Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

Chen, Szu‐Ju; Lee, Ni‐Chung; Chien, Yin‐Hsiu; Hwu, Wuh‐Liang; Lin, Chin‐Hsien

doi:10.1002/brb3.1414

Cited by 11 publications

(13 citation statements)

References 43 publications

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“…Mean Age of Examination (in years) of recruited cases has been listed in Table 1. On evaluation of SCA positive patients' ages (at examination), it is observed that SCA2 is prevalent in younger population (18-29 years); SCA12 in elder age group (50)(51)(52)(53)(54)(55)(56)(57)(58)(59) and other SCA types in middle age group (30-49) (Figure 2).…”

Section: Age Distribution Of Patientsmentioning

confidence: 99%

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

Sharma

Sonakar²,

Tyagi

et al. 2022

Advanced Genetics

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Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30–40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients’ referrals (Pan‐India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co‐occurrence of SCA‐subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA‐FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.

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Section: Age Distribution Of Patientsmentioning

confidence: 99%

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

Sharma

Sonakar²,

Tyagi

et al. 2022

Advanced Genetics

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“…Genomic DNA was isolated from 10 mL of venous blood from all participants, following a standard protocol. Trinucleotide repeat expansions at the SCA1, 2, 3, 6, 17 and DRPLA genes were excluded from all participants, following the methods described previously [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…Recent advances in genetic studies have identified more than 40 genes causing distinct subtypes of SCA [ 14 ]. We and other groups have previously described the clinical features of Taiwanese patients with the most common genetic causes of SCA [ 15 , 16 ]. To extend our knowledge of the genetic architecture and pathophysiology of SCA in our population, we performed whole-genome sequencing (WGS) and comparative analysis in a genetically undiagnosed multiplex family with SCA.…”

Section: Introductionmentioning

confidence: 99%

Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48)

et al. 2021

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Background Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort. Methods We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron–exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated. Results We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein’s activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development. Conclusions Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.

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“…We continued our literature search for Asia-specific phenotypic aspects using a citation-based search, rather than an additional broad literature search as we expected that it would result in a rather small selection of studies. Two recent studies were used as a starting point [4,5]. Other studies suggesting Asia-specific elements within a SCA subtype were reviewed and included.…”

Section: Methodsmentioning

confidence: 99%

“…However, only a few Asian studies have actually reported on the frequency of parkinsonism or other movement disorders in SCAs. A Taiwanese study found that parkinsonism was the most common non-ataxic manifestation (21.1%) in a cohort of 90 SCA1, SCA2, SCA3, SCA6, and SCA17 patients [5]. Studies from other Asian countries reported a lower prevalence of parkinsonism.…”

Section: Part Ii: Phenotypic Differences Compared To Other Continents and Asia Specific Phenotypesmentioning

confidence: 99%

Spinocerebellar ataxias in Asia: Prevalence, phenotypes and management

Prooije

Norlinah

Azmin

et al. 2021

Parkinsonism & Related Disorders

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Heterogeneous nonataxic phenotypes of spinocerebellar ataxia in a Taiwanese population

Cited by 11 publications

References 43 publications

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

Genetics of Ataxias in Indian Population: A Collative Insight from a Common Genetic Screening Tool

Clinical and functional characterization of a novel STUB1 frameshift mutation in autosomal dominant spinocerebellar ataxia type 48 (SCA48)

Spinocerebellar ataxias in Asia: Prevalence, phenotypes and management

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