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

Leigh A Rettenmaier; Jin Yun Helen Chen; Jason MacMore; Anoopum S Gupta; Chih-Chun Lin; Christopher D Stephen; David Pellerin; Bernard Brais; Jeremy D Schmahmann

doi:10.1007/s12311-025-01882-3

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

Journal article

Peer reviewed

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

Leigh A Rettenmaier, Jin Yun Helen Chen, Jason MacMore, Anoopum S Gupta, Chih-Chun Lin, Christopher D Stephen, David Pellerin, Bernard Brais and Jeremy D Schmahmann

Cerebellum (London, England), Vol.24(5), p.133

07/18/2025

DOI: 10.1007/s12311-025-01882-3

PMID: 40679574

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Abstract

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) (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) , 2/30 (GAA) . 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%.

Adolescent

Adult

Aged

Female

Fibroblast Growth Factors - genetics

Genetic Testing

Hospitals, General

Humans

Male

Massachusetts

Middle Aged

Phenotype

Spinocerebellar Ataxias - diagnosis

Spinocerebellar Ataxias - genetics

Spinocerebellar Degenerations - diagnosis

Spinocerebellar Degenerations - genetics

Young Adult

Details

Title: Subtitle: Spinocerebellar Ataxia Type 27B can be Suspected Based on Clinical Phenotype: The Massachusetts General Hospital Ataxia Center Experience
Creators: Leigh A Rettenmaier - Massachusetts Mental Health Center
Jin Yun Helen Chen - Mass General Brigham
Jason MacMore - Mass General Brigham
Anoopum S Gupta - Massachusetts Mental Health Center
Chih-Chun Lin - Massachusetts Mental Health Center
Christopher D Stephen - Massachusetts Mental Health Center
David Pellerin - Montreal Neurological Institute and Hospital
Bernard Brais - McGill University
Jeremy D Schmahmann - Harvard University
Resource Type: Journal article
Publication Details: Cerebellum (London, England), Vol.24(5), p.133
DOI: 10.1007/s12311-025-01882-3
PMID: 40679574
NLM abbreviation: Cerebellum
ISSN: 1473-4222
eISSN: 1473-4230
Grant note: 189963 / CIHR
Language: English
Date published: 07/18/2025
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9984945918602771

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