Phenotypic Heterogeneity in a SOD1 G93D Italian ALS Family: An Example of Human Model to Study a Complex Disease

Department of Laboratory Medicine, Medical Genetics, Niguarda Ca' Granda Hospital, Milan, Italy.
Journal of Molecular Neuroscience (Impact Factor: 2.34). 12/2010; 44(1):25-30. DOI: 10.1007/s12031-010-9480-4
Source: PubMed


We report different clinical expression in seven members of a large family with amyotrophic lateral sclerosis (ALS) and the G93D mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene. The ALS clinical course in the proband showed an unusually fast progression of the disease compared to the paucisymptomatic presentation associated to this mutation in the two previously Italian families described. The remaining mutation carriers did not show the aggressive clinical course displayed by the proband. We selected few genes known to be ALS modifiers searching for genetic variants that could explain the wide phenotypic diversity within the family. Exclusion of causative genes such as TDP43, FUS, PGRN and VAPB was performed too. We believe that this kind of family with contrasting phenotypes of ALS may be considered an excellent human model to study the relationship between a wider genetic profile, including modifier genes, and the clinical expression of the disease. Therefore, the novelty of our approach is also represented by the study of a single family to reproduce a composite structure in which search for possible modifier genes/genetic variants linked to SOD1 mutated.

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    • "No mutation was found in patient ZM. Our findings confirm the hypothesis that variants of ANG gene may influence clinical manifestations in patients bearing SOD1 mutation (Penco et al., 2011). ANG mutations were recently reported in 2 patients harboring FUS mutations , but the possible effect on phenotypic variability was not investigated (Millecamps et al., 2010). "
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