Familial amyotrophic lateral sclerosis with a novel Leu126Ser mutation in the copper/zinc superoxide dismutase gene showing mild clinical features and Lewy body-like hyaline inclusions

Background: Mutations in the SOD1 gene are responsible for approximately 25 % of all familial amyotrophic lateral sclerosis (ALS) cases. However, the c orrelation between the clinical and pathological features and the various S OD1 gene mutations has not been well characterized. Objectives: To screen the SOD1 gene in search of potential mutations and to obtain clinical and pathological data for 2 Japanese families with ALS. Design: Clinical histories and neurological findings, gross and microscopic pathological features, and DNA analysis of the SOD1 gene. Results: The 2 families with ALS showed a novel missense mutation in the SO D1 gene, which was heterozygous for point mutation TTG to TCG, causing subs titution of leucine for serine at codon 126 (Leu126Ser) in exon 5. Clinical ly, patients showed slower disease progression and lack of upper motor neur on signs. Neuropathologically, the autopsied patient showed the form of fam ilial ALS with posterior column involvement, and the pontocerebellar tract and the dentate nuclei of the cerebellum were also involved. Furthermore, a bundant Lewy body-like hyaline inclusions were observed in the affected mot or and nonmotor neurons. Conclusions: Familial ALS with a novel Leu126Ser mutation in the SOD1 gene showed mild clinical features and lack of upper motor neuron signs. We beli eve that Leu126Ser might be associated with the clinical features and that the mutation site in the SOD1 gene and disease duration might be associated with the formation of Lewy body-like hyaline inclusions.