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From the Departments of Biochemistry (Drs. Orrell and deBelleroche, and J.J. Habgood, I. Gardiner, J. Greenwood, and A.W. King) and Clinical Neuroscience (Drs. Orrell and Lane), Charing Cross and Westminster Medical School, London, England; the Department of Biochemistry (Drs. Bowe and Hallewell), Imperial College of Science, Technology and Medicine, London, England; and the Department of Clinical Chemistry (Dr. Marklund), Umea University Hospital, Umea, Sweden.
Supported by the Motor Neurone Disease Association, The American ALS Association, The Special Trustees of Charing Cross and Westminster Hospitals, Wellcome Trust Grant 038968, The Swedish Natural Science Research Council, and the Council of Vasterbotten County, Sweden.
Received May 6, 1996. Accepted in final form August 27, 1996.
Address correspondence and reprint requests to Dr. Richard W. Orrell, Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 673, Rochester, NY 14642.
Article abstract-Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide dismutase, occur in patients with a familial form of amyotrophic lateral sclerosis (ALS). We investigated 71 families with more than one individual affected by ALS for clinical features and SOD-1 mutations. Mutations were identified in 14 families, indicating the presence of SOD-1 mutations in around 20% of this population. There were 10 different heterozygote missense point mutations in eight different codons, and a novel two-base frameshift insertion (132insTT), which leads to substitution of aspartic acid for glutamic acid at codon 132, and a premature stop codon at 133, with predicted truncation of the protein. SOD enzyme activity was reduced to around 50% of normal in individuals with SOD-1 mutations, and may be a useful predictor for the presence of these mutations. A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models. In general, the finding of an SOD-1 mutation does not accurately predict a prognosis or disease severity.
NEUROLOGY 1997;48: 746-751
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