ATXN10 – Spinocerebellar Ataxia Type 10

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia and, variably, seizures ([HP:0001251], [HP:0001250]) and cerebellar atrophy ([HP:0001272]). It is caused by large intronic ATTCT pentanucleotide repeat expansions in ATXN10, with pathogenic alleles ranging from ~1400 to >4500 repeats.

Genetic evidence for ATXN10 in SCA10 is based on multiple independent cohorts. An initial report described intronic expansions in all affected members of five Mexican families, with expansion sizes up to 22.5 kb and inverse correlation with age of onset (PMID:11017075). Subsequent studies identified 28 Brazilian patients from five families presenting pure ataxia without epilepsy (PMID:15505178) and demonstrated reduced epilepsy penetrance in 80 Brazilian patients (epilepsy in 3.75% vs 60% elsewhere) (PMID:20818609).

The SCA10 expansion shows a conserved Amerindian haplotype across Latin American populations. A haplotype study of 56 families from Brazil and Peru confirmed a common 19-CGGC-14 motif in 47–65% of pedigrees, distinct from controls (p<0.001) (PMID:28905220) and replicated in 16 Brazilian and 3 Peruvian families with progression rates of 0.444 and 0.287 points/year (PMID:28560845). Cases in non‐American ancestries include a Sioux Native American patient with 1400 repeats (PMID:24278426), atypical Han Chinese pedigrees lacking seizures in five patients (PMID:35441258), and a single Chinese Han family with classic ataxia (PMID:27066563).

Segregation across >14 independent families and >70 affected individuals underpins a Definitive association. The repeat expansion consistently segregates with disease in autosomal dominant inheritance, with age at onset correlating inversely with expansion size (PMID:11017075). Genetic modifiers include repeat interruptions influencing epilepsy risk and parkinsonian presentations (PMID:28890930).

Functional studies reveal that Ataxin-10 interacts with polo-like kinase 1 (Plk1); Plk1 phosphorylates Ataxin-10 at Ser77/Thr82, regulating cytokinesis. ATXN10 knockdown in HeLa cells induces multinucleation rescued by wild-type but not phospho-deficient Ataxin-10, implicating disrupted protein turnover in pathogenesis (PMID:21857149).

Key take-home: ATXN10 intronic ATTCT repeat expansions are a well-established autosomal dominant cause of SCA10, with strong genotype–phenotype correlations and functional concordance, informing genetic testing and prognostic counseling.

References

• Nature genetics • 2000 • Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. PMID:11017075
• Neurology • 2004 • Clinical phenotype of Brazilian families with spinocerebellar ataxia 10. PMID:15505178
• Movement disorders : official journal of the Movement Disorder Society • 2010 • Spinocerebellar ataxia type 10: Frequency of epilepsy in a large sample of Brazilian patients. PMID:20818609
• Cell cycle (Georgetown, Tex.) • 2011 • Phosphorylation of Ataxin-10 by polo-like kinase 1 is required for cytokinesis. PMID:21857149
• PloS one • 2013 • Expansion of the Spinocerebellar ataxia type 10 (SCA10) repeat in a patient with Sioux Native American ancestry. PMID:24278426
• Neuromolecular medicine • 2017 • Haplotype Study in SCA10 Families Provides Further Evidence for a Common Ancestral Origin of the Mutation. PMID:28905220
• European journal of neurology • 2017 • Spinocerebellar ataxia type 10: common haplotype and disease progression rate in Peru and Brazil. PMID:28560845
• Cerebellum (London, England) • 2023 • Spinocerebellar Ataxia Type 10 with Atypical Clinical Manifestation in Han Chinese. PMID:35441258

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