FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS WITH A MUTATION IN EXON-4 OF THE CU ZN SUPEROXIDE-DISMUTASE GENE - PATHOLOGICAL AND IMMUNOCYTOCHEMICAL CHANGES/

Detailed molecular pathology studies and clinicopathological phenotypi ng of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degene ration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examinaton including immunocytochemistry of ubiquitin and neurofilament epitopes was perfor med, The case falls into the category of ''amyotrophic lateral scleros is (ALS) with posterior column involvement.'' Critical analysis of the findings indicates a truly multisystem disorder in which ascending se nsory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilam ent phosphorylation was not a prominent feature. Ubiquitinated neurona l inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dem entia. The motor cortex was preserved despite severe distal axonal los s in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long pr ojecting axons. The differences and similarities compared to previousl y reported case with I113T (exon 4) and A4T (exon 1) mutations are dis cussed, Findings related to inflammatory cell infiltration, ubiquitina tion and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.