G507D mutation in FUS gene causes familial amyotrophic lateral sclerosis with a specific genotype-phenotype correlation.

Mutations in FUS gene have been described classically in young ALS patients with aggressive disease course. Here we report a large family carrying a missense mutation c.1520 G>A in FUS gene with a tight association with an atypical FUS-ALS phenotype. A 60-year-old man with unilateral leg involvement at onset showed very slow disease progression with selective posterior legs atrophy, tracing his aunt's disease history. His father and uncle died for ALS after a long disease course. Another patient with a 14 years history of ALS with the same phenotype, was found to belong to the same family. In all cases, genetic analysis of FUS gene revealed a missense mutation c.1520 G>A (p.G507D) inherited with a heterozygous pattern. Co-segregation of p.G507D mutation and a specific disease phenotype within the family, characterised by predominant involvement at the lower limbs, slow progression, late bulbar and respiratory failure, demonstrates pathogenicity of this mutation, establishes a well-defined genotype-phenotype correlation and expands the clinical spectrum of heterogeneity in FUS-ALS.