GAA-FGF14 Expansions and CACNA1A Variants: Phenotypic Overlap and Diagnostic Implications
Elisabetta Indelicato1, Zofia Fleszar2,3, David Pellerin4,5
1Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Summary
Spinocerebellar ataxia 27B (SCA27B) is caused by FGF14 repeat expansions. This study found SCA27B in 9% of patients with CACNA1A variants, suggesting reevaluation for late-onset ataxia.
Area of Science:
- Neurogenetics
- Neurology
- Genomics
Background:
- Spinocerebellar ataxia 27B (SCA27B) is linked to FGF14 intronic repeat expansions.
- SCA27B presents with chronic cerebellar ataxia and episodic symptoms, overlapping with CACNA1A spectrum disorders.
Purpose of the Study:
- To determine the frequency of GAA-FGF14 repeat expansions in patients initially diagnosed with CACNA1A-related ataxia.
- To investigate the diagnostic utility of FGF14 testing in this patient cohort.
Main Methods:
- Cross-sectional, multicenter study design.
- Genetic testing for GAA-FGF14 repeat expansions in patients with CACNA1A variants.
- Reclassification of CACNA1A variants of uncertain significance (VUSs).
Main Results:
- Pathogenic GAA-FGF14 expansions (≥250 repeats) were identified in 9% (6/67) of patients with CACNA1A variants.
- Patients with GAA-FGF14 expansions exhibited late-onset (>40 years) and carried CACNA1A VUSs.
- Four of six patients with GAA-FGF14 expansions had their CACNA1A VUSs reclassified as likely benign, confirming SCA27B diagnosis.
Conclusions:
- Late-onset ataxia initially attributed to CACNA1A variants warrants reevaluation for SCA27B.
- Genetic testing for GAA-FGF14 repeat expansions is crucial, especially when CACNA1A variants of uncertain significance are present.
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