Spinocerebellar Ataxia Type 12: From CAG Repeat Expansion to Cortico-Cerebellar Neurodegeneration

Spinocerebellar ataxia type 12 (SCA12) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the PPP2R2B gene. Unlike most spinocerebellar ataxias, SCA12 typically begins with a prominent upper limb action tremor, often mimicking essential tremor, and may precede gait ataxia by several years. As the disease progresses, patients develop cerebellar signs, dysarthria, hyperreflexia, and variable cognitive and neuropsychiatric symptoms, including anxiety and depression. Neuroimaging commonly shows cerebellar and cerebral cortical atrophy with relative sparing of brainstem and deep subcortical structures, creating a recognizable radiological pattern. The disorder demonstrates marked phenotypic variability and a strong founder effect in northern India, complicating genotype–phenotype correlations and diagnosis. Emerging evidence suggests that dysregulation of protein phosphatase 2A–related pathways contribute to selective cerebro-cerebellar neurodegeneration. Although no disease-modifying therapy exists, symptomatic treatment of tremor and psychiatric manifestations can substantially improve quality of life. This review integrates clinical, molecular, and neuroimaging evidence to position SCA12 as a distinct CAG repeat disorder characterized by tremor-dominant onset, cortico-cerebellar neurodegeneration, and RNA-mediated toxicity, highlighting the need for biomarker-driven diagnosis and targeted therapeutic development