GAA‐FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications

Background An intronic (GAA)•(TTC) repeat expansion in FGF14 was recently identified as the cause of spinocerebellar ataxia 27B (SCA27B), a disorder presenting with both chronic cerebellar ataxia and episodic symptoms. The phenotype of SCA27B overlaps with that of CACNA1A spectrum disorders. Objecti...

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Vydáno v:Movement disorders Ročník 40; číslo 10; s. 2262 - 2268
Hlavní autoři: Indelicato, Elisabetta, Fleszar, Zofia, Pellerin, David, Nachbauer, Wolfgang, Zuchner, Stephan, Traschütz, Andreas, Amprosi, Matthias, Schöls, Ludger, Haack, Tobias B., Brais, Bernard, Boesch, Sylvia, Synofzik, Matthis
Médium: Journal Article
Jazyk:angličtina
Vydáno: Hoboken, USA John Wiley & Sons, Inc 01.10.2025
Wiley Subscription Services, Inc
Témata:
Adult
Aged
Ataxia
CACNA1A
Calcium Channels - genetics
Cerebellar ataxia
Cerebellum
Cross-Sectional Studies
episodic ataxia
Female
Fibroblast Growth Factors - genetics
GAA‐FGF14 ataxia
Humans
Male
Middle Aged
Movement disorders
Phenotype
Phenotypes
SCA27B
spinocerebellar ataxia 27B
Spinocerebellar Ataxias - diagnosis
Spinocerebellar Ataxias - genetics
CACNA1A
spinocerebellar ataxia 27B
SCA27B
GAA‐FGF14 ataxia
episodic ataxia
ISSN:0885-3185, 1531-8257
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Shrnutí:Background An intronic (GAA)•(TTC) repeat expansion in FGF14 was recently identified as the cause of spinocerebellar ataxia 27B (SCA27B), a disorder presenting with both chronic cerebellar ataxia and episodic symptoms. The phenotype of SCA27B overlaps with that of CACNA1A spectrum disorders. Objective The objective of this work was to investigate the prevalence of GAA‐FGF14 repeat expansions in patients with ataxia so far considered to be related to underlying CACNA1A variants. Methods This is a cross‐sectional multicenter study. Results GAA‐FGF14 testing showed pathogenic expansions (≥250 repeats) in 6/67 (9%) patients carrying CACNA1A variants. All patients with a pathogenic GAA‐FGF14 expansion had a disease onset >40 years and carried variants of uncertain significance (VUSs) in CACNA1A. Genetic reevaluation led to the reclassification of CACNA1A VUSs as likely benign in four of six patients, who were ultimately diagnosed with SCA27B. Conclusions Late‐onset ataxia cases previously considered as CACNA1A‐related disorder should be reevaluated and tested for SCA27B, particularly if related to a VUS in CACNA1A. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Bibliografie:PRECISE.net
Full financial disclosures and author roles may be found in the online version of this article.
E.I., Z.F., W.N., M.A., S.B., L.S., A.T., and M.S. are members of the European Reference Network for Rare Neurological Diseases (Project ID 739510). D.P. holds a fellowship award from the Canadian Institutes of Health Research. Z.F. was supported by the MINT‐Clinician Scientist program of the Medical Faculty Tübingen, funded by the Deutsche Forschungsgemeinschaft (German Research Foundation; Grant 493665037). This project was supported by the Clinician Scientist program
funded by the Else Kröner‐Fresenius‐Stiftung (M.S., Z.F., and A.T.).
Nothing to report.
Relevant conflicts of interest/financial disclosures
Funding agencies
Elisabetta Indelicato, Zofia Fleszar, and David Pellerin contributed equally as cofirst authors.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.30328