ATXN7 – Autosomal Dominant Cerebellar Ataxia Type II

Autosomal dominant cerebellar ataxia type II, also known as spinocerebellar ataxia type 7 (MONDO_0016163), is caused by CAG repeat expansions in the ATXN7 gene (ATXN7). Clinically, SCA7 presents with progressive cerebellar ataxia and retinal degeneration leading to macular atrophy and visual impairment. Ataxin-7 is a component of the SAGA complex and regulates histone acetylation, and pathological polyglutamine tracts disrupt neuronal transcription homeostasis. Pathological expansions confer neuronal vulnerability in the cerebellum and retina, correlating with disease severity. The phenotype ranges from infantile-onset to adult-onset syndromes with variable penetrance and anticipation.

Genetic evidence for ATXN7–SCA7 is robust and meets strong ClinGen criteria. Numerous case series and family studies have identified CAG repeat expansions exceeding 37 repeats in affected individuals. In nine Indian families comprising 22 affected individuals, repeat sizes ranged from 40 to 94, inversely correlating with age at onset (PMID:25900954). Four Swedish families showed repeat lengths from 40 to >200 (PMID:9425223). A consanguineous Mexican pedigree demonstrated germline expansion from 37 to 72 repeats with complete segregation in four offspring (PMID:25664129). De novo expansions on intermediate alleles and anticipation phenomena have been consistently observed. Founder effects have been documented in Scandinavia (PMID:11175279) and a shared haplotype extends between South African and Zambian patients (PMID:26003224).

Functional assays support a toxic gain-of-function mechanism mediated by polyglutamine expansion. In cell models, mutant ataxin-7 co-aggregates with p53, reducing its transcriptional activity and increasing NOX1 expression, leading to impaired mitochondrial respiration, heightened glycolysis, and 20% lower ATP levels (PMID:25647692). Cellular models also demonstrate that mutant ataxin-7 forms intranuclear inclusions correlating with disease severity. Restoring p53 function or suppressing NOX1 activity reverses metabolic dysfunction and ameliorates toxicity. Mouse studies preventing caspase-7 cleavage of ataxin-7 (D266N) showed improved motor performance, reduced neurodegeneration, and extended lifespan, indicating proteolysis as a key mediator of toxicity (PMID:25859008). Rescue of metabolic defects via p53 restoration or NOX1 inhibition further validates these pathways as therapeutic targets.

Phenotypic variability includes an ALS-like presentation in a 45-year-old with a 39-CAG expansion who lacked overt ataxia or retinal dystrophy, suggesting that shorter expansions or modifying factors can yield incomplete or divergent clinical manifestations (PMID:34870541). This phenotypic variability underscores the need for comprehensive genetic testing in neurodegenerative presentations. It highlights that shorter expansions may produce divergent neurodegenerative phenotypes. Further studies are required to delineate modifiers influencing clinical heterogeneity.

Integration of genetic segregation in multiple pedigrees, broader founder analyses, and concordant functional rescue experiments underpin a Strong ClinGen classification for the ATXN7–SCA7 association. Segregation analyses in multiple pedigrees exceed LOD thresholds, and functional studies bolster causality. No significant refuting evidence has been reported. Additional longitudinal cohorts and natural history studies exist but exceed the current scoring framework.

CAG repeat expansions in ATXN7 are predictive biomarkers for SCA7 diagnosis and genetic counseling. Early identification enables stratification for emerging therapies targeting polyglutamine toxicity. Repeat sizing informs prognosis and guides family planning. Functional assays provide mechanistic insight and potential drug targets. Multigenerational testing can anticipate disease course. This gene–disease link is clinically actionable.

References

• Human molecular genetics • 1998 • Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation. PMID:9425223
• International journal of clinical and experimental medicine • 2014 • Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report. PMID:25664129
• The Indian journal of medical research • 2015 • Spinocerebellar ataxia 7 (SCA7) in Indian population: predilection of ATXN7-CAG expansion mutation in an ethnic population. PMID:25900954
• European journal of human genetics : EJHG • 2000 • Evidence for a common Spinocerebellar ataxia type 7 (SCA7) founder mutation in Scandinavia. PMID:11175279
• Journal of the neurological sciences • 2015 • Evidence for a common founder effect amongst South African and Zambian individuals with Spinocerebellar ataxia type 7. PMID:26003224
• Biochimica et biophysica acta • 2015 • Altered p53 and NOX1 activity cause bioenergetic defects in a SCA7 polyglutamine disease model. PMID:25647692
• Human molecular genetics • 2015 • Proteolytic cleavage of ataxin-7 promotes SCA7 retinal degeneration and neurological dysfunction. PMID:25859008
• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2022 • Amyotrophic lateral sclerosis associated with a pathological expansion in the ATXN7 gene. PMID:34870541

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