ATXN1 – Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, progressive neurodegenerative disorder characterized by cerebellar ataxia, pyramidal signs and multisystem involvement due to neuronal loss in the cerebellum, brainstem and spinal tracts. Pathogenesis is driven by CAG repeat expansions in exon 8 of ATXN1 leading to an expanded polyglutamine tract in the Ataxin-1 protein and toxic gain-of-function.

Genetic evidence is robust: a Siberian kindred comprising 78 genotyped affected individuals and over 650 at-risk relatives demonstrated expanded alleles (39–72 repeats) in all symptomatic patients (PMID:8619528). In addition, 35 Brazilian families with autosomal dominant ataxia carried pathogenic expansions segregating with disease (PMID:9629399), and further cohorts from China and India confirm SCA1 mutations in multiple unrelated families.

Segregation analysis across multiple generations showed complete co-segregation of expanded CAG repeats with disease status in 78 affected relatives (PMID:8619528) and absence of expansion in unaffected members, supporting high penetrance. One female carrier remained asymptomatic beyond age 66, indicating occasional reduced penetrance.

Pathogenic alleles feature uninterrupted CAG repeats ≥39, with intermediate alleles (27–38 repeats) exhibiting variable age at onset and penetrance. A case report described a patient harboring one allele with 61 repeats and one intermediate allele of 37 repeats, both uninterrupted, correlating with early onset and rapid progression (PMID:39289638).

Functional studies demonstrate that polyglutamine-expanded Ataxin-1 misregulates transcription via aberrant interactions with SMRT and HDAC3 in Drosophila and mammalian cells (PMID:15016912), sequesters the repressor Capicua and perturbs its activity (PMID:17190598), and alters splicing factor binding controlled by phosphorylation at Ser776 (PMID:20037628). These models recapitulate neuronal toxicity and are concordant with human pathology.

Although rare presentations mimicking multiple system atrophy with glial cytoplasmic inclusions have been described (PMID:8967756), the core SCA1 neuropathology of Purkinje cell loss and spinocerebellar degeneration remains consistent. No studies have refuted the ATXN1–SCA1 association.

Integration of extensive genetic and experimental data supports a Strong clinical validity classification. ATXN1 CAG repeat testing is clinically actionable for diagnosis, prognosis and genetic counseling in patients with dominantly inherited ataxia.

References

• Annals of Neurology • 1996 • Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions. PMID:8967756
• Annals of Neurology • 1996 • Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. PMID:8619528
• Arquivos de Neuro-Psiquiatria • 1997 • Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients. PMID:9629399
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. PMID:15016912
• Cell • 2006 • ATAXIN-1 interacts with the repressor Capicua in its native complex to cause SCA1 neuropathology. PMID:17190598
• PLoS One • 2009 • Phosphorylation of S776 and 14-3-3 binding modulate ataxin-1 interaction with splicing factors. PMID:20037628
• BMC Neurology • 2024 • Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report. PMID:39289638

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