We describe a patient with late-onset ataxia, parkinsonism, tremor, and neuropathy with a novel FAT2 gene frameshift variant, a gene primarily expressed in the cerebellum and recently implicated in spinocerebellar ataxia type 45 (SCA45).

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant (AD), neurodegenerative disorders that manifest with cerebellar dysfunction. SCA45 is associated with FAT2 gene variants and is characterized by late-onset, pure cerebellar ataxia with autosomal dominant inheritance pattern. So far, only two families and one sporadic case with likely pathogenic FAT2 variants have been reported, all of which involved missense variants.

A 57-year-old woman presented with 3 years of progressive ataxia, neuropathy and mild tremor in the setting of a mood disorder. Family history was notable for a mother, maternal grandfather, and maternal great grandmother with similar symptoms. Exam revealed limb and gait ataxia, normal eye movements, mild symmetric parkinsonism, subtle postural and action tremor, and length-dependent neuropathy. Medications included aripiprazole. Lab work-up for metabolic, inflammatory, and immune related etiologies was negative. MRI brain showed no significant atrophy or lesions. CT brain showed calcification in the globus pallidus internus bilaterally. Genetic testing revealed a heterozygous frameshift variant (c.3039_3040del; p.Cys1014Profs*11) in the FAT2 gene.

Our patient’s inheritance pattern, cerebellar dysfunction and age of onset are consistent with SCA45. However, her phenotype includes tremor and neuropathy in addition to cerebellar ataxia, which contrasts with previously reported cases of a pure cerebellar syndrome associated with FAT2 missense variants. Our patient has a frame-shift mutation that likely resulted in a non-functional protein. This type of variant has not been reported before and can currently only be classified as a variant of unknown significance (VUS) as affected family members are deceased. This case adds to the growing body of information regarding FAT2 gene variants and their relation to hereditary ataxia.