Takeshi Nakano

Asymptomatic homozygous gene carrier in a family with type I familial amyloid polyneuropathy

Type I familial amyloid polyneuropathy (FAP) is a molecular disorder with a mutation of the transthyretin (TTR) gene, and most patients previously examined were reported to be heterozygous for this mutant gene. In the present study a rapid and easy DNA diagnostic method employing the polymerase chain reaction revealed an asymptomatic homozygous TTR gene carrier in a Japanese family with type I FAP. The level of the variant TTR (methionine instead of valine at position 30) in his serum was much higher than that usually found in type I FAP patients. However, the histological findings of the biopsied rectum and abdominal fat tissues failed to demonstrate amyloid deposits, and the autonomic nerves from his rectal mucosa were normally preserved. Moreover, his 72-year-old mother (a TTR gene heterozygote) was supposed to start amyloid deposition in her late sixties. It is suggested that in addition to the mutant TTR gene some other factors control the development of the disease.

Accumulation of lysosphingolipids in tissues from patients with GM1 and GM2 gangliosidoses.

Abstract: By using a sensitive method, we assayed lysocom‐pounds of gangliosides and asialogangliosides in tissues from four patients with GM2 gangliosidosis (one with Sand‐hoff disease and three with Tay‐Sachs disease) and from three patients with GM1 gangliosidosis [one with infantile type (fetus), one with late‐infantile, and one with adult type]. In the brain and spinal cord of all the patients except for an adult GM 1 gangliosidosis patient, abnormal accumulation of the lipids was observed, though the concentration in the fetal tissue was low. In GM2 gangliosidosis, the amounts of lyso GM2 ganglioside accumulated in the brain were similar among the patient with Sandhoff disease and the patients with Tay‐Sachs disease, whereas the concentration of asialo lyso GM2 ganglioside in the brain was higher in the former patient than in the latter patients. By comparing the sphingoid bases of neutral sphingolipids, gangliosides, and lysosphingolipids, it was suggested that lysosphingolipids in the diseased tissue are synthesized by sequential glycosylation from free sphingoid bases, but not by deacyla‐tion of the sphingolipids. Because lysosphingolipids are known to be cytotoxic, the abnormally accumulated lysosphingolipids may well be the pathogenetic agent for the neuronal degeneration in gangliosidoses.

Juvenile Sandhoff disease: a Japanese patient carrying a mutation identical to that found earlier in a Canadian patient

A 35-year-old Japanese man with juvenile Sandhoff disease is described. He showed progressive neurogenic muscular atrophy, cerebellar ataxia and mental deterioration, beginning at age 10 years. The accumulation of GM2 ganglioside in the submucosal nerve cell was confirmed by positive immunostaining using anti-GM2 ganglioside antibody. Biochemical evaluation revealed nearly absent beta-hexosaminidase A and B activities in leukocytes and cultured fibroblasts. Hydrolysis of [3H]globoside I in the intact fibroblasts was apparently disturbed but the rate of hydrolysis was higher than those seen in cells from patients with infantile Sandhoff disease. Analysis of the beta-hexosaminidase beta-subunit gene of the patient disclosed a point mutation (a G-to-A transition) within intron 12. The mutation generates a new splice junction resulting in a 24-base insertion between exons 12 and 13 in the processed mRNA and consequently an 8-amino acid insertion in the translation product. This mutation is identical to that originally found in a Canadian patient with juvenile Sandhoff disease. A possible relationship with the clinical phenotype and the gene abnormality is discussed.

Treatment of myasthenia gravis with dropped head: a report of 2 cases and review of the literature.

We report two patients with myasthenia gravis (MG) who showed dropped head as an early myasthenic manifestation. They had elevated anti-acetylcholine receptor antibody and showed improvement of the symptoms after intravenous injection of edorophonium chloride. One patient had thymoma and developed myasthenic crisis two weeks after thymectomy. The patient recovered from the crisis after a combination of immunoadsorption plasmapheresis (IAPP) and initiation of steroid and tacrolimus. The other patient without thymoma initiated treatment with steroid, tacrolimus and IAPP and showed complete recovery one month later. Dropped head in MG can recover well with immunosuppression therapy using steroid, and IAPP is helpful in getting a rapid improvement of dropped head as well as recovery from myasthenic crisis. When we consider treatment for MG with dropped head, we should take into account that MG of this type can develop myasthenic crisis and use the same treatment strategy as that for generalized MG.

ULTRASTRUCTURAL FINDINGS OF RECTAL AND SKIN BIOPSIES IN ADULT GM1-GANGLIOSIDOSIS

We report the ultrastructural findings in rectal and skin biopsies in four cases with adult GM1‐gangliosidosis. The rectal specimens taken under endoscopic control contained submucosal plexuses, which were easily identified on light‐microscopic and electron‐microscopic examination. In all cases the ganglion cells in submucosal plexus contained characteristic osmiophilic lamellar Inclusions, some of which were typical membranous cytoplasmic bodies, but others showed pleomorphism in shape and diameter. Lipofuscin bodies were commonly observed in the ganglion cells, Schwanns cells, vascular endothelial cells, and perithelial cells in rectal biopsy, and membrane‐bound clear vacuoles were occasionally seen in the cytoplasm of rectal and cutaneous fibroblasts. However, the axons of unmyelinated nerves in both biopsies showed a normal appearance, and there was no significant change in the eccrine glands in skin biopsy. Comparing rectal and skin biopsies, the former was found to be more valuable for morphological diagnosis of this disease, and our ultrastructural examination of rectal biopsy revealed that enteric nerve cells were involved even in adult GM1‐gangliosidosis with a benign course and restricted cerebral lesions.

Detection of immune complexes in experimental allergic neuritis

Circulating immune complexes were assayed in the sera of animals with experimental allergic neuritis (EAN), and immunofluorescent staining and immunohistological examination were performed to clarify the role of immune complexes in the pathogenesis of EAN. The level of immune complexes in the sera of animals with clinical signs of EAN was from 1:32 to 1:64. Control animals showed a titer of immune complexes from 1:2 to 1:4. Animals with EAN showed deposition of immune complexes, which were detected by FITC-conjugated anti-rat IgG or C3-complement, in the vessels of the peripheral nerve. These findings suggest that immune complexes may contribute to the immunopathogenesis of EAN.