Cu/Zn superoxide dismutase gene mutations in amyotrophic lateral sclerosis: correlation between genotype and clinical features.

Received 21 May 1996 and in revised form 2 September 1996 Accepted 9 September 1996 Background Amyotrophic lateral sclerosis (ALS) is a fatal disease in which degeneration of upper and lower motor neurons leads to progressive weakness of bulbar, limb, thoracic, and abdominal muscles with relative sparing of oculomotor muscles and sphincter function. Although the clinical manifestations and pathological changes have been known since the time of Charcot and Joffroy,' the cellular and molecular processes leading to the selective loss of motor neurons are not understood. Recent developments in research on ALS, and in particular, the identification of mutations in the gene encoding Cu/Zn superoxide dismutase (CuZnSOD) in patients with the familial form of ALS2 may provide new treatment strategies. Although familial ALS accounts for only 5%-10% of all patients with ALS,3 4 it iS indistinguishable clinically from sporadic ALS.6 It is likely, therefore, that understanding of the mechanisms leading to motor neuron degeneration in familial ALS may provide fundamental insights into the pathogenesis of the sporadic form as well. The family of superoxide dismutase enzymes, of which CuZnSOD is one, comprises a series of important physiological antioxidant defence mechanisms in aerobic organisms.7 Superoxide dismutases inactivate the superoxide radical (02--) generated as a byproduct of normal and aberrant metabolic reactions by converting 02-into hydrogen peroxide (H20,) and oxygen (02):