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Two siblings with congenital myopathy showing myasthenic manifestations together with congenital cataract are reported. Their muscle weakness fluctuated and was alleviated by edrophonium chloride. Their serum creatine kinase activity was elevated, and the waning phenomenon was observed on repetitive nerve stimulation. Biopsied muscle showed degenerative changes with type 1 fibre predominance and abnormal morphology of neuromuscular junctions.

Local cerebral metabolic rate for glucose (LCMRglc) was measured with positron emission tomography using the 18F-fluorodeoxy-glucose method in five patients with chorea due to different underlying diseases. Hypometabolism was observed in the striatum bilaterally in patients with Huntington's disease, choreoacanthocytosis, sporadic progressive chorea and dementia, and pseudo-Huntington form of dentato-rubro-pallido-luysian atrophy (DRPLA). The patient with hemichorea showed hypometabolism in the striatum on the contralateral side to the chorea. The patient with pseudo-Huntington form of DRPLA showed a diffusely decreased LCMRglc in other structures including the cerebral cortex, thalamus and cerebellum. These findings indicated that dysfunction of the striatum is relevant to the genesis of chorea in all these patients, even though the extent of dysfunction in other structures is different in each case.

The relationship between surface marker expression and encephalitogenicity of lymphocytes from various lymphoid organs of Lewis rats was studied. The encephalitogenicities after culture with BP were spleen cells greater than lymph node cells much greater than thymus cells, in this descending order. The cells from every lymphoid organ proliferated significantly in response to BP. In spleen and lymph node cells, the expression of W3/25 and OX-3 molecules on T cells increased markedly after culture with BP, but the expression of OX-19 or OX-8 molecules did not change significantly. The up-regulations of W3/25 and OX-3 molecules were more pronounced in spleen cells than in lymph node cells. Thymus cells also showed a significant increase in the W3/25 molecule after the culture with BP. Therefore, T cells from all the lymphoid organs showed a selective up-regulation of the W3/25 molecule after culture with BP, and the degree of the up-regulation seems to correspond to the encephalitogenic potency in vivo. Since the W3/25 molecule apparently plays a direct role in the effector phase of experimental allergic encephalomyelitis (EAE) by enhancing BP-reactive T cell/antigen-presenting cell interaction in the central nervous system, the up-regulation on BP-cultured T cells may strengthen interaction with the class II major histocompatibility complex molecule on antigen-presenting cells, and therefore, contribute to the efficient transfer of EAE.

The amyloid beta-protein(BP) is an important component of amyloid fibrils of both Alzheimer's disease(AD) and adult Down syndrome(DS). It has been hypothesized that sporadic AD may involve the duplication of a subregion of chromosome 21 containing the BP locus. However, an improved method for detection of the BP gene duplication using polymorphic Hind III fragments led us to a conclusion that BP gene duplication is rare, if any, in (Japanese) sporadic AD patients, indicating that the duplication of the BP gene itself is not the common underlying genetic defect in AD.

Using two-color flow cytometric analysis, we studied peripheral blood lymphocyte subsets in 15 patients with human T-cell lymphotropic virus type I-associated myelopathy. The percentage of CD4+ 4B4+ cells (helper inducer T cell) was significantly increased in the patients with the myelopathy, compared with 16 healthy control subjects who were seronegative for human T-cell lymphotropic virus type I. However, there was no difference in the percentage of CD4+ 2H4+ cells (suppressor inducer T cell) between the two groups. The ratio of CD4+ 4B4+ cells to CD4+ cells and CD4+ 4B4+ to CD4+ 2H4+ cells was also elevated in these patients. The percentage of CD4+ DR+ cells and CD8+ DR+ cells, both of which are phenotypically activated T cells, and the ratio of CD4+ DR+ cells to CD4+ cells and of CD8+ DR+ cells to CD8+ cells are also increased in the patients, compared with the control subjects. The percentage of CD4+ 4B4+ cells showed positive correlations with values of spontaneous proliferation of peripheral blood lymphocytes and serum IgG level in patients with the myelopathy.

Galactosylsphingosine (psychosine) in somatic organs from a patient with globoid cell leukodystrophy and from the twitcher mouse, an animal model of human globoid cell leukodystrophy was assayed. There was an abnormal accumulation of galactosylsphingosine as in nervous tissues, albeit the concentrations being lower than those in nervous tissues. Galactosylsphingosine accumulation in the kidney of the twitcher mouse increased with age. These findings indicate that globoid cell leukodystrophy is a generalized galactosylsphingosine storage disease.

In a case of cerebrotendinous xanthomatosis (CTX), confirmed biochemically and histologically quantitative histological studies of the biopsies sural nerve revealed significantly higher incidence of de- and remyelination and onion bulb than in controls. The density of total myelinated fibers fell within the range of controls, although the density of large myelinated fibers seemed to be slightly decreased. It was suggested that the preferential involvement of the myelin sheath and Schwann cell may exist in CTX.

A 45-year-old Japanese man presented with lipid storage myopathy, fatty liver, cardiomyopathy, vacuolated leukocytes (Jordans' anomaly) and perceptive deafness. His parents were consanguineous and his younger sister was also affected. Histopathological and biochemical studies revealed an abnormal accumulation of triglyceride in muscle, liver, leukocytes, gastrointestinal endothelial cells and cultured skin fibroblasts. On electron microscopy, the vacuoles lacked limiting membranes and were adjacent to the mitochondria. Total and free carnitines in muscle were normal levels. Production rate of 14CO2 or acid-soluble [14C]metabolites from [1-14C]palmitate in the patient's cells was decreased to about 50% of that in control cells, whereas that from [1-14C]butyrate was normal. Long-chain fatty acyl esterase activities in the patient's leukocytes were normal at both pH 4.0 and pH 8.0. Despite the strong suggestion of an impaired metabolism of long-chain fatty acids, there were no evidences of abnormalities in carnitine metabolism or uptake of fatty acids into cells. The disorder is clinically different from defects in carnitine metabolism, defects in the carnitine-acylcarnitine translocase system or in mitochondrial beta-oxidation enzymes. Although the underlying metabolic defect has not been elucidated, this disease seems to be an autosomal-recessively inherited disorder of systemic triglyceride storage, probably due to an impaired regulation of lipolysis and triacylglycerol synthesis.

Abnormal accumulation of lysosulfatide (sulfogalactosylsphingosine) was evident in autopsied tissues from a boy with late-infantile metachromatic leukodystrophy. The concentration was high in the cerebral white matter, spinal cord and sciatic nerve (116-787 pmol/mg protein) and low in the cerebral gray matter, kidney and liver (4-40 pmol/mg protein). As is the case with galactosylsphingosine, lysosulfatide inhibited cytochrome c oxidase activity, in a dose-dependent manner. Judging from the tissue distribution of the accumulated lysosulfatide and because of the cytotoxicity, the lysosulfatide presumably explains the demyelination seen in the nervous tissues of patients with metachromatic leukodystrophy.

Neutral and acid protease activities inhibited by chymostatin, leupeptin, pepstatin and HgCl2 in mononuclear cells and granulocytes showed no significant differences between myotonic dystrophy patients and controls. These results suggest that chymotrypsin and cathepsin B and D activities are probably normal in leukocytes in myotonic dystrophy.

A variant of human transthyretin(TTR, prealbumin) with methionine for valine substitution at position 30 is a major component of amyloid fibrils found in patients of familial amyloidotic polyneuropathy(FAP) type I, an autosomal dominant genetic disease. But the molecular nature of the variant TTR has been obscure, because most of plasma TTR from FAP patients is a mixture of variant and wild type TTR and no pure preparation of the variant has been available. For this reason, we constructed a system in which the variant type TTR was efficiently synthesized. In this system, the recombinant variant TTR was first synthesized as a fusion protein with E. coli outer membrane protein A (ompA) signal peptide, processed to eliminate the signal peptide and finally secreted to the culture medium. The final concentration of the recombinant variant TTR in the medium was about 5 mg/l. SDS polyacrylamide gel electrophoresis and gel filtration analysis suggested that the recombinant variant TTR can form tetramer as seen for native one. Purification of the protein was accomplished by only two steps of chromatography.

The alpha-keto acid dehydrogenase complex and its component enzymes, lactate dehydrogenase, pyruvate carboxylase, cytochrome c oxidase, succinate-cytochrome c reductase, NADH-cytochrome c reductase, and the concentration of cytochromes and enzymes of beta-oxidation in muscle from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes were studied and no specific defect was found. These results raise the possibility that the mitochondrial changes in the patient may be secondary.

Plasma copper was significantly reduced in Wilson's disease with decreased ceruloplasmin levels, while there was no significant difference in erythrocyte copper levels between Wilson's disease and controls. Mean zinc and manganese levels in plasma were increased in Wilson's disease, but these differences were not significant. Mean magnesium level in plasma was normal. The levels of these metals in erythrocytes showed no difference between Wilson's disease and controls. Our results suggest that the abnormal copper level in plasma is not due to the primary metabolic defects, but is probanly due to the level of the binding proteins in plasma to this metal, ceruloplasmin, in Wilson's disease.

The in vivo metabolism of galactosylceramide (gal-cer) in normal mice and in twitcher mice, a model of human GLD, was examined following intracerebral administration of gal-cer containing [1-14C] stearic acid. In normal mice, gal-cer was hydrolyzed to ceramide within 6 hours and ceramide was hydrolyzed to sphingosine and fatty acid. Most of the released fatty acid was immediately incorporated into other lipids. About 75% of injected gal-cer was hydrolyzed 80 hours after the injection, while in the twitcher mouse, only 17% of gal-cer was hydrolyzed. These results show that degradation of gal-cer is impaired in the twitcher mouse brain, but contradict to the fact that there was no evidence of any accumulation of gal-cer in the brain. This discrepancy may be due to the different sorting routes of biosynthesized and exogenously-administered gal-cer in the mouse brain. Most of the biosynthesized gal-cer is incorporated into myelin, while the injected gal-cer is incorporated into lysosomes.

Peripheral neuropathy was not found even six to ten years after the onset of visual symptoms in a family with primary amyloidosis, except in the propositus at the terminal stage. The propositus had mainly ocular and CNS involvement. An ocular manifestation, the vitreous opacity, was the only involvement in the family members, in spite of the long clinical course. This family may have a different type of familial primary amyloidosis from that previously reported.

We examined the autologous mixed lymphocyte reaction in human T-cell lymphotropic virus type I-associated myelopathy to elucidate the known increase in spontaneous proliferation of peripheral blood lymphocytes. Proliferative responses in the autologous mixed lymphocyte reaction test were significantly increased (34,205 cpm) in cells from 9 patients with the myelopathy, as compared with findings (18,695 cpm) in the control subjects. When non-T-cell fractions were depleted from autologous mixed lymphocyte reaction cultures, proliferative responses were completely suppressed in the control subjects, while proliferation of the peripheral blood lymphocytes from the groups with the myelopathy were not affected by depletion of non-T-cell fractions. The increase in spontaneous proliferation of peripheral blood lymphocytes in patients with the myelopathy is probably not related to an increase in autologous mixed lymphocyte reactions.

Phospholipid classes that included plasmalogens of erythrocyte membranes in seven myotonic dystrophy (MyD) patients and seven normal controls were analyzed by HPLC. No significant difference in phospholipid classes was found between patients with MyD and normal controls, but there was a visible difference in peak profiles of compounds of the phosphatidylethanolamine class. In the study of plasmalogens, we used two preparation methods: exposure to HCl and deacylation with mild alkaline. The area ratio of the plasmalogen form to the diacyl form in the phosphatidylethanolamine class of MyD erythrocyte membranes was significantly lower than that of normal controls. Fatty acid analyses showed that fatty acids of both phosphatidylethanolamine subclasses have less unsaturation in MyD.

Four cases in two generations of a Japanese family are described as affected by an autosomal dominant-inherited cerebellar ataxia, pyramidal and extrapyramidal signs, and abnormal ocular movements, resembling Machado-Joseph disease. The neuro-ophthalmologic examination suggests the involvement of multiple motor control systems. The neuropathologic examination of one case showed neuronal loss in the subthalamic nuclei, pallidum, dentate nuclei of cerebellum, and red nuclei, which is distinct from Machado-Joseph disease.

Acrylamide administration to rats caused clear alteration of blood thiamine content, which appeared to reflect suppressed intake and/or utilization of the vitamin in the body. Decreased utilization of thiamine does not seem to be induced by decreased binding of thiamine pyrophosphate (TPP) and apotransketolase, because acrylamide did not affect the Km of TPP for transketolase activity.

Peripheral blood lymphocytes from seventeen non-thymectomized and nine thymectomized patients with myasthenia gravis (MG) and thirteen healthy controls were examined for the presence of surface markers characteristic of T and B lymphocytes by rosette formation with sheep red blood cells (SRBC). T cells were identified by their capacity to spontaneously form rosettes with SRBCs. The percentage of B lymphocytes was determined by the erythrocyte antibody complement (EAC) rosette-forming test. The EAC complex was prepared with either whole rabbit anti-SRBC serum or with the IgM fraction of rabbit anti-SRBC serum. The two kind of erythrocyte complement rosette-forming cells (EAC-RFC) are designated erythrocyte-haemolysin-complement RFC (EA(H)C-RFC), and erythrocyte-IgM-complement RFC (EA(M)C-RFC). The percentage of total lymphocytes and T cells was not altered in MG patients. The percentage of 'active' T cells, which have been considered to be more actively involved in cellular immunity, was also similar in MG patients and controls. A significant increase in EA(H)C-RFC occurred in both thymectomized and non-thymectomized MG patients, while in B cells detected by EA(M)C-RFC no alterations were found. The increase in EA(H)C-RFC in lymphocytes from MG patients may be due to an increase in the 19S antibody-forming B lymphocytes or to an increase in T cells which have Fc receptors on their surface.

Effects of taurine on the total ATPase activity inhibited by ouabain were investigated in the human erythrocyte membrane. The enzyme activity was not activated by taurine in the absence of calcium, but was significantly activated by taurine (15-60 mM) in the presence of calcium (5 mM) by which the enzyme is inhibited. Since taurine does not form a chelate complex with calcium ion, this activation may be due to an action of taurine in the presence of calcium through competition with these ions on the membrane.

Two prospective projects were started in May 1985 to evaluate the long-term effects of bromocriptine in patients with Parkinson's disease. One of the projects is to see if combination therapy with levodopa and bromocriptine is superior to levodopa alone with regard to the prevention of late side effects of levodopa therapy. The other is to see the long-term effects of bromocriptine monotherapy. Patients with Parkinson's disease were allocated randomly to either combination or levodopa group in the first project. Parkinsonian symptoms, disabilities of daily life and severity of late side effects of long-term levodopa therapy were evaluated by a semiquantitative rating scale. This communication represents the first interim report. Methods of the studies and synopsis of the results at the end of the 12th month are described. A total of 702 patients was enrolled in the study (combination therapy, n = 216; levodopa therapy, n = 200, bromocriptine monotherapy, n = 286). At the end of the 12th month, the numbers of patients who dropped out from the study were 19, 16 and 55 in the three groups, respectively. It appears to be too early to make any definite conclusion with regard to which mode of treatment is superior, however, some evidence suggesting a superiority of the combination therapy over levodopa alone was noted in managing wearing-off phenomenon and dyskinesia. As many patients are sticking to the originally intended mode of treatment, it appears to be possible to obtain more meaningful data in several years.

Metabolism of free sphingoid bases present in normal tissues [Kobayashi, T., Mitsuo, K. & Goto, I. (1988) Eur. J. Biochem. 172, 747-752] was examined in mouse tissues and in human cultured fibroblasts. Subcellular fractionation studies of the mouse liver revealed most of free sphingoid bases to be in the membrane fractions. Fibroblasts from patients with Farber's disease contained concentrations of free sphingoid bases similar to those seen in the normal fibroblasts. When L-cycloserine, a potent inhibitor of the first reaction of sphingoid base synthesis, was added to the culture medium, the concentration of free sphingoid bases in fibroblasts decreased, dose-dependently. Thus, most of the free sphingoid bases in the tissue probably do not derive from the degradation of sphingolipids but are newly synthesized. Free sphingoid bases in microsomes from the brainstem and spinal cord were acylated or glycosylated when incubated with acyl-CoA or UDP-glycoside. However, the reaction for the synthesis of ceramide was much greater and more rapid than that of glycosylsphingosine synthesis. In liver microsomes, ceramide synthesis from endogenous free sphingoid bases was observed but synthesis of glycosylsphingosine was not evident. Therefore, the main pathway of metabolism of free sphingoid bases is presumably acylation (to ceramide) but not glycosylation (to lysoglycosphingolipid).