Objective: This study aimed to investigate the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases.
Background: Partial phenotypic overlap has been suggested between multiple system atrophy (MSA) and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14.
Method: We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1,003 controls. The FGF14 repeat locus was genotyped using long-range PCR and bidirectional repeat-primed PCRs, and expansions were confirmed with targeted long-read Oxford Nanopore Technologies sequencing.
Results: We identified 19 multiple system atrophy cases carrying an FGF14 GAA≥250 expansion (2.89%, n=19/657), a significantly higher frequency than in controls (1.40%, n=12/1,003) (p=0.04). Long-read Oxford Nanopore Technologies sequencing confirmed repeat sizes and polymorphisms detected by PCR, with high concordance (Pearson’s r=0.99, p<0.0001). Seven multiple system atrophy patients had a pathogenic FGF14 GAA≥300 expansion (five pathologically confirmed and two clinically diagnosed) and 12 had intermediate GAA250-299 expansion (six pathologically confirmed and six clinically diagnosed). A similar proportion of cerebellar-predominant and parkinsonism-predominant multiple system atrophy cases had FGF14 expansions. multiple system atrophy patients carrying an FGF14 GAA≥250 expansion exhibited severe gait ataxia, autonomic dysfunction and parkinsonism in keeping with a MSA phenotype, with a faster progression to falls (p=0.03) and regular wheelchair use (p=0.02) compared to the multiple system atrophy cases without FGF14 GAAexpansion. The length of the GAA•TTC repeat expansion lengths inversely correlated with survival in multiple system atrophy patients (r = −0.67; p=0.02), but not with age of onset.
Conclusion: Therefore, screening for FGF14 GAA•TTC repeat expansion should be considered for multiple system atrophy patients with rapid loss of mobility and for complete diagnostic accuracy at inclusion in disease-modifying multiple system atrophy drug trials.
To cite this abstract in AMA style:
V. Chelban, D. Pellerin, N. Vijiaratnam, S. Sambin, M. Ostrozovicova, C. Girges, P. Leigh, L. Beichert, C. Bonnet, M. Renaud, W. Meissner, A. Sieben, D. Crosiers, P. Cras, S. Zuchner, J-C. Corvol, M. Farrer, M. Synofzik, B. Brais, T. Warner, H. Morris, Z. Jaunmuktane, T. Foltynie, H. Houlden. The Role of FGF14 GAA Repeat Expansions in Multiple System Atrophy: Frequency, Phenotypic Correlations, and Prognostic Implications [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/the-role-of-fgf14-gaa-repeat-expansions-in-multiple-system-atrophy-frequency-phenotypic-correlations-and-prognostic-implications/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-fgf14-gaa-repeat-expansions-in-multiple-system-atrophy-frequency-phenotypic-correlations-and-prognostic-implications/