Triple A syndrome in Japan.

INTRODUCTION: Triple A syndrome is an autosomal recessive disease, characterized by esophageal achalasia, alacrima, and adrenal insufficiency, as well as involvement of the central, peripheral, and autonomic nervous systems. This disease mimics amyotrophic lateral sclerosis in some patients. The causative gene encodes ALADIN, a nuclear pore complex (NPC) component. Only 5 patients have been reported in Japan. METHODS: We conducted the first nationwide survey of triple A syndrome. Identified mutants were expressed as GFP-fusion proteins in cultured cells. RESULTS: Two new patients were identified, and 1 had a novel mutation (p.Ser182fsX19). All mutant proteins tested were mislocalized from NPC to cytoplasm. CONCLUSIONS: The most consistent neurological manifestation of triple A syndrome in Japanese patients was progressive bulbospinal muscular atrophy with both upper and lower motor neuron involvement, which mimicked motor neuron disease, similar to that seen in patients in Western countries. The identification of the new patients suggests that more cases are undiagnosed in Japan.

Recurrent high-dose intravenous methylprednisolone succinate pulse therapy-induced hepatopathy in a patient with multiple sclerosis.

OBJECTIVE: We describe recurrent and reversible hepatopathy in a girl with multiple sclerosis (MS) after glucocorticoid pulse therapy, to point out the possibility that glucocorticoid may harm the liver. CLINICAL PRESENTATION AND INTERVENTION: An 11-year-old girl with MS, who was treated with high-dose methylprednisolone succinate pulse therapy, developed elevation of liver enzymes. The episodes of hepatopathy occurred 1-5 weeks after the therapy and disappeared within several weeks. The examination for antinuclear antibody and viruses which can cause hepatitis produced negative results. CONCLUSION: The present case emphasizes the possible effects of high-dose glucocorticoids in the induction of liver enzymes and the importance of follow-up liver tests after pulse therapy.

Possible de novo CTG repeat expansion in the DMPK gene of a patient with cardiomyopathy.

CTG triplet repeats of "normal" length in the myotonic dystrophy protein kinase (DMPK) gene have been previously believed to be stable and new pathological expansion was not believed to occur. Here we report possible de novo CTG repeat expansion in the DMPK gene in a patient with cardiomyopathy, who was not diagnosed as having myotonic dystrophy type 1 (DM1) by conventional genetic tests.

Biological roles of anti-GM1 antibodies in patients with Guillain-Barré syndrome for nerve growth factor signaling.

To reveal the biological and pathological roles of anti-GM1 antibody in Guillain-Barré syndrome (GBS), we examined its effects on nerve growth factor (NGF) induced TrkA autophosphorylation (NGF-TrkA signaling) in PC12 cells, a sympathetic nerve cell line. The NGF-TrkA signaling is enhanced by exogenous GM1 ganglioside and this phenomenon is regarded as one of the functional aspects of GM1. The IgGs purified from patients' sera inhibited the NGF-TrkA signaling in GM1 pre-incubated PC12 cells. The degrees of inhibition by IgGs from patients paralleled their immunological reactivity to GM1. In addition, the IgGs also inhibited the neurite outgrowth of NGF-treated PC12 cells. Immunoglobulins in the rabbit sera, which were immunized by GM1, also caused a similar suppressive phenomenon. These results suggested that the anti-GM1 antibody could play roles in pathophysiology in anti-GM1 antibody positive GBS through interfering with the neurotrophic action of NGF and GM1 mediated signal modulation including NGF-TrkA signaling. It is suggested that the modulation of GM1 function is one important action of antibodies and could be one of the important mechanisms in GBS.

In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).

We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.