To describe a novel ATXN2 variant: a polyglutamine repeat expansion within the fully penetrant range of Spinocerebellar Ataxia Type 2 (SCA2), asymptomatic in heterozygous alleles; however, it presents as a neurodegenerative disorder in the homozygous state.

Spinocerebellar ataxias are autosomal dominant cerebellar ataxias. SCA2 is a complex ataxia with various extracerebellar signs, resulting from a CAG repeat expansion in ATXN2. Fully penetrant alleles commonly have 37-39 repeats. ATXN2 is a complex modulator of neurological disease; Intermediate-length CAG repeat expansions increase the likelihood of neurodegenerative disorder development, and homozygous variants are exceedingly rare.

Three individuals, two siblings and a cousin, were investigated for a neurodegenerative disorder with overlapping phenotypes. The probands and their five immediate family members underwent whole genome sequencing with ExpansionHunter followed by repeat-primed PCR.

Genetic sequencing identified a homozygous 39/39 CAG repeat expansion with 4 CAA interruptions in the ATXN2 gene of all three probands. Following intellectual or learning difficulties during childhood, they developed a pyramidal syndrome with spastic gait and a major neurocognitive disorder with prominent frontal signs during their mid-twenties. Over the course of 5-10 years, all patients completely loss their autonomy. Shared phenotypical features included ataxia, dysphagia, aphasia, atypical parkinsonism, myoclonus, incontinence, frontal-predominant diffuse cortical atrophy, symmetric leukoencephalopathy, and cerebellar atrophy. A 39 CAG heterozygous allele was identified in four unaffected parents (age 65+) and one sibling in his thirties. Three asymptomatic carriers consented to evaluation and had normal neurological exams, neuropsychological assessments, and cerebral MRIs. Considering the carriers' ages and their heterozygous pathogenic variant for SCA2, clinical and radiological signs of disease were anticipated but not observed.

This study describes a novel ATXN2 variant associated with an early-onset neurodegenerative disorder in the homozygous state. The potential for autosomal recessive transmission or reduced penetrance in the heterozygous state expands our current understanding of ATXN2 variants.