Clinical characteristics of SOD1 gene mutations in UK families with ALS

Five to ten percent of patients with ALS have a family history of the disea se, inheritance is usually autosomal dominant. Mutations of the SOD1 gene w ere first identified in a proportion of families with ALS by Rosen et al. T he SOD1 gene encodes the enzyme copper zinc superoxide dismutase. Patients were studied from throughout the UK, where more than one individual in the family had ALS. Clinical history and examination of the individual and fami ly were obtained, and DNA extracted from leukocytes of whole blood samples. Mutations were identified by standard sequencing methods. To date, 12 diff erent mutations of SOD1 have been identified in 17 different families, repr esenting around 20% of all ALS families studied. The mutations were mainly single base substitutions - H48Q, G72S, G93R, G93V, E100G, D101N, D101G, C1 08V, I113T, D125H, I149T - and also an insertion mutation - 132insTT - lead ing to a premature stop codon. The mutations were present in exons 2-5. We did not identify mutations in exon I, although these have been identified b y others in different patient samples. We have identified SOD1 mutations in around 20% of UK families with ALS studied. This is similar to that report ed in other populations. Mutations have now been identified in all exons of SOD1. The individual mutations do not precisely predict disease severity, and generally it is difficult to give a specific prognosis based on the ind ividuals' SOD1 mutations. We continue to investigate the possible pathogeni c mechanisms of the SOD1 mutations. We have studied the neuropathology in p atients with SOD1 mutations. We are also performing linkage studies to iden tify the genes involved in the 80% of families where an SOD1 mutation has n ot been identified. (C) 1999 Elsevier Science B.V. All rights reserved.