SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.

BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.

A de novo SPAST mutation leading to somatic mosaicism is associated with a later age at onset in HSP.

SPG4/SPAST, the gene-encoding spastin, is responsible for the most frequent form of autosomal dominant hereditary spastic paraplegia (HSP). SPG4-HSP is a heterogeneous disorder characterized by both interfamilial and intrafamilial variation, especially regarding the severity and the age at onset. In this study, we investigated the origin of the mutation and the factors involved in intra-familial heterogeneity in a family with a SPG4 mutation. We demonstrated that the mutation occurred de novo and show evidence of somatic mosaicism in the grandfather, who was the only affected member of six siblings. His disease began at age 55, much later than in his daughter, who had onset at age 18, and his grandson, in whom onset was at age 5. These observations indicate that de novo mutations can occur in SPG4, and that somatic mosaicism might account for intra-familial variation in SPG4-linked HSP.