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Keywords:

  • amyotrophic lateral sclerosis;
  • Mendelian genes;
  • penetrance;
  • phenotype;
  • prognosis

Although clinical picture of amyotrophic lateral sclerosis (ALS) is a stereotypical one, resulting from combination of signs secondary to dysfunction of both upper motor neuron (UMN) and lower motor neuron (LMN), clinical heterogeneity is a consistent feature of the disease. Age of onset, relative mix of UMN and LMN signs, duration of the disease and association with other conditions are major factors contributing to variable clinical phenotypes. Genetically, familial forms of ALS are associated with a large number of pleiotropic genes whose mutations impair different biochemical pathways, resulting in overlapping clinical and pathological phenotypes. Over the last few years contribution of large- and low-effect genes to sporadic ALS is increasingly recognized.