Variance of age at onset in a Japanese family with amyotrophic lateral sclerosis associated with a novel cu/zn superoxide dismutase mutation

Abstract

Although about 5 to 10% of amyotrophic lateral sclerosis (ALS) cases are familial, the pathophysiology of ALS remains unknown. A new point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene, resulting in an amino acid substitution of leucine84 by valine (L84V), in a Japanese patient with familial ALS (FALS) was identified. This L84V substitution was not observed in 57 normal Japanese control subjects. The enzymatic activities of Cu/Zn SOD of skin fibroblasts were significantly reduced to 75% of the control level in the affected patient. The progression of the disease with this mutation is very rapid, but the age at onset varies with sex or generation within a family.

Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions

“…The CD68 method has increased sensitivity for the detection of descending corticospinal tract degeneration compared with LFB staining [38]. Clinical manifestations are predominantly restricted to the lower motor neurons in Ala4Val [4], Ala4Thr [29], His46Arg [15], His48Gln [31], Leu84Val [39], and Ser134Asn [40]. Pathological examinations of cases with Ala4Val and Ala4Thr confirmed the involvement of the lower motor neurons with sparing of the upper motor neurons, whereas autopsy analysis of a case with the His48Gln mutation showed both upper and lower motor involvement [31].…”

Superoxide dismutase-1 mutation-related neurotoxicity in familial amyotrophic lateral sclerosis

“…40,[50][51][52] The clinical courses of A4T, A4V, G41S, L84V, L106V, I112T and A145T mutants progress rapidly (0.5-1.5 years) compared to those of other mutants. 13,28,50,51 The duration of illness for G37R, G41D, H46R, G93C, G93D and L144F mutants is longer (5-40 years) than those for other mutants. 50,51 Pyramidal tract sign appears mild in A4T, A4V, L84V and S134D mutants.…”

Neuronal NOS is dislocated during muscle atrophy in amyotrophic lateral sclerosis

“…Approximately 10% of the cases of ALS are inherited, usually as an autosomal dominant trait. In 25% of familial cases, the disease is caused by mutations in the gene encoding cytosolic copper-zinc superoxide dismutase (SOD1) [4][5][6]. The reason why the motor neuron is selectively damaged has not been elucidated.…”