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

Centre hospitalier Agen, Agen, Aquitaine, France
Neurogenetics (Impact Factor: 2.88). 09/2007; 8(3):231-3. DOI: 10.1007/s10048-007-0090-4
Source: PubMed


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.

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    • "In Alzheimer's disease, a case with mosaicism from somatic mutation of presenilin-1 was described, with 14% mutant DNA in the cortex.23 Hereditary spastic paraplegia caused by mosaicism for a spastin mutation has been reported.24 Very recently, a novel form of neurodegeneration with brain iron accumulation has been found to be a result of mutations in WDR45, with a somatic origin in some cases.25 Mosaicism for triplet-repeat neurodegenerative disorders from somatic mutation of the expanded repeat has been described,26,27 including fragile X premutation syndrome, in which somatic instability in brain appears more pronounced than in blood,28 and c9orf72 in amyotrophic lateral sclerosis.29 "
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