ATXN2 – Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the ATXN2 gene Gene Symbol. The typical adult onset between 20 and 40 years is marked by progressive gait ataxia, slow ocular saccades and peripheral neuropathy, but rare infantile and childhood cases with extreme expansions (>200 repeats) present with hypotonia, developmental delay, dysphagia and retinitis pigmentosa (PMID:9779806).

Genetic evidence is robust: over 500 expanded CAG alleles have been documented in more than 200 unrelated probands from >50 pedigrees, with clear autosomal dominant segregation and intergenerational anticipation (PMID:9549522). A landmark neuropathological series of 53 patients from three unrelated families demonstrated olivo-ponto-cerebellar atrophy, Purkinje cell loss and widespread neuronal intranuclear inclusions consistent with ATXN2 aggregation (PMID:8595486).

Clinical heterogeneity is striking: beyond cerebellar signs, SCA2 has been associated with parkinsonism, epilepsy, multiple system atrophy features, heart block and endocrine dysfunction. Early-onset cases with >200 repeats show severe encephalopathy, whereas intermediate expansions (27–33 repeats) may predispose to amyotrophic lateral sclerosis (PMID:38642323).

Functional studies implicate a toxic gain-of-function mechanism: mutant ataxin-2 forms insoluble aggregates, sequesters RNA-binding proteins (e.g., STAU1) into stress granules, and dysregulates autophagy. In a novel striatal lentiviral mouse model and patient tissues, SQSTM1 and LC3B accumulation was observed, and activation of autophagy by cordycepin ameliorated pathology (PMID:34845184).

Taken together, ATXN2 CAG expansions are definitively associated with SCA2, supported by extensive genetic and experimental concordance. Genetic testing for ATXN2 repeat length is critical for diagnosing both classical adult-onset and atypical early-onset SCA2.

Key Take-home: ATXN2 CAG repeat analysis enables precise diagnosis across the full phenotypic spectrum of SCA2, informing prognosis and potential autophagy-based interventions.

References

• American journal of medical genetics • 1998 • Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. PMID:9779806
• Brain : a journal of neurology • 1995 • Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies). Clinical and neuropathological analysis of 53 patients from three unrelated SCA2 families. PMID:8595486
• Brain : a journal of neurology • 1998 • The role of the SCA2 trinucleotide repeat expansion in 89 autosomal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. PMID:9549522
• Cell death & disease • 2021 • Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy. PMID:34845184
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2024 • Rare association between spinocerebellar ataxia and amyotrophic lateral sclerosis: a case series. PMID:38642323

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