|
1
|
Kılıç M, İcil S, Sezer A, Kaya-Güneş Ö, Comoğlu SS. Sialidosis type 1 in a Turkish family: a case report and review of literatures. J Pediatr Endocrinol Metab 2025; 38:176-186. [PMID: 39733340 DOI: 10.1515/jpem-2024-0468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 12/10/2024] [Indexed: 12/31/2024]
Abstract
OBJECTIVES Sialidosis type 1 is a rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the NEU1 gene, which encodes the sialic acid-degrading enzyme α-neuraminidase. Sialidosis type 1 is a milder form with a late-onset phenotype, characterized by progressive myoclonic epilepsy and ataxia with cherry-red spots. Sialidosis type 2 is an early-onset and more severe form presenting with dysmorphic features, hepatosplenomegaly and cognitive delay. Clinical diagnosis is usually supported by increased urinary bound sialic acid excretion and confirmed by genetic analysis or demonstration of α-neuraminidase enzyme deficiency in cultured fibroblasts. The aim of this study was to present a case of type 1 sialidosis, review the literature, and investigate genotype-phenotype correlations, symptom frequencies, and race-specific mutations in patients diagnosed with type 1 sialidosis. CASE PRESENTATION We report herein a family of four Turkish siblings affected with sialidosis type 1 associated with a homozygous variant, c.403G>A p. (Asp135Asn), in the NEU1 gene. A systematic literature review on sialidosis type 1 was carried out, by the PubMed database was searched using keywords included sialidosis and/or NEU1 gene. We selected case reports or series that included genetically confirmed type 1 sialidosis from 1996 to 2023. So far, nearly genetically confirmed 80 patients from unrelated 65 families, more than 40 NEU1 disease causing mutations, have been identified in patients with sialidosis type 1. Among the reported mutations, missense variants are the most common, and few nonsense, frameshift, exonic duplications or small deletions have been reported. c.239C>T p. (Pro80Leu) variant in Chinese and Japanese patients, c.649G>A p. (Val217Met) variant in Japanese patients, c.880C>T p. (Arg294Cys) variant in Indian patients, c.629C>T p. (Pro210Leu) variant in Ecuadorian patients, c.982G>A p. (Gly328Ser) variant in Italian patients, and c.403G>A p (Asp135Asn) and c.625del p. (Glu209Serfs*94) variants in Turkish patients were found higher. CONCLUSIONS Race-specific variants were found with higher percentages in certain populations.
Collapse
Affiliation(s)
- Mustafa Kılıç
- Department of Pediatrics, Metabolism Unit, Ankara Etlik City Hospital, Ankara, Türkiye
| | - Suzan İcil
- Department of Pediatrics, Metabolism Unit, Ankara Etlik City Hospital, Ankara, Türkiye
| | - Abdullah Sezer
- Department of Genetics, Ankara Etlik City Hospital, Ankara, Türkiye
| | - Öznur Kaya-Güneş
- Department of Genetics, Ankara Etlik City Hospital, Ankara, Türkiye
| | - Selim S Comoğlu
- Department of Neurology, Ankara Etlik City Hospital, Ankara, Türkiye
| |
Collapse
|
|
2
|
Ding Y, Cheng M, Gong C. Two cases of type I sialidosis and a literature review. Orphanet J Rare Dis 2024; 19:440. [PMID: 39605025 PMCID: PMC11600752 DOI: 10.1186/s13023-024-03431-3] [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: 05/28/2024] [Accepted: 10/25/2024] [Indexed: 11/29/2024] Open
Abstract
OBJECTIVE This study aims to compare the clinical and electrophysiological characteristics of two cases of type I sialidosis in Chinese children with those reported in prior literature. The goal is to elucidate the clinical and genetic features of type I sialidosis. METHODS Clinical investigations and genetic analyses were conducted on an 11-year-old girl, primarily presenting with short stature, who was admitted in June 2020, and a 10-year-old boy, admitted in July 2023, exhibiting rapid weight gain and accompanying visual impairment as primary manifestations. A literature review was performed by summarizing data from 31 published articles encompassing 69 genetically confirmed cases of type I sialidosis up to 2023 for comparative analysis. RESULTS Patient 1 exhibited short stature, self-reported poor night vision, a history of occasional febrile seizures, mild scoliosis, bilateral cherry-red spots in the fundus, and prolonged P100 latency in both eyes as observed in visual evoked potentials (VEP). Genetic analysis revealed that she carried compound-heterozygous variants c.239 C > T (p.P80L) and c.880 C > T (p.R294C) in the NEU1 gene, inherited from her parents. Patient 2 presented with rapid weight gain and visual impairment, bilateral cherry-red spots in the fundus, abnormal neuroepithelial layer reflexes in both macular areas, approximately normal P100 latency but severely reduced amplitude in VEP after pupillary dilation, and severe bilateral optic nerve conduction block with relatively normal retinal cell function. Compound-heterozygous variants c.239 C > T (p.P80L) and c.803 A > G (p.T268C) were identified in the NEU1 gene of the Patient 2, inherited from his parents. By combining the cases reported in 31 literature articles with the 2 cases in our study, a total of 71 type I sialidosis patients were analyzed. The most common symptoms observed were muscle spasms (91.5%), followed by ataxia (75%) and seizures (63.6%). Intellectual impairment and abnormal electroencephalograms were more prevalent in Caucasian patients. Additionally, abnormal somatosensory evoked potentials, large cortical waves, and prolonged latency of VEP were more frequently observed in both Asian and Caucasian patients, serving as alternative indicators for early diagnosis. CONCLUSION NEU1 gene analysis provides essential guidance for genetic counseling and prenatal diagnosis. The exon 2 variant c.239 C > T (p.P80L) in the NEU1 gene may represent a mutation hotspot among Chinese patients.
Collapse
Affiliation(s)
- Yuan Ding
- Department of Endocrinology, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Genetics, Metabolism, Beijing, 100045, China
- MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56#Nan Lishi Rd, West District, Beijing, 100045, China
| | - Ming Cheng
- Department of Endocrinology, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Genetics, Metabolism, Beijing, 100045, China
- MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56#Nan Lishi Rd, West District, Beijing, 100045, China
| | - Chunxiu Gong
- Department of Endocrinology, Beijing Children's Hospital, Capital Medical University, National Centre for Children's Health, Genetics, Metabolism, Beijing, 100045, China.
- MOE Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56#Nan Lishi Rd, West District, Beijing, 100045, China.
| |
Collapse
|
|
3
|
Lin J, Li Y, Chen B, Su H, Zeng Y, Zeng R, Zhang Y, Chen R, Cai N, Chen Y, Yuan R, Jiang J, Yao X, Wang N, Chen W, Yang K. Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation. Ann Clin Transl Neurol 2024; 11:2998-3009. [PMID: 39482827 PMCID: PMC11572746 DOI: 10.1002/acn3.52212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 08/14/2024] [Accepted: 09/03/2024] [Indexed: 11/03/2024] Open
Abstract
OBJECTIVE Expand genetic screening for atypical Type I sialidosis (ST-1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population. METHODS We enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation. RESULTS A total of 31 patients from 23 unrelated families were genetically diagnosed with ST-1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST-1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic-clonic seizures. Mobility and independence varied greatly across the cohort. Cherry-red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians. INTERPRETATION ST-1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry-red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.
Collapse
Affiliation(s)
- Jingjing Lin
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Yun‐Lu Li
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Bo‐Li Chen
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Hui‐Zhen Su
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Yi‐Heng Zeng
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Rui‐Huang Zeng
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Yu‐Duo Zhang
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Ru‐Kai Chen
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Nai‐Qing Cai
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Yi‐Kun Chen
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Ru‐Ying Yuan
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Jun‐Yi Jiang
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Xiang‐Ping Yao
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Ning Wang
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Wan‐Jin Chen
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| | - Kang Yang
- Department of Neurology and Institute of Neurology of First Affiliated HospitalInstitute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical UniversityFuzhou350005China
| |
Collapse
|
|
4
|
Dehnavi AZ, Bemanalizadeh M, Kahani SM, Ashrafi MR, Rohani M, Toosi MB, Heidari M, Hosseinpour S, Amini B, Zokaei S, Rezaei Z, Aryan H, Amanat M, Vahidnezhad H, Mohammadi P, Garshasbi M, Tavasoli AR. Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients. Orphanet J Rare Dis 2023; 18:177. [PMID: 37403138 DOI: 10.1186/s13023-023-02780-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 06/18/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and PLA2G6-related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the PLA2G6. METHODS An extensive review of the patients' data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease's underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach. RESULTS Eighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% - 1.10, and upper 95% - 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype-phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on PLA2G6. CONCLUSION PLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype.
Collapse
Affiliation(s)
- Ali Zare Dehnavi
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Bemanalizadeh
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Seyyed Mohammad Kahani
- Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran
| | - Mahmoud Reza Ashrafi
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Rohani
- Skull Base Research Center, The Five Senses Health Institute, Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
- Department of Neurology, Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Beiraghi Toosi
- Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Morteza Heidari
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Sareh Hosseinpour
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Behnam Amini
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Zokaei
- Dr. Farhud's Genetic Clinic, Tehran, Iran
- School of Advanced Medical Science, Islamic Azad University, Tehran, Iran
| | - Zahra Rezaei
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
| | - Hajar Aryan
- Dr. Farhud's Genetic Clinic, Tehran, Iran
- National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Man Amanat
- Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Hassan Vahidnezhad
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Pouria Mohammadi
- Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Garshasbi
- Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran.
| | - Ali Reza Tavasoli
- Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.
- Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
5
|
Khan A, Sergi CM. NEU1-A Unique Therapeutic Target for Alzheimer's Disease. Front Pharmacol 2022; 13:902259. [PMID: 35847014 PMCID: PMC9277458 DOI: 10.3389/fphar.2022.902259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/17/2022] [Indexed: 11/16/2022] Open
Abstract
Neuraminidase 1 (NEU1) is considered to be the most abundant and ubiquitous mammalian enzyme, with a broad tissue distribution. It plays a crucial role in a variety of cellular mechanisms. The deficiency of NEU1 has been implicated in various pathological manifestations of sialidosis and neurodegeneration. Thus, it is a novel therapeutic target for neurodegenerative changes in the Alzheimer's brain. However, to manipulate NEU1 as a therapeutic target, it is imperative to understand that, although NEU1 is commonly known for its lysosomal catabolic function, it is also involved in other pathways. NEU1 is involved in immune response modulation, elastic fiber assembly modulation, insulin signaling, and cell proliferation. In recent years, our knowledge of NEU1 has continued to grow, yet, at the present moment, current data is still limited. In addition, the unique biochemical properties of NEU1 make it challenging to target it as an effective therapeutic option for sialidosis, which is a rare disease but has an enormous patient burden. However, the fact that NEU1 has been linked to the pathology of Alzheimer's disease, which is rapidly growing worldwide, makes it more relevant to be studied and explored. In the present study, the authors have discussed various cellular mechanisms involving NEU1 and how they are relevant to sialidosis and Alzheimer's disease.
Collapse
Affiliation(s)
- Aiza Khan
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Consolato M. Sergi
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
- Division of Anatomic Pathology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada
| |
Collapse
|
|
6
|
Teive HAG, Cassou E, Coutinho L, Camargo CHF, Munhoz RP. Ramsay Hunt syndrome: New impressions in the era of molecular genetics. Parkinsonism Relat Disord 2022; 97:101-104. [PMID: 35430109 DOI: 10.1016/j.parkreldis.2022.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/22/2022] [Accepted: 04/04/2022] [Indexed: 11/27/2022]
Abstract
More frequent use of next-generation sequencing led to a paradigm shift in assessing heredodegenerative diseases. This is particularly notable in progressive myoclonus epilepsy (PME) and progressive myoclonus ataxia (PMA) where a group of disorders linked to novel genetic mutations has now been added to these phenotypical realms. Despite the historical value of Ramsay Hunt's contribution defining the syndrome later known as PMA, recent genetic developments have made this eponym obsolete and a new definition and classification of PMA and PME seem necessary. A rational possibility is to adopt the wider term progressive myoclonus ataxia and epilepsy syndrome (PMAES), which can be subdivided into its main subtypes, PME and PMA, whenever clinical data is sufficient to make that distinction.
Collapse
Affiliation(s)
- Hélio A G Teive
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil; Neurodegenerative Diseases Group, Postgraduate Program in Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil.
| | - Emanuel Cassou
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil.
| | - Léo Coutinho
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil.
| | - Carlos Henrique F Camargo
- Neurodegenerative Diseases Group, Postgraduate Program in Internal Medicine, Hospital de Clínicas, Federal University of Paraná, Curitiba, Paraná, Brazil.
| | - Renato P Munhoz
- Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
7
|
Abstract
The presence of unprovoked, recurrent seizures, particularly when drug resistant and associated with cognitive and behavioral deficits, warrants investigation for an underlying genetic cause. This article provides an overview of the major classes of genes associated with epilepsy phenotypes divided into functional categories along with the recommended work-up and therapeutic considerations. Gene discovery in epilepsy supports counseling and anticipatory guidance but also opens the door for precision medicine guiding therapy with a focus on those with disease-modifying effects.
Collapse
Affiliation(s)
- Luis A Martinez
- Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Drive, Houston, TX 77030, USA
| | - Yi-Chen Lai
- Department of Pediatrics, Section of Pediatric Critical Care Medicine, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Drive, Houston, TX 77030, USA
| | - J Lloyd Holder
- Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Drive, Houston, TX 77030, USA
| | - Anne E Anderson
- Department of Pediatrics, Section of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, 1250 Moursund Drive, Houston, TX 77030, USA.
| |
Collapse
|
|
8
|
Seol B, Kim YD, Cho YS. Modeling Sialidosis with Neural Precursor Cells Derived from Patient-Derived Induced Pluripotent Stem Cells. Int J Mol Sci 2021; 22:ijms22094386. [PMID: 33922276 PMCID: PMC8122832 DOI: 10.3390/ijms22094386] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 01/16/2023] Open
Abstract
Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1G227R and NEU1V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1G227R- and NEU1V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1G227R- and NEU1V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy-lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.
Collapse
Affiliation(s)
- Binna Seol
- Stem Cell Research Laboratory (SCRL), Immunotherapy Research Center (IRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (B.S.); (Y.-D.K.)
| | - Young-Dae Kim
- Stem Cell Research Laboratory (SCRL), Immunotherapy Research Center (IRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (B.S.); (Y.-D.K.)
| | - Yee Sook Cho
- Stem Cell Research Laboratory (SCRL), Immunotherapy Research Center (IRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Korea; (B.S.); (Y.-D.K.)
- Department of Bioscience, KRIBB School, University of Science & Technology, 113 Gwahak-ro, Yuseong-gu, Daejeon 34113, Korea
- Correspondence: ; Tel.: +82-42-860-4479; Fax: +82-42-860-4608
| |
Collapse
|
|
9
|
Cao LX, Liu Y, Song ZJ, Zhang BR, Long WY, Zhao GH. Compound heterozygous mutations in the neuraminidase 1 gene in type 1 sialidosis: A case report and review of literature. World J Clin Cases 2021; 9:623-631. [PMID: 33553400 PMCID: PMC7829734 DOI: 10.12998/wjcc.v9.i3.623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Type 1 sialidosis, also known as cherry-red spot-myoclonus syndrome, is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life. The most common symptoms are myoclonus, ataxia and seizure. It is rarely encountered in the Chinese mainland.
CASE SUMMARY A 22-year-old male presented with complaints of progressive myoclonus, ataxia and slurred speech, without visual symptoms; the presenting symptoms began at the age of 15-year-old. Whole exome sequencing revealed two pathogenic heterozygous missense variants [c.239C>T (p.P80L) and c.544A>G (p.S182G) in the neuraminidase 1 (NEU1) gene], both of which have been identified previously in Asian patients with type 1 sialidosis. All three patients identified in Mainland China come from three unrelated families, but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants. Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis.
CONCLUSION Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis, we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.
Collapse
Affiliation(s)
- Lan-Xiao Cao
- Department of Neurology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Ying Liu
- Central Laboratory, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Zhao-Jun Song
- Central Laboratory, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Bao-Rong Zhang
- Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
| | - Wen-Ying Long
- Central Laboratory, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| | - Guo-Hua Zhao
- Department of Neurology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu 322000, Zhejiang Province, China
| |
Collapse
|
|
10
|
Rossi M, van der Veen S, Merello M, Tijssen MAJ, van de Warrenburg B. Myoclonus-Ataxia Syndromes: A Diagnostic Approach. Mov Disord Clin Pract 2020; 8:9-24. [PMID: 33426154 DOI: 10.1002/mdc3.13106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 09/30/2020] [Accepted: 10/14/2020] [Indexed: 12/30/2022] Open
Abstract
Background A myriad of disorders combine myoclonus and ataxia. Most causes are genetic and an increasing number of genes are being associated with myoclonus-ataxia syndromes (MAS), due to recent advances in genetic techniques. A proper etiologic diagnosis of MAS is clinically relevant, given the consequences for genetic counseling, treatment, and prognosis. Objectives To review the causes of MAS and to propose a diagnostic algorithm. Methods A comprehensive and structured literature search following PRISMA criteria was conducted to identify those disorders that may combine myoclonus with ataxia. Results A total of 135 causes of combined myoclonus and ataxia were identified, of which 30 were charted as the main causes of MAS. These include four acquired entities: opsoclonus-myoclonus-ataxia syndrome, celiac disease, multiple system atrophy, and sporadic prion diseases. The distinction between progressive myoclonus epilepsy and progressive myoclonus ataxia poses one of the main diagnostic dilemmas. Conclusions Diagnostic algorithms for pediatric and adult patients, based on clinical manifestations including epilepsy, are proposed to guide the differential diagnosis and corresponding work-up of the most important and frequent causes of MAS. A list of genes associated with MAS to guide genetic testing strategies is provided. Priority should be given to diagnose or exclude acquired or treatable disorders.
Collapse
Affiliation(s)
- Malco Rossi
- Movement Disorders Section Neuroscience Department Buenos Aires Argentina.,Argentine National Scientific and Technological Research Council (CONICET) Buenos Aires Argentina
| | - Sterre van der Veen
- Pontificia Universidad Católica Argentina (UCA) Buenos Aires Argentina.,Department of Neurology University of Groningen, University Medical Center Groningen Groningen The Netherlands
| | - Marcelo Merello
- Movement Disorders Section Neuroscience Department Buenos Aires Argentina.,Argentine National Scientific and Technological Research Council (CONICET) Buenos Aires Argentina.,Pontificia Universidad Católica Argentina (UCA) Buenos Aires Argentina
| | - Marina A J Tijssen
- Department of Neurology University of Groningen, University Medical Center Groningen Groningen The Netherlands.,Expertise Center Movement Disorders Groningen University Medical Center Groningen (UMCG) Groningen The Netherlands
| | - Bart van de Warrenburg
- Department of Neurology, Donders Institute for Brain, Cognition & Behaviour Radboud University Medical Center Nijmegen The Netherlands
| |
Collapse
|
|
11
|
Atwal PS, Midei M, Adams D, Fay A, Heerinckx F, Milner P. The infantile neuroaxonal dystrophy rating scale (INAD-RS). Orphanet J Rare Dis 2020; 15:195. [PMID: 32727524 PMCID: PMC7392694 DOI: 10.1186/s13023-020-01479-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 07/21/2020] [Indexed: 11/10/2022] Open
Abstract
Background INAD is an autosomal recessive neurogenetic disorder caused by biallelic pathogenic variants in PLA2G6. The downstream enzyme, iPLA2, plays a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids. The clinical presentation occurs between 6 months and 3 years with global developmental regression, hypotonia, and progressive spastic tetraparesis. Progression is often rapid, resulting in severe spasticity, visual impairment, and cognitive decline, with many children not surviving past the first decade of life. To date, no accepted tool for assessing the severity of INAD exists; other commonly used scales (e.g. CHOP-INTEND, Modified Ashworth, Hammersmith Functional Motor Scale) do not accurately gauge the current severity of INAD, nor are they sensitive/specific enough to monitor disease progression. Finally, these other scales are not appropriate, because they do not address the combination of CNS, peripheral nerve, and visual pathology that occurs in children with INAD. Methods We have developed and validated a structured neurological examination for INAD (scored out of 80). The examination includes six main categories of pediatric developmental evaluation: 1) gross motor-and-truncal-stability skills, 2) fine motor skills, 3) bulbar function, 4) ocular function, 5) temporo-frontal function, and, 6) Functional evaluation of the autonomic nervous system. A cohort of patients diagnosed with INAD were followed prospectively to validate the score against disease severity and disease progression. Results We show significant correlation between the total neurological assessment score and months since symptom onset with a statistically significant (p = 6.7 × 10− 07) correlation between assessment score and disease onset. As hypothesized, the coefficient of months-since-symptom-onset is strongly negative, indicating a negative correlation between total score and months since symptom onset. Conclusion We have developed and validated a novel neurological assessment score in INAD that demonstrates strong correlation with disease severity and disease progression.
Collapse
Affiliation(s)
| | | | - Darius Adams
- Atlantic Medical Group, Morris Township, NJ, USA
| | - Alexander Fay
- University of California San Francisco (UCSF), San Francisco, CA, USA
| | | | | |
Collapse
|
|
12
|
Han X, Wu S, Wang M, Li H, Huang Y, Sui R. Genetic and clinical characterization of mainland Chinese patients with sialidosis type 1. Mol Genet Genomic Med 2020; 8:e1316. [PMID: 32453490 PMCID: PMC7434748 DOI: 10.1002/mgg3.1316] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/25/2020] [Accepted: 04/28/2020] [Indexed: 12/26/2022] Open
Abstract
Background Sialidosis type 1 is a rare inherited disorder with a high disability. No genetically confirmed mainland Chinese patient with sialidosis type 1 has been reported. This study evaluated the phenotypes and genotypes of mainland Chinese patients with sialidosis type 1. Methods It was a retrospective case series study. Four unrelated patients were enrolled. Comprehensive clinical evaluations and molecular genetic analysis of the NEU1 gene were performed. Results Three out of four patients presented progressive myoclonus epilepsy. The best‐corrected visual acuity ranged from 20/2000 to 20/25. Punctate cataracts were found in all of the patients. Distinct macular cherry red spots were observed in three patients by fundoscopy, and a relatively normal fundus was revealed in one patient. Optical coherence tomography (OCT) showed increased reflectivity of the nerve fiber and ganglion cell layers, and fundus autofluorescence (FAF) revealed hyperautofluorescent areas surrounding the fovea in all of the patients. Only superficial retinal vessels can be observed using OCT angiography; the deeper capillary plexus could not be observed. Visual evoked potential revealed varying degrees of decreased amplitude and/or prolonged latency of P100 or P2 waves. The most frequent sequence variant identified was c.544A>G (p.S182G) (NM_000434.3). Conclusions Our study first described the ophthalmic and neurologic characteristics of a small cohort of unrelated mainland Chinese patients with sialidosis type 1. We found that c.544A>G (p. S182G) might be a hotspot variant in Chinese patients. The accumulation of metabolic products in the nerve fiber and ganglion cell layers is a characteristic ocular finding that could be sensitively detected by OCT and FAF imaging.
Collapse
Affiliation(s)
- Xiaoxu Han
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shijing Wu
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Min Wang
- Department of Ophthalmology, Eye and ENT Hospital of Fudan University, Shanghai, China
| | - Hui Li
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yan Huang
- Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ruifang Sui
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Ocular Fundus Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| |
Collapse
|
|
13
|
Li X, Zhang Q. Heterozygous structural variation mimicking homozygous missense mutations in NEU1 associated with presenting clinical signs in eyes alone. Ophthalmic Genet 2020; 41:279-283. [PMID: 32270733 DOI: 10.1080/13816810.2020.1747085] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION Biallelic mutations in neuraminidase 1 (NEU1) are associated with cherry-red spots. Whole genome sequencing contributes to eliminating pseudo-homozygous mutations when large-scale deletion of one allele in NEU1 and other genes occurs. PATIENTS AND METHODS Bilateral cherry-red spots in the macula were the only detectable sign in an 11-year-old girl with reduced visual acuity over the last two years. Targeted exome sequencing of genes for inherited eye diseases identified a homozygous c.544A>G (p.Ser182Gly) variation in the NEU1 gene. This variant was also present in her mother in the heterozygous state but not in her father. Whole genome sequencing identified a heterozygous 27.5 kb deletion involving the whole coding exons of NEU1 in her father. Sanger sequencing disclosed the breakpoint of the deletion. This heterozygous deletion was also detected in the patient, so the c.544A>G mutation should be heterozygous in the patient. CONCLUSION The results of this case remind us of the limitations of routine exome sequencing and the need to perform segregation studies and deletion/duplication analysis or WGS if parental studies do not support exome findings. In addition, patients with sialidosis may present with ocular manifestations without systemic signs early in the disease course.
Collapse
Affiliation(s)
- Xueqing Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University , Guangzhou, China
| | - Qingjiong Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University , Guangzhou, China
| |
Collapse
|
|
14
|
Mosca R, van de Vlekkert D, Campos Y, Fremuth LE, Cadaoas J, Koppaka V, Kakkis E, Tifft C, Toro C, Allievi S, Gellera C, Canafoglia L, Visser G, Annunziata I, d’Azzo A. Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I. J Clin Med 2020; 9:jcm9030695. [PMID: 32143456 PMCID: PMC7141319 DOI: 10.3390/jcm9030695] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/26/2022] Open
Abstract
Congenital deficiency of the lysosomal sialidase neuraminidase 1 (NEU1) causes the lysosomal storage disease, sialidosis, characterized by impaired processing/degradation of sialo-glycoproteins and sialo-oligosaccharides, and accumulation of sialylated metabolites in tissues and body fluids. Sialidosis is considered an ultra-rare clinical condition and falls into the category of the so-called orphan diseases, for which no therapy is currently available. In this study we aimed to identify potential therapeutic modalities, targeting primarily patients affected by type I sialidosis, the attenuated form of the disease. We tested the beneficial effects of a recombinant protective protein/cathepsin A (PPCA), the natural chaperone of NEU1, as well as pharmacological and dietary compounds on the residual activity of mutant NEU1 in a cohort of patients’ primary fibroblasts. We observed a small, but consistent increase in NEU1 activity, following administration of all therapeutic agents in most of the fibroblasts tested. Interestingly, dietary supplementation of betaine, a natural amino acid derivative, in mouse models with residual NEU1 activity mimicking type I sialidosis, increased the levels of mutant NEU1 and resolved the oligosacchariduria. Overall these findings suggest that carefully balanced, unconventional dietary compounds in combination with conventional therapeutic approaches may prove to be beneficial for the treatment of sialidosis type I.
Collapse
Affiliation(s)
- Rosario Mosca
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
| | - Diantha van de Vlekkert
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
| | - Yvan Campos
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
| | - Leigh E. Fremuth
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
- Department of Anatomy and Neurobiology, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jaclyn Cadaoas
- Ultragenyx Pharmaceutical, Novato, CA 94949, USA; (J.C.); (V.K.); (E.K.)
| | - Vish Koppaka
- Ultragenyx Pharmaceutical, Novato, CA 94949, USA; (J.C.); (V.K.); (E.K.)
| | - Emil Kakkis
- Ultragenyx Pharmaceutical, Novato, CA 94949, USA; (J.C.); (V.K.); (E.K.)
| | - Cynthia Tifft
- Office of the Clinical Director & Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health (NHGRI), Bethesda, MD 20892, USA;
| | - Camilo Toro
- Undiagnosed Disease Network, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Simona Allievi
- Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (S.A.); (C.G.)
- Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy;
| | - Cinzia Gellera
- Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; (S.A.); (C.G.)
- Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy;
| | - Laura Canafoglia
- Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy;
| | - Gepke Visser
- Department of Metabolic Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;
| | - Ida Annunziata
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
| | - Alessandra d’Azzo
- Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; (R.M.); (D.v.d.V.); (Y.C.); (L.E.F.); (I.A.)
- Correspondence: ; Tel.: +1-901-595-2698
| |
Collapse
|
|
15
|
Ahn JH, Kim AR, Lee C, Kim NKD, Kim NS, Park WY, Kim M, Youn J, Cho JW, Kim JS. Type 1 Sialidosis Patient With a Novel Deletion Mutation in the NEU1 Gene: Case Report and Literature Review. THE CEREBELLUM 2019; 18:659-664. [PMID: 30635863 DOI: 10.1007/s12311-019-1005-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Recent advances in next-generation sequencing technologies have uncovered the genetic backgrounds of various diseases. Type 1 sialidosis (OMIM#256550) is a rare autosomal recessive lysosomal storage disease caused by a mutation in the NEU1 (OMIM * 608272) gene. In this study, we aimed to review the previous reports of type 1 sialidosis and compare those with the first case of type 1 sialidosis in Korea. A 36-year-old woman presented with progressive ataxia, myoclonus, and seizure since the age of 12. Whole-exome sequencing revealed a pathogenic missense variant c.928G > A (p.D310N) and novel c.15_16del (p.P6Qfs*21) of the NEU1 gene as final causal candidate as compound heterozygotes. We reviewed the literature and selected the clinical reports of genetically confirmed type 1 sialidosis patients. A total of 45 patients in 17 reports were identified. Cherry-red spot, myoclonus, ataxia, and seizure were reported in 51.2%, 100.0%, 87.8%, and 73.7% of patients, respectively. Abnormalities of cognitive function, EEG, and brain MRI and visual symptoms were reported in 22.2%, 40.7%, 66.7%, and 70.2% of patients, respectively. Overall, our patient showed similar clinical features to previous type 1 sialidosis patients, but she did not complain of visual symptoms despite having cherry-red spots. We summarize the clinical features of type 1 sialidosis and report the first case of type 1 sialidosis with novel deletion variant in the NEU1 gene in the Korean population. Our study suggests the importance of ophthalmologic examinations in patients with myoclonus, ataxia, and seizure who do not complain of visual symptoms.
Collapse
Affiliation(s)
- Jong Hyeon Ahn
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Ah Reum Kim
- Samsung Medical Center, Samsung Genome Institute, Gangnam-gu, Seoul, Republic of Korea
| | - Chung Lee
- Samsung Medical Center, Samsung Genome Institute, Gangnam-gu, Seoul, Republic of Korea
| | - Nayoung K D Kim
- Samsung Medical Center, Samsung Genome Institute, Gangnam-gu, Seoul, Republic of Korea
| | - Nam-Soon Kim
- Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
| | - Woong-Yang Park
- Samsung Medical Center, Samsung Genome Institute, Gangnam-gu, Seoul, Republic of Korea
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do, Republic of Korea
| | - Minkyeong Kim
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Jinyoung Youn
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Jin Whan Cho
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
- Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea
| | - Ji Sun Kim
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
- Neuroscience Center, Samsung Medical Center, Seoul, Republic of Korea.
| |
Collapse
|
|
16
|
Fan SP, Lee NC, Lin CH. Clinical and electrophysiological characteristics of a type 1 sialidosis patient with a novel deletion mutation in NEU1 gene. J Formos Med Assoc 2019; 119:406-412. [PMID: 31371146 DOI: 10.1016/j.jfma.2019.07.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/26/2019] [Accepted: 07/17/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND/PURPOSE Type 1 sialidosis is a rare autosomal recessive lysosomal storage disease caused by Neuraminidase 1 (NEU1) gene mutations. We report a type 1 sialidosis patient with a novel deletion mutation in NEU1 and compared the phenotypes within different ethnicities. METHODS Targeted next generation sequencing and segregation analysis were performed to identify the causative gene mutation of the index patient. The clinical and electrophysiological characteristics of the patient were compared to those reported in previous studies of type 1 sialidosis from 1996 to 2019. RESULTS A 16-year-old boy presented with progressive onset of seizure, myoclonus, and ataxia since 5 years of age. Targeted next generation sequencing revealed the pathogenic missense variant c.544A>G (p.Ser182Gly) and the novel c.314_352del (p.A106_G118del) deletion in NEU1 in a compound heterozygote state. The leukocyte neuraminidase activity was significantly decreased (0.0323 nmol/mg protein/hour, normal reference: 0.326 ± 0.095 nmol/mg protein/hour). A total of 46 patients were identified in 18 reports from the literature. The most common symptoms were myoclonus (100%), followed by ataxia (88.3%) and seizure (72.5%). Notably, impaired cognition (50.0% vs. 21.7%, P = 0.04) and cherry-red spots (61.1% vs. 40.7%, P = 0.02) were less frequently reported in Asian patients than in Caucasian patients. Abnormal somatosensory evoked potentials with giant cortical waves and prolonged visual evoked potential latency were found consistently in Asian and Caucasian patients, and could be a surrogate marker of early diagnosis. CONCLUSION Our findings suggest a distinct phenotype of infrequent cherry-red spots and abnormal evoked potentials in Asian patients with type 1 sialidosis.
Collapse
Affiliation(s)
- Sung-Pin Fan
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|