Seiichiro Sugimoto

Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase

We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1 +/- 13.2 (mean +/- S.D.) years, with the age at onset being 39.7 +/- 10.5 years old (mean +/- S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8 +/- 3.2 years after the onset. Upper limb weakness started at 15.5 +/- 8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarkes columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme.

Posterior tibial somatosensory evoked potentials in Duchenne-type progressive muscular dystrophy

Posterior tibial somatosensory evoked potentials were recorded from 10 patients with Duchenne-type progressive muscular dystrophy (DMD). The results of the patients were compared with age-matched controls. The ratio of height to latency (H/P38 and H/N22-P38) decreased significantly in DMD, which indicated central conduction disturbances in DMD.

Axonal transport in mdx mouse sciatic nerve

Anterograde and retrograde flows of acetylcholinesterase (AChE) in sciatic nerves of adult mdx mice were compared with those of normal mice. Specific molecular forms of AChE were resolved by high-performance liquid chromatography such that slow anterograde (G1 + G2), fast anterograde and fast retrograde (G4 and A12) flows could be simultaneously studied. Although we found no difference in the total AChE activity and the molecular forms in non-ligated nerves between mdx and the normal mice, ligated nerves showed significant differences. The total AChE activity accumulated at the proximal segment of ligated nerve was higher in mdx mice than in normal mice after 24 h ligation. The G1 + G2 molecular forms were accumulated more in the proximal segment of mdx than the normal. A12, on the other hand, was more abundant in both segments of mdx mice than the normal. No statistically significant difference in the accumulated amount of G4 molecular form was present between mdx and the normal mice at either proximal or distal segment. These results indicated that axonal flow in sciatic nerve likely plays a role in muscle regeneration, and that the transport machinery in dystrophin-deficient mdx neuron is probably normal.

Kinetic properties and isozyme composition of myosin in the mdx mutant mouse

Skeletal muscle fibers from muscular dystrophic mice (C57BL/10-mdx) 1-4 months of age show elevated free Ca2+ concentrations both at resting and stimulated states, although contractility of adult (2-12 months old) mouse is similar to that of normal mouse. To evaluate the sensitivity of the contractile system of adult mdx mouse muscle to elevated free Ca2+ concentration, Mg2(+)-adenosine triphosphatase (ATPase) activity was examined using myosin, myosin B, and reconstituted actomyosin. Myosin Mg2(+)-ATPase activity of the mdx mouse was significantly higher than that of the normal mouse. Myosin B ATPase activity of the mdx mouse was also higher than that of normal mouse in free Ca2+ concentrations between 10(-9) and 10(-5) M, though there was no difference in the Ca2+ concentration required for half maximal activation of ATPase activity, 2 x 10(-7) M. Polymerized actin (FA) isolated from normal and mdx mice activated rabbit myosin Mg2(+)-ATPase identically, while activation of Mg2(+)-ATPase in mdx myosin by rabbit FA was significantly lower than that in normal mouse myosin. Rapid Pi liberation by Mg2(+)-ATPase in mdx mouse myosin was about half that of normal mouse myosin, being consistent with low activation of Mg2(+)-ATPase activity by rabbit FA. Polyacrylamide gel electrophoresis in the presence of pyrophosphate showed that myosin molecules of mdx and normal mice were both composed of three isozymes, although the fast migrating myosin isozyme (M1) was decreased while the slow migrating band (M3) was increased in mdx myosin. Subunit composition of myosin analyzed by polyacrylamide gel electrophoresis in the presence of SDS showed that the content of the smallest light chain (LC3) in mdx myosin was lower than that of normal mouse myosin, which agreed with findings that mdx myosin contained less M1 isozyme than normal myosin. These results indicated that the lowered response of mdx muscle fibers to elevated Ca2+ concentration can be attributed to the isozyme composition of myosin in mdx mouse.