Article

Journal of Molecular Neuroscience

, Volume 44, Issue 1, pp 25-30

First online:

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

  • Silvana PencoAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital Email author 
  • , Christian LunettaAffiliated withNEuroMuscular Omnicentre, Fondazione Serena Onlus, Niguarda Ca’ Granda Hospital
  • , Lorena MoscaAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital
  • , Eleonora MaestriAffiliated withNEuroMuscular Omnicentre, Fondazione Serena Onlus, Niguarda Ca’ Granda Hospital
  • , Francesca AvemariaAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital
  • , Claudia TarlariniAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital
  • , Maria Cristina PatrossoAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital
  • , Alessandro MarocchiAffiliated withDepartment of Laboratory Medicine, Medical Genetics, Niguarda Ca’ Granda Hospital
  • , Massimo CorboAffiliated withNEuroMuscular Omnicentre, Fondazione Serena Onlus, Niguarda Ca’ Granda Hospital

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Abstract

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.

Keywords

Complex disease FALS Genetic variations Human model SOD1 mutation