Genetics of familial ALS and consequences for diagnosis

Familial amyotrophic lateral sclerosis (fALS) is a well-recognised conditio n that accounts for almost 10% of all cases of ALS. Most cases are now know n to be transmitted by an autosomal dominant trait. When fALS is compared c linically to sporadic ALS, 20% of cases manifest atypical features such as pain, paraesthesia or urgency micturition. Moreover, a disease duration of over 10 years, with very slow progression, appears to occur almost exclusiv ely in cases of fALS, Studies of superoxide dismutase (SOD1) mutations in f ALS have shown that the disease may be multidegenerative, with oculomotor o r cerebellar involvement. Molecular genetics has also demonstrated that not all SOD1 mutations have a dominant influence, and the detailed description of the Scandinavian D90A homozygous mutation is very informative in this r egard. Misdiagnosis of fALS can be attributed to one of the following situa tions: (i) atypical phenotype ALS with a multidegenerative profile; (ii) un usually long lasting ALS with mild motor neuron involvement; (iii) signific ant clinical heterogeneity between affected family members; (iv) low reliab ility of family history; (v) existence of an unknown or unexpected mode of transmission; and (vi) other multidegenerative disorders with motor neuron involvement, Pedigrees and fALS cases corresponding to these situations are presented. (C) 1999 Published by Elsevier Science B.V. All rights reserved .