Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy

Abstract 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. This study investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. 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. 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 GAA expansion. 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. 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.