbert N. Neuronal Ceroid Lipofuscinosis Type 2: A Case Series from Argentina. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2022. [DOI: 10.1590/2326-4594-jiems-2022-0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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Gardner E, Mole SE. The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses. Front Neurol 2021; 12:754045. [PMID: 34733232 PMCID: PMC8558747 DOI: 10.3389/fneur.2021.754045] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.
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Affiliation(s)
- Emily Gardner
- MRC Laboratory for Molecular Cell Biology and Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Sara E Mole
- MRC Laboratory for Molecular Cell Biology and Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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Soldati C, Lopez‐Fabuel I, Wanderlingh LG, Garcia‐Macia M, Monfregola J, Esposito A, Napolitano G, Guevara‐Ferrer M, Scotto Rosato A, Krogsaeter EK, Paquet D, Grimm CM, Montefusco S, Braulke T, Storch S, Mole SE, De Matteis MA, Ballabio A, Sampaio JL, McKay T, Johannes L, Bolaños JP, Medina DL. Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype. EMBO Mol Med 2021; 13:e13742. [PMID: 34411438 PMCID: PMC8495452 DOI: 10.15252/emmm.202013742] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [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: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 11/30/2022] Open
Abstract
Batten diseases (BDs) are a group of lysosomal storage disorders characterized by seizure, visual loss, and cognitive and motor deterioration. We discovered increased levels of globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 diseases and used fluorescent-conjugated bacterial toxins to label Gb3 to develop a cell-based high content imaging (HCI) screening assay for the repurposing of FDA-approved compounds able to reduce this accumulation within BD cells. We found that tamoxifen reduced the lysosomal accumulation of Gb3 in CLN3 and CLN7 cell models, including neuronal progenitor cells (NPCs) from CLN7 patient-derived induced pluripotent stem cells (iPSC). Here, tamoxifen exerts its action through a mechanism that involves activation of the transcription factor EB (TFEB), a master gene of lysosomal function and autophagy. In vivo administration of tamoxifen to the CLN7Δex2 mouse model reduced the accumulation of Gb3 and SCMAS, decreased neuroinflammation, and improved motor coordination. These data strongly suggest that tamoxifen may be a suitable drug to treat some types of Batten disease.
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Affiliation(s)
- Chiara Soldati
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
| | - Irene Lopez‐Fabuel
- Institute of Functional Biology and GenomicsCSICUniversity of SalamancaSalamancaSpain
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES)Instituto de Salud Carlos IIIMadridSpain
- Institute of Biomedical Research of SalamancaUniversity Hospital of SalamancaCSICUniversity of SalamancaSalamancaSpain
| | - Luca G Wanderlingh
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
| | - Marina Garcia‐Macia
- Institute of Functional Biology and GenomicsCSICUniversity of SalamancaSalamancaSpain
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES)Instituto de Salud Carlos IIIMadridSpain
- Institute of Biomedical Research of SalamancaUniversity Hospital of SalamancaCSICUniversity of SalamancaSalamancaSpain
| | - Jlenia Monfregola
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
| | | | - Gennaro Napolitano
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
- Medical Genetics UnitDepartment of Medical and Translational ScienceFederico II UniversityNaplesItaly
| | | | - Anna Scotto Rosato
- Faculty of MedicineWalther Straub Institute of Pharmacology and ToxicologyLudwig‐Maximilians UniversityMunichGermany
| | - Einar K Krogsaeter
- Faculty of MedicineWalther Straub Institute of Pharmacology and ToxicologyLudwig‐Maximilians UniversityMunichGermany
| | - Dominik Paquet
- Institute for Stroke and Dementia Research (ISD)University HospitalLMU MunichMunichGermany
- Munich Cluster for Systems Neurology (SyNergy)MunichGermany
| | - Christian M Grimm
- Faculty of MedicineWalther Straub Institute of Pharmacology and ToxicologyLudwig‐Maximilians UniversityMunichGermany
| | - Sandro Montefusco
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
| | - Thomas Braulke
- Department Osteology & BiomechanicsUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Stephan Storch
- University Children's Research@Kinder‐UKEUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Sara E Mole
- Medical Research Council Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child HealthUniversity College LondonLondonUK
| | - Maria A De Matteis
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
- Department of Molecular Medicine and Medical BiotechnologyUniversity of Napoli Federico IINaplesItaly
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
- Medical Genetics UnitDepartment of Medical and Translational ScienceFederico II UniversityNaplesItaly
- Baylor College of MedicineHoustonTXUSA
- Jan and Dan Duncan Neurological Research InstituteTexas Children's HospitalHoustonTXUSA
| | - Julio L Sampaio
- Cellular and Chemical Biology DepartmentInstitut Curie, U1143 INSERM, UMR3666 CNRSPSL Research UniversityParisFrance
| | - Tristan McKay
- School of Healthcare ScienceManchester Metropolitan UniversityManchesterUK
| | - Ludger Johannes
- Cellular and Chemical Biology DepartmentInstitut Curie, U1143 INSERM, UMR3666 CNRSPSL Research UniversityParisFrance
| | - Juan P Bolaños
- Institute of Functional Biology and GenomicsCSICUniversity of SalamancaSalamancaSpain
- Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES)Instituto de Salud Carlos IIIMadridSpain
- Institute of Biomedical Research of SalamancaUniversity Hospital of SalamancaCSICUniversity of SalamancaSalamancaSpain
| | - Diego L Medina
- Telethon Institute of Genetics and Medicine (TIGEM), PozzuoliNaplesItaly
- Medical Genetics UnitDepartment of Medical and Translational ScienceFederico II UniversityNaplesItaly
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Unraveling neuronal ceroid lipofuscinosis type 2 (CLN2) disease: A tertiary center experience for determinants of diagnostic delay. Eur J Paediatr Neurol 2021; 33:94-98. [PMID: 34119739 DOI: 10.1016/j.ejpn.2021.05.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/27/2021] [Accepted: 05/30/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To evaluate the clinical phenotype, disease course, laboratory, and genetic features of patients with CLN2 disease over a 20 year period with a special emphasis on risk factors for diagnostic delay. METHODS Thirty patients (23 families) with CLN2 disease, evaluated between 1996 and 2019 in a tertiary referral center in Turkey, were included. Clinical features, diagnostic pathway, disease course, genetic data, electrophysiological, and neuroimaging findings were analyzed, retrospectively. The patients diagnosed between 1996 and 2009, and 2010-2019 were defined as group 1 (G1), and group 2 (G2), respectively. Patients in these two groups were also compared. RESULTS The median age at symptom-onset was 36 months (20 months-7 years). Most common presenting symptoms were seizures (70%), followed by language delay (43%), and psychomotor regression (27%). Median age at diagnosis was 5.2 years (1.6-11 years) with a median 27 months (1 month-7 years) of diagnostic delay. Age at diagnosis was earlier in G2 (4.6 years vs 7 years, p = 0.002), with a shorter time to diagnosis (21 months vs 39 months, p = 0.004). Median time between the onset of first symptoms and death was 8.3 years (SE 1.0). Electroencephalograms (EEG) revealed abnormal features predominantly in posterior hemispheral regions and a photoparoxysmal response to intermittent photic stimulation was detected in 53% of the patients. Cerebellar (96%)/cerebral atrophy (83%), and white matter changes (57%) were the most common radiological abnormalities. CONCLUSIONS Most of our patients presented with late-infantile onset seizures. Despite increased availability of enzymatic and molecular testing, there is still a considerable diagnostic delay.
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Murray SJ, Russell KN, Melzer TR, Gray SJ, Heap SJ, Palmer DN, Mitchell NL. Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease. Exp Eye Res 2021; 207:108600. [PMID: 33930398 DOI: 10.1016/j.exer.2021.108600] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 04/12/2021] [Accepted: 04/21/2021] [Indexed: 01/01/2023]
Abstract
Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5-/- or CLN6-/- animals, respectively. Electroretinography (ERG) was performed every month following treatment, and retinal histology was assessed post-mortem in the treated compared to untreated eye. In CLN5-/- animals, ERG amplitudes were normalised in the treated eye whilst the untreated eye declined in a similar manner to CLN5 affected controls. In CLN6-/- animals, ERG amplitudes in both eyes declined over time although the treated eye showed a slower decline. Post-mortem examination revealed significant attenuation of retinal atrophy and lysosomal storage body accumulation in the treated eye compared with the untreated eye in CLN5-/- animals. This proof-of-concept study provides the first observation of efficacious intravitreal gene therapy in a large animal model of NCL. In particular, the single administration of AAV9-mediated intravitreal gene therapy can successfully ameliorate retinal deficits in CLN5-/- sheep. Combining ocular gene therapy with brain-directed therapy presents a promising treatment strategy to be used in future sheep trials aiming to halt neurological and retinal disease in CLN5 Batten disease.
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Affiliation(s)
- Samantha J Murray
- Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln, 7647, New Zealand
| | - Katharina N Russell
- Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln, 7647, New Zealand
| | - Tracy R Melzer
- Department of Medicine, University of Otago, Christchurch and the New Zealand Brain Research Institute, Christchurch, 8011, New Zealand
| | - Steven J Gray
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Stephen J Heap
- McMaster & Heap Veterinary Practice, Christchurch, 8025, New Zealand
| | - David N Palmer
- Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln, 7647, New Zealand; Department of Radiology, University of Otago, Christchurch, 8140, New Zealand
| | - Nadia L Mitchell
- Faculty of Agricultural and Life Sciences, Lincoln University, Lincoln, 7647, New Zealand; Department of Radiology, University of Otago, Christchurch, 8140, New Zealand.
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Schaefers J, van der Giessen LJ, Klees C, Jacobs EH, Sieverdink S, Dremmen MHG, Spoor JKH, van der Ploeg AT, van den Hout JMP, Huidekoper HH. Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa. Orphanet J Rare Dis 2021; 16:221. [PMID: 33990214 PMCID: PMC8120778 DOI: 10.1186/s13023-021-01858-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/06/2021] [Indexed: 11/30/2022] Open
Abstract
Background Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. Results We evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment). Conclusion We show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.
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Affiliation(s)
- J Schaefers
- Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - L J van der Giessen
- Department of Pediatric Physiotherapy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - C Klees
- Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - E H Jacobs
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - S Sieverdink
- Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - M H G Dremmen
- Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - J K H Spoor
- Department of Pediatric Neurosurgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - A T van der Ploeg
- Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - J M P van den Hout
- Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - H H Huidekoper
- Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
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Zhang X, Zhang D, Thompson JA, Chen SC, Huang Z, Jennings L, McLaren TL, Lamey TM, De Roach JN, Chen FK, McLenachan S. Gene correction of the CLN3 c.175G>A variant in patient-derived induced pluripotent stem cells prevents pathological changes in retinal organoids. Mol Genet Genomic Med 2021; 9:e1601. [PMID: 33497524 PMCID: PMC8104174 DOI: 10.1002/mgg3.1601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/28/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
Background Mutations in CLN3 cause Batten disease, however non‐syndromic CLN3 disease, characterized by retinal‐specific degeneration, has been also described. Here, we characterized an induced pluripotent stem cell (iPSC)‐derived disease model derived from a patient with non‐syndromic CLN3‐associated retinopathy. Methods Patient‐iPSC, carrying the 1 kb‐deletion and c.175G>A variants in CLN3, coisogenic iPSC, in which the c.175G>A variant was corrected, and control iPSC were differentiated into neural retinal organoids (NRO) and cardiomyocytes. CLN3 transcripts were analyzed by Sanger sequencing. Gene expression was characterized by qPCR and western blotting. NRO were characterized by immunostaining and electron microscopy. Results Novel CLN3 transcripts were detected in adult human retina and control‐NRO. The major transcript detected in patient‐NRO displayed skipping of exons 2 and 4–9. Accumulation of subunit‐C of mitochondrial ATPase (SCMAS) protein was demonstrated in patient‐derived cells. Photoreceptor progenitor cells in patient‐NRO displayed accumulation of peroxisomes and vacuolization of inner segments. Correction of the c.175G>A variant restored CLN3 mRNA and protein expression and prevented SCMAS and inner segment vacuolization. Conclusion Our results demonstrate the expression of novel CLN3 transcripts in human retinal tissues. The c.175G>A variant alters splicing of the CLN3 pre‐mRNA, leading to features consistent with CLN3 deficiency, which were prevented by gene correction.
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Affiliation(s)
- Xiao Zhang
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
| | - Dan Zhang
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
| | - Jennifer A Thompson
- Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Shang-Chih Chen
- Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
| | - Zhiqin Huang
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
| | - Luke Jennings
- Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
| | - Terri L McLaren
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Tina M Lamey
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - John N De Roach
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia
| | - Fred K Chen
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia.,Australian Inherited Retinal Disease Registry and DNA Bank, Department of Medical Technology and Physics, Sir Charles Gairdner Hospital, Perth, WA, Australia.,Department of Ophthalmology, Royal Perth Hospital, Perth, WA, Australia.,Department of Ophthalmology, Perth Children's Hospital, Nedlands, WA, Australia
| | - Samuel McLenachan
- Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia.,Ocular Tissue Engineering Laboratory, Lions Eye Institute, Perth, WA, Australia
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38
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Abstract
Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.
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Shematorova EK, Shpakovski GV. Current Insights in Elucidation of Possible Molecular Mechanisms of the Juvenile Form of Batten Disease. Int J Mol Sci 2020; 21:ijms21218055. [PMID: 33137890 PMCID: PMC7663513 DOI: 10.3390/ijms21218055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/21/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022] Open
Abstract
The neuronal ceroid lipofuscinoses (NCLs) collectively constitute one of the most common forms of inherited childhood-onset neurodegenerative disorders. They form a heterogeneous group of incurable lysosomal storage diseases that lead to blindness, motor deterioration, epilepsy, and dementia. Traditionally the NCL diseases were classified according to the age of disease onset (infantile, late-infantile, juvenile, and adult forms), with at least 13 different NCL varieties having been described at present. The current review focuses on classic juvenile NCL (JNCL) or the so-called Batten (Batten-Spielmeyer-Vogt; Spielmeyer-Sjogren) disease, which represents the most common and the most studied form of NCL, and is caused by mutations in the CLN3 gene located on human chromosome 16. Most JNCL patients carry the same 1.02-kb deletion in this gene, encoding an unusual transmembrane protein, CLN3, or battenin. Accordingly, the names CLN3-related neuronal ceroid lipofuscinosis or CLN3-disease sometimes have been used for this malady. Despite excessive in vitro and in vivo studies, the precise functions of the CLN3 protein and the JNCL disease mechanisms remain elusive and are the main subject of this review. Although the CLN3 gene is highly conserved in evolution of all mammalian species, detailed analysis of recent genomic and transcriptomic data indicates the presence of human-specific features of its expression, which are also under discussion. The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.
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Affiliation(s)
- Elena K. Shematorova
- Laboratory of Mechanisms of Gene Expression, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia;
- National Research Center “Kurchatov Institute”, 1, Academika Kurchatova pl., 123182 Moscow, Russia
| | - George V. Shpakovski
- Laboratory of Mechanisms of Gene Expression, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, 117997 Moscow, Russia;
- National Research Center “Kurchatov Institute”, 1, Academika Kurchatova pl., 123182 Moscow, Russia
- Correspondence: ; Tel.: +7-(495)-330-4953; Fax: +7-(495)-335-7103
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Butz ES, Chandrachud U, Mole SE, Cotman SL. Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165571. [DOI: 10.1016/j.bbadis.2019.165571] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/12/2019] [Accepted: 10/14/2019] [Indexed: 12/15/2022]
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Katz ML, Buckley RM, Biegen V, O'Brien DP, Johnson GC, Warren WC, Lyons LA. Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6. G3 (BETHESDA, MD.) 2020; 10:2741-2751. [PMID: 32518081 PMCID: PMC7407459 DOI: 10.1534/g3.120.401407] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 06/06/2020] [Indexed: 01/04/2023]
Abstract
A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat's clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat's disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.
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Affiliation(s)
- Martin L Katz
- Neurodegenerative Diseases Research Laboratory and Department of Ophthalmology,
| | | | | | | | | | - Wesley C Warren
- Life Sciences Center, University of Missouri, Columbia, MO and
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Gowda VK, Vegda H, Sugumar K, Narayanappa G, Srinivasan VM, Santhoshkumar R, Bhat M, Balu S, Naveen MR. Neuronal Ceroid Lipofuscinosis: Clinical and Laboratory Profile in Children from Tertiary Care Centre in South India. J Pediatr Genet 2020; 10:266-273. [PMID: 34849271 DOI: 10.1055/s-0040-1715575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 07/08/2020] [Indexed: 10/23/2022]
Abstract
Neuronal ceroid Lipofuscinosis (NCL), inherited disorders of lysosomal storage disorders, constitute the most common progressive encephalopathies with an incidence of 1.3 to 7 in 100,000 live births. We reported clinical, electrophysiological, radiological, ultrastructural, and molecular genetic features of NCL. This is a retrospective review, in a tertiary care center from January 2016 to December 2019. All children with clinical features of NCL and confirmed by pathogenic mutation and/or enzyme assay were included. A total of 60 children (male:female = 3:1) were studied. The commonest type was CLN 2 (41.7%). Neuroregression, seizures, and ataxia were present in all cases. Retinal arterial attenuation was seen in 38.33% cases. Magnetic resonance imaging (MRI) brain was abnormal in all patients, thalamic and caudate nucleus atrophy common in CLN1 (62%). Electroencephalography was abnormal in all children, but photoparoxysmal response at low intermittent photic stimulation frequencies was seen in four children of CLN2. Electron microscopy done in 43 children revealed abnormal inclusions in 20 (46.52%) children. Enzyme study showed low levels in 36 (78%) out of 46 cases. Of these, 21 had low tripeptidyl peptidase and 15 had low palmitoyl protein thioesterase levels. Molecular testing done in 26 cases showed pathogenic variant in 23 (88%) cases. Infantile onset with thalamic atrophy on MRI is common in CLN1 and refractory epilepsy, visual impairment and specific EEG changes are common in CLN2. These features are helpful in selecting enzyme assay for CLN1 versus CLN2. Electron microscopy helped in the diagnosis and genetic testing in subtyping. Thus, a multimode approach played a role in the diagnosis of NCL.
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Affiliation(s)
- Vykuntaraju K Gowda
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Hemadri Vegda
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Kiruthiga Sugumar
- Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, India
| | - Gayathri Narayanappa
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | | | - Rashmi Santhoshkumar
- Electron Microscope Laboratory, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Maya Bhat
- Department of Neuroradiology, National institute of Mental Health and Neurosciences, Bangalore, India
| | - Sam Balu
- Molecular Genetics Department, Eurofins Clinical Genetics, Bangalore, India
| | - Mohan Rao Naveen
- Molecular Genetics Department, Eurofins Clinical Genetics, Bangalore, India
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Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, Roman D, Collette JR, Booth C, Chang KT, Sifers RN, Jung SY, Weimer JM, Chen R, Schekman RW, Sardiello M. A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer. J Clin Invest 2020; 130:4118-4132. [PMID: 32597833 PMCID: PMC7410054 DOI: 10.1172/jci130955] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 05/05/2020] [Indexed: 12/18/2022] Open
Abstract
Lysosomal enzymes are synthesized in the endoplasmic reticulum (ER) and transferred to the Golgi complex by interaction with the Batten disease protein CLN8 (ceroid lipofuscinosis, neuronal, 8). Here we investigated the relationship of this pathway with CLN6, an ER-associated protein of unknown function that is defective in a different Batten disease subtype. Experiments focused on protein interaction and trafficking identified CLN6 as an obligate component of a CLN6-CLN8 complex (herein referred to as EGRESS: ER-to-Golgi relaying of enzymes of the lysosomal system), which recruits lysosomal enzymes at the ER to promote their Golgi transfer. Mutagenesis experiments showed that the second luminal loop of CLN6 is required for the interaction of CLN6 with the enzymes but dispensable for interaction with CLN8. In vitro and in vivo studies showed that CLN6 deficiency results in inefficient ER export of lysosomal enzymes and diminished levels of the enzymes at the lysosome. Mice lacking both CLN6 and CLN8 did not display aggravated pathology compared with the single deficiencies, indicating that the EGRESS complex works as a functional unit. These results identify CLN6 and the EGRESS complex as key players in lysosome biogenesis and shed light on the molecular etiology of Batten disease caused by defects in CLN6.
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Affiliation(s)
- Lakshya Bajaj
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
| | - Jaiprakash Sharma
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
| | - Alberto di Ronza
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
| | - Pengcheng Zhang
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA
| | - Aiden Eblimit
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Rituraj Pal
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
| | - Dany Roman
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
| | - John R. Collette
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
| | - Clarissa Booth
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA
| | - Kevin T. Chang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
| | - Richard N. Sifers
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA
| | - Sung Y. Jung
- Department of Biochemistry and Molecular Biology
| | - Jill M. Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, South Dakota, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, South Dakota, USA
| | - Rui Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Human Genome Sequencing Center, and
- Department of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA
| | - Randy W. Schekman
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA
- Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, California, USA
| | - Marco Sardiello
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, Texas, USA
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Langin L, Johnson TB, Kovács AD, Pearce DA, Weimer JM. A tailored Cln3 Q352X mouse model for testing therapeutic interventions in CLN3 Batten disease. Sci Rep 2020; 10:10591. [PMID: 32601357 PMCID: PMC7324379 DOI: 10.1038/s41598-020-67478-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/29/2020] [Indexed: 12/16/2022] Open
Abstract
CLN3 Batten disease (CLN3 disease) is a pediatric lysosomal storage disorder that presents with progressive blindness, motor and cognitive decline, seizures, and premature death. CLN3 disease results from mutations in CLN3 with the most prevalent mutation, a 966 bp deletion spanning exons 7-8, affecting ~ 75% of patients. Mouse models with complete Cln3 deletion or Cln3Δex7/8 mutation have been invaluable for learning about both the basic biology of CLN3 and the underlying pathological changes associated with CLN3 disease. These models, however, vary in their disease presentation and are limited in their utility for studying the role of nonsense mediated decay, and as a consequence, in testing nonsense suppression therapies and read-through compounds. In order to develop a model containing a disease-causing nonsense point mutation, here we describe a first-of-its-kind Cln3Q352X mouse model containing a c.1054C > T (p.Gln352Ter) point mutation. Similar to previously characterized Cln3 mutant mouse lines, this novel model shows pathological deficits throughout the CNS including accumulation of lysosomal storage material and glial activation, and has limited perturbation in behavioral measures. Thus, at the molecular and cellular level, this mouse line provides a valuable tool for testing nonsense suppression therapies or read through compounds in CLN3 disease in the future.
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Affiliation(s)
- Logan Langin
- Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th N, Sioux Falls, SD, 57104, USA
| | - Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th N, Sioux Falls, SD, 57104, USA
| | - Attila D Kovács
- Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th N, Sioux Falls, SD, 57104, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
| | - David A Pearce
- Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th N, Sioux Falls, SD, 57104, USA.
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
| | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, 2301 E. 60th N, Sioux Falls, SD, 57104, USA.
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
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Li W, Fan X, Zhang Y, Huang L, Jiang T, Qin Z, Su J, Luo J, Yi S, Zhang S, Shen Y. A novel pathogenic frameshift variant unmasked by a large de novo deletion at 13q21.33-q31.1 in a Chinese patient with neuronal ceroid lipofuscinosis type 5. BMC MEDICAL GENETICS 2020; 21:100. [PMID: 32393339 PMCID: PMC7216669 DOI: 10.1186/s12881-020-01039-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 04/29/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. CASE PRESENTATION In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. CONCLUSIONS This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.
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Affiliation(s)
- Wei Li
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Xin Fan
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Yue Zhang
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Limei Huang
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Tingting Jiang
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Zailong Qin
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Jiasun Su
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Jingrong Luo
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Shang Yi
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
| | - Shujie Zhang
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yiping Shen
- Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China.
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, USA.
- Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA.
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Favret JM, Weinstock NI, Feltri ML, Shin D. Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases. Front Mol Biosci 2020; 7:57. [PMID: 32351971 PMCID: PMC7174556 DOI: 10.3389/fmolb.2020.00057] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.
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Affiliation(s)
| | | | | | - Daesung Shin
- Hunter James Kelly Research Institute, Department of Biochemistry and Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
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Guelbert N, Atanacio N, Denzler I, Embiruçu EK, Mancilla N, Naranjo R, Pessoa A, Spécola N, Tavera L, Troncoso M, Vergara D. Position of Experts Regarding Follow-Up of Patients with Neuronal Ceroid Lipofuscinosis-2 Disease in Latin America. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2020. [DOI: 10.1590/2326-4594-jiems-2020-0012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Rosenberg JB, Chen A, Kaminsky SM, Crystal RG, Sondhi D. Advances in the Treatment of Neuronal Ceroid Lipofuscinosis. Expert Opin Orphan Drugs 2019; 7:473-500. [PMID: 33365208 PMCID: PMC7755158 DOI: 10.1080/21678707.2019.1684258] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 10/21/2019] [Indexed: 12/27/2022]
Abstract
Neuronal ceroid lipofuscinoses (NCL) represent a class of neurodegenerative disorders involving defective lysosomal processing enzymes or receptors, leading to lysosomal storage disorders, typically characterized by observation of cognitive and visual impairments, epileptic seizures, ataxia, and deterioration of motor skills. Recent success of a biologic (Brineura®) for the treatment of neurologic manifestations of the central nervous system (CNS) has led to renewed interest in therapeutics for NCL, with the goal of ablating or reversing the impact of these devastating disorders. Despite complex challenges associated with CNS therapy, many treatment modalities have been evaluated, including enzyme replacement therapy, gene therapy, stem cell therapy, and small molecule pharmacotherapy. Because the clinical endpoints for the evaluation of candidate therapies are complex and often reliant on subjective clinical scales, the development of quantitative biomarkers for NCLs has become an apparent necessity for the validation of potential treatments. We will discuss the latest findings in the search for relevant biomarkers for assessing disease progression. For this review, we will focus primarily on recent pre-clinical and clinical developments for treatments to halt or cure these NCL diseases. Continued development of current therapies and discovery of newer modalities will be essential for successful therapeutics for NCL. AREAS COVERED The reader will be introduced to the NCL subtypes, natural histories, experimental animal models, and biomarkers for NCL progression; challenges and different therapeutic approaches, and the latest pre-clinical and clinical research for therapeutic development for the various NCLs. This review corresponds to the literatures covering the years from 1968 to mid-2019, but primarily addresses pre-clinical and clinical developments for the treatment of NCL disease in the last decade and as a follow-up to our 2013 review of the same topic in this journal. EXPERT OPINION Much progress has been made in the treatment of neurologic diseases, such as the NCLs, including better animal models and improved therapeutics with better survival outcomes. Encouraging results are being reported at symposiums and in the literature, with multiple therapeutics reaching the clinical trial stage for the NCLs. The potential for a cure could be at hand after many years of trial and error in the preclinical studies. The clinical development of enzyme replacement therapy (Brineura® for CLN2), immunosuppression (CellCept® for CLN3), and gene therapy vectors (for CLN1, CLN2, CLN3, and CLN6) are providing encouragement to families that have a child afflicted with NCL. We believe that successful therapies in the future may involve the combination of two or more therapeutic modalities to provide therapeutic benefit especially as the patients grow older.
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Affiliation(s)
- Jonathan B Rosenberg
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Alvin Chen
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Stephen M Kaminsky
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Ronald G Crystal
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
| | - Dolan Sondhi
- Department of Genetic Medicine, Weill Cornell Medical College, New York, New York
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Wright GA, Georgiou M, Robson AG, Ali N, Kalhoro A, Holthaus SK, Pontikos N, Oluonye N, de Carvalho ER, Neveu MM, Weleber RG, Michaelides M. Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy. Ophthalmol Retina 2019; 4:433-445. [PMID: 31926949 PMCID: PMC7479512 DOI: 10.1016/j.oret.2019.11.005] [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: 11/04/2019] [Revised: 11/07/2019] [Accepted: 11/07/2019] [Indexed: 12/31/2022]
Abstract
Purpose To characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification. Design Retrospective case series. Participants Eight children (5 female) with JNCL. Methods Review of clinical notes, retinal imaging including fundus autofluorescence and OCT, electroretinography (ERG), and both microscopy and molecular genetic testing. Main Outcome Measurements Demographic data, signs and symptoms, visual acuity (VA), fundus autofluorescence and OCT findings, ERG phenotype, and microscopy/molecular genetics. Results Participants presented with rapid bilateral vision loss over 1 to 18 months, with mean VA deteriorating from 0.44 logarithm of the minimum angle of resolution (logMAR) (range, 0.20–1.78 logMAR) at baseline to 1.34 logMAR (0.30 logMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean, 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean, 8.3 years). Six children displayed eccentric fixation, and 6 children had cognitive or neurologic signs at the time of diagnosis (75%). Seven patients had bilateral bull’s-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in 1 patient. OCT imaging revealed near complete loss of outer retinal layers and marked atrophy of the nerve fiber and ganglion cell layers at the central macula. An electronegative ERG was present in 4 patients (50%), but with additional a-wave reduction, there was an undetectable ERG in the remaining 4 patients. Blood film microscopy revealed vacuolated lymphocytes, and electron microscopy showed lysosomal (fingerprint) inclusions in all 8 patients. Conclusions In a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counseling, support, and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early-phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease.
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Affiliation(s)
- Genevieve A Wright
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | - Michalis Georgiou
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | - Anthony G Robson
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | - Naser Ali
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | | | - Sm Kleine Holthaus
- UCL Institute of Ophthalmology, University College London, London, United Kingdom
| | - Nikolas Pontikos
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | | | | | - Magella M Neveu
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom
| | - Richard G Weleber
- Casey Eye Institute, Oregon Health & Science University, Portland, Oregon
| | - Michel Michaelides
- UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
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Jilani A, Matviychuk D, Blaser S, Dyack S, Mathieu J, Prasad AN, Prasad C, Kyriakopoulou L, Mercimek‐Andrews S. High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. JIMD Rep 2019; 50:20-30. [PMID: 31741823 PMCID: PMC6850977 DOI: 10.1002/jmd2.12057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/14/2019] [Accepted: 05/23/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the CLN genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the CLN genes from a single clinical molecular diagnostic laboratory. METHODS We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the CLN genes. RESULTS Six hundred and ninety three individuals underwent the direct Sanger sequencing of the CLN genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety-one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including CLN1 (PPT1) (n = 10), CLN2 (TPP1) (n = 33), CLN3 (n = 17), CLN5 (n = 7), CLN6 (n = 10), CLN7 (MFSD8) (n = 10), and CLN8 (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of CLN genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset CLN1 (PPT1) and adult onset CLN6 diseases were nonclassical phenotypes. CONCLUSION In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
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Affiliation(s)
- Abdulhakim Jilani
- Division of Clinical and Metabolic Genetics, Department of PaediatricsUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Diana Matviychuk
- Division of Genome Diagnostics, Department of Paediatric Laboratory MedicineThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Susan Blaser
- Division of Neuroradiology, Department of Medical ImagingUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Sarah Dyack
- Division of Medical Genetics, Department of Pediatrics, IWK Health CentreUniversity of DalhouiseHalifaxNova ScotiaCanada
| | - Jean Mathieu
- Neuromuscular Disease ClinicUniversity of SherbrookeQuebecCanada
| | - Asuri N. Prasad
- Division of Clinical Neurosciences, Department of Paediatrics, Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
| | - Chitra Prasad
- Division of Medical Genetics Department of Paediatrics, Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
| | - Lianna Kyriakopoulou
- Division of Genome Diagnostics, Department of Paediatric Laboratory MedicineThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of Paediatric Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Saadet Mercimek‐Andrews
- Division of Clinical and Metabolic Genetics, Department of PaediatricsUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
- Genetics and Genome Biology Program, Research InstituteThe Hospital for Sick ChildrenTorontoOntarioCanada
- Institute of Medical SciencesUniversity of TorontoTorontoOntarioCanada
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