Spinocerebellar Ataxia Type 27B can be Suspected Based on Clinical Phenotype: The Massachusetts General Hospital...

Spinocerebellar Ataxia type 27B (SCA27B) is caused by an intronic GAA repeat expansion in the fibroblast growth factor 14 (FGF14) gene. The core clinical phenotype is a slowly progressive, adult-onset cerebellar ataxia, often with downbeat nystagmus (DBN) and episodic worsening. We tested whether clinical phenotyping could predict this genetic disorder. We screened the Massachusetts General Hospital Ataxia Center registry (n = 3,182) for patients with a) isolated DBN, b) DBN with ataxia, and c) autosomal dominant cerebellar ataxia (ADCA) that had eluded genetic diagnosis. Patient histories, examinations, and imaging were reviewed. Genetic analysis for FGF14 expansion was performed. Of 65 identified patients, 39 completed genetic testing. Among 14 with isolated DBN, 9 carried an FGF14 repeat expansion (GAA)_≥250 (range, 295-461), 1 had a potentially pathogenic allele (247 repeats), and 4 had normal alleles. Among 19 with DBN plus ataxia, 12 tested positive (276-431 repeats), 1 had a suspected pathogenic allele (228 repeats), and 6 had normal alleles. All 4 ADCA patients tested positive (320-483 repeats), as did 2 presymptomatic siblings. Our cohort enriched for suspicion of SCA27B had confirmed or suspected pathogenic FGF14-GAA expansion in 74.4% (29/39). Diagnostic success rate was 90.0% (27/30) in patients with onset > 45 years: 25/30 (GAA)_≥250, 2/30 (GAA)_200-249. Cerebellar atrophy was seen in 97.1% (34/35), mostly in the vermis/paravermis. Clinically meaningful improvement with 4-aminopyridine occurred in 71.0% (22/31) of patients. SCA27B can be reliably recognized from its core clinical phenotype in up to 90% of cases, enabling successful pharmacotherapy in 71.0%.