FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS - MOLECULAR PATHOLOGY OF A PATIENT WITH A SOD1 MUTATION

We report the clinical, genetic, and neuropathologic findings in a pat ient with rapidly progressive familial amyotrophic lateral sclerosis ( ALS). We detected a point mutation at codon 48 of the Cu/Zn superoxide dismutase gene (SOD1) leading to a substitution of histidine by gluta mine in the copper-binding domain. The histopathologic features are co nsistent with those described in rapidly progressive sporadic ALS and do not support claims that sporadic and familial disease are different pathologic entities. Neurofilamentous accumulations, hyaline, and ubi quitinated inclusions were present in the motor cortex, brainstem, and anterior horn cells, but there was no evidence of abnormal SOD1 immun oreactivity. This confirms that the cytoskeletal pathology specific to ALS is secondary to an unknown biochemical disturbance caused by muta nt SOD1 molecules and not its toxic accumulation.