Pearls & Oy-sters: SCA27B as an Elusive Genetic Cause of Episodic Neurologic Symptoms in Later Adulthood

Spinocerebellar ataxia type 27B (SCA27B) is a recently identified autosomal dominant form of late-onset cerebellar ataxia (LOCA) caused by a guanine-adenine-adenine (GAA) > 250 intronic repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Recent studies suggest that SCA27B may account for 10%-60% of undiagnosed patients with LOCA. Age at onset ranges from 40s to 70s, and clinical features include slowly progressive pancerebellar syndrome with prominent gait ataxia and cerebellar oculomotor abnormalities. Positive family history may be absent, particularly given the characteristically late onset of this condition. It is important to note that up to half of the patients with SCA27B report episodic symptoms, including imbalance, vertigo, visual disturbances, or dysarthria, which might initially manifest without clear interictal clinical or radiologic features of cerebellar ataxia. These features can result in the misdiagnosis of SCA27B. We present 2 patients with LOCA. Both patients initially received alternative working diagnoses, which were re-examined several years later only after symptoms and imaging findings progressed. First-line genetic testing for both patients was unrevealing because of the deep intronic location of the causative variant. Ultimately, whole-genome-based testing in one case and targeted FGF14 trinucleotide repeat analysis in the other revealed the diagnosis of SCA27B. These cases highlight SCA27B as a cause of episodic neurologic symptoms in an older adult population. Furthermore, these cases demonstrate the potential pitfalls of panel and exome-based genetic testing, given the important role of pathogenic intronic variants in the spectrum of neurogenetic disorders.