Autoimmunity to gephyrin in Stiff-Man syndrome.

Stiff-Man syndrome (SMS) is a rare disease of the central nervous system (CNS) characterized by chronic rigidity, spasms, and autoimmunity directed against synaptic antigens, most often the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). In a subset of cases, SMS has an autoimmune paraneoplastic origin. We report here the identification of high-titer autoantibodies directed against gephyrin in a patient with clinical features of SMS and mediastinal cancer. Gephyrin is a cytosolic protein selectively concentrated at the postsynaptic membrane of inhibitory synapses, where it is associated with GABA(A) and glycine receptors. Our findings provide new evidence for a close link between autoimmunity directed against components of inhibitory synapses and neurological conditions characterized by chronic rigidity and spasms.

Effects of exercise on adiponectin and adiponectin receptor levels in rats.

Adiponectin reportedly reduces insulin-resistance. Exercise has also been shown to lessen insulin-resistance, though it is not known whether exercise increases levels of adiponectin and/or its receptors or whether its effects are dependent on exercise intensity and/or frequency. Catecholamine levels have been shown to increase during exercise and to fluctuate based on exercise intensity and duration. In light of this information, we examined the effects of exercise on catecholamine, adiponectin, and adiponectin receptor levels in rats. Our data showed that blood adiponectin levels increased by 150% in animals that exercised at a rate of 30 m/min for 60 min 2 days per week, but not 5 days, per week; no such increase was observed in rats that exercised at a rate of 25 m/min for 30 min. The effects of exercise on adiponectin receptor mRNA were variable, with adiponectin receptor 1 (AdipoR1) levels in muscle increasing up to 4 times while adiponectin receptor 2 (AdipoR2) levels in liver fell to below half in response to exercise at a rate of 25 m/min for 30 min 5 days per week. We also observed that urinary epinephrine levels and plasma lipids were elevated by exercise at a rate of 25 m/min for 30 min 2 days per week. Exercise frequency at a rate of 25 m/min for 30 min correlated with AdipoR1 and AdipoR2 mRNA expression in the muscle and liver, respectively (r=0.640, p<0.05 and r=-0.808, p<0.0005, respectively). Urinary epinephrine levels correlated with AdipoR2 mRNA expression in liver tissues (r=-0.664, p<0.05) in rats that exercised at a rate of 25 m/min for 30 min. Thus, exercise may regulate adiponectin receptor mRNA expression in tissues, which might cause increases in glucose uptake and fatty acid oxidation in the muscle. The effect of exercise on adiponectin levels depends on the specific conditions of the exercise.

Primary position upbeat nystagmus increased on downward gaze: clinicopathologic study of a patient with multiple sclerosis.

We describe a patient with multiple sclerosis who had primary position upbeat nystagmus that increased in amplitude on downward gaze. Pathologic examination revealed demyelinating foci with macrophage infiltration in the lower medulla, involving the perihypoglossal nuclei (the intercalatus nuclei). A lesion of this region may be responsible for upbeat nystagmus.

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene.

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation.

Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation.

A patient with hereditary neuropathy presented with asymmetric distal weakness. On nerve biopsy, there was demyelination and onion-bulb formation, and molecular analysis revealed that the patient was heterozygous for an MPZ mutation. The patient improved with corticosteroid treatment.

Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells.

Aggregations of the alpha1A-calcium channel protein have been previously demonstrated in spinocerebellar ataxia type 6 (SCA6). Here the authors show that small aggregates, labeled by a monoclonal antibody 1C2 that preferentially detects expanded polyglutamine larger than that in SCA6 mutation, are present mainly in the cytoplasm but also in the nucleus of Purkinje cells. Although the length of expansion is small in SCA6, the current finding might indicate that SCA6 conforms to the pathogenic mechanism(s) in other polyglutamine diseases.

Immunohistochemical staining of dystrophin on formalin-fixed paraffin-embedded sections in Duchenne/Becker muscular dystrophy and manifesting carriers of Duchenne muscular dystrophy.

We succeeded in immunostaining of monoclonal anti-dystrophin antibodies on formalin-fixed and paraffin-embedded muscle sections from patients with Duchenne muscular dystrophy, patients with Becker muscular dystrophy, and manifesting carriers of Duchenne muscular dystrophy using Catalyzed Signal Amplification(TM) system. The Catalyzed Signal Amplification system is an extremely sensitive immunohistochemistry staining procedure based on the peroxidase-catalyzed deposition of a biotinylated phenolic compound. We used three mouse monoclonal antibodies: DYS1, DYS2, and DYS3. Muscle sections were treated using the Target Retrieval Solution(TM) and the Catalyzed Signal Amplification system. In control patients, DYS1 and DYS2 were stained at the sarcolemma, but DYS3 remained unstained. In Duchenne muscular dystrophy patients, DYS1 and DYS2 staining were undetected. In Becker muscular dystrophy patients, the immunolabeling of DYSI and DYS2 were weak and discontinuous. In manifesting carriers of Duchenne muscular dystrophy, DYS1 and DYS2 staining showed a mosaic pattern of dystrophin-positive fibers and dystrophin-negative fibers. DYS1 and DYS2 staining patterns of this study are similar to those of frozen sections using conventional methods previously reported. In cases from whom frozen muscle sections cannot be obtained, immunohistochemical dystrophin analysis using the Catalyzed Signal Amplification system will be beneficial for the diagnosis and the screening of neuromuscular diseases.

Malignant hyperthermia in a patient with Becker muscular dystrophy: dystrophin analysis and caffeine contracture study.

We present a 17-year-old boy with Becker muscular dystrophy (BMD) who developed hyperthermia and heart failure after general anesthesia. He presented clinical features of malignant hyperthermia (MH), and had masseter spasm and elevated body temperature (38.7 degrees C) with very high serum CK activity (107,000 IUl-1). Dystrophin tests confirmed a clinical diagnosis of BMD in the patient, i.e. faint and patchy immunostaining pattern of skeletal muscle, truncated dystrophin protein and a deletion of exons 3 and 4 of the dystrophin gene. To inquire into the mechanism of MH associated in the patient, we tested caffeine contracture reaction by the skinned fiber method. We found an increased sensitivity to caffeine only in type 1 muscle fibers. The rate of Ca(2+)-induced Ca2+ release (CICR) was normal, suggesting that the mechanism of "MH" observed in our patient with BMD is not the same as that of classical MH. A possible mechanism might be related to derangements of the sarcoplasmic reticulum membrane in BMD, which sensitize the membrane to caffeine or other agents.

Cross-cultural traits for personality of patients with Parkinson's disease in Japan.

Recent studies suggest that Parkinson's disease (PD) is associated with particular personality traits. Using Cloningers's Tridimensional Personality Questionnaire (TPQ), Menza and colleagues [1993: Neurology 43:505-508] reported a possible association between PD and a reduced score in the novelty seeking (NS) dimension of the TPQ. We sought to determine whether this association, which was found in a study conducted in the United States, could also be found among Japanese PD patients. We performed personality assessments of 67 Japanese PD patients, using the TPQ test. The results suggest that Japanese PD patients have significantly lower scores in the NS dimension of the TPQ, as well as significantly higher harm avoidance (HA) scores, compared with matched control subjects. Furthermore, the PD patients undergoing treatment for depression using antidepressant drugs scored significantly higher in the HA dimension than PD patients who did not receive antidepressant drug treatment. Our results suggest that the high HA score, and the low NS score in the TPQ test observed in patients with PD, is a cross-cultural phenomenon, although the influence of depression, long-term treatment, and premorbid gene/environmental interactions may also affect these personality traits. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:1-3, 2000.

Argentophilic intracytoplasmic inclusions in multiple system atrophy.

Argentophilic intracytoplasmic glial inclusions were recently reported in olivo-ponto-cerebellar atrophy (OPCA). We examined the brains of 3 cases of OPCA [2 with striato-nigral degeneration (SND) and 1 without SND], 1 case of pure autonomic failure (PAF) without pathology of OPCA or SND, as well as 36 controls including 2 cases of Holmes' type cerebellar cortical atrophy and 2 cases of Joseph's disease. Although the inclusions were tubulin-positive, the immunoreactivity was different from that of the dendrites. Electron microscopically, the microtubular structures composing the inclusion were fuzzy with granular material. These findings may indicate that the microtubules composing the inclusions are modified. Inclusion-bearing cells appeared to be oligodendrocytes while many of them had larger and lighter nuclei than those of normal-looking oligodendrocytes without the inclusions. The inclusions were widely distributed in a characteristic fashion beyond the typical lesions of OPCA, SND and PAF. The distribution pattern was essentially the same in the case of PAF and 3 cases of OPCA irrespective of the presence or absence of OPCA or SND lesions. In contrast, argentophilic inclusions were not observed in other types of spinocerebellar degeneration, in Holmes' type cerebellar cortical atrophy or in Joseph's disease. It is suggested, in line with other studies, that the inclusion may be specific to OPCA and related disorders which include PAF and a useful marker to distinguish OPCA from other neurodegenerative diseases.

Subacute leucoencephalopathy induced by carmofur, a 5-fluorouracil derivative.

Three cases of leucoencephalopathy induced by carmofur (1-hexylcarbamoyl-5-fluorouracil), an antineoplastic derivative of 5-fluorouracil are reported and the literature is reviewed. Initial symptoms were unsteady gait and dementia developing several weeks or months after carmofur had been started. Symptoms increased gradually even after stopping the drug. Severe encephalopathy with confusion, delirium or coma appeared frequently. Symptoms were usually reversible but death occasionally occurred. The EEG showed marked slowing. Computed tomography of the brains of severely intoxicated patients showed marked hypodensity of the entire cerebral white matter. Carmofur must be discontinued immediately if any psychomotor symptoms develop.

Histological determination of nitric oxide synthase (NOS) and NADPH-diaphorase in ragged-red fibers from patients with mitochondrial encephalomyopathies.

To determine localization of nitric oxide synthase in diseased muscle, we performed immunohistochemical analyses of neuronal-type nitric oxide synthase (nNOS) and endothelial-type nitric oxide synthase (ec-NOS) in biopsied muscles from five patients with mitochondrial encephalomyopathies. Immunostaining of nNOS was prominent in the sarcolemmal region of the ragged-red fibers, and weak in the sarcolemmal region of normal fibers. Immunostaining of ec-NOS was strongly positive in the myofibrils of ragged-red fibers. Ec-NOS immunoreactivity corresponded to fibers positive for SDH by histochemistry. Histochemical methods revealed prominent staining for NADPH-diaphorase on surface membranes of the ragged-red fibers. Findings suggest that nitric oxide is important in the muscles of patients with mitochondrial encephalomyopathies.

De novo expansion of a CAG repeat in a Japanese patient with sporadic Huntington's disease.

A 49-year-old man was admitted to our hospital complaining of dysarthria and involuntary movements of his neck and extremities. He had first begun to experience involuntary neck movements at the age of 40 and his symptoms gradually progressed thereafter. There was no family history of neurological disorders. On admission he showed memory disturbance, dysarthria, and choreic movements. The involuntary movements affected his face, neck, trunk, and extremities. MRI of the brain revealed atrophy of both the cerebral cortex and the head of the caudate nucleus. DNA samples for molecular analysis were obtained from the patient and both of his parents. In this pedigree, the father carried a premutated allele of 35 CAG repeats and transmitted an expanded allele of 43 CAG repeats to his son. Paternity and maternity were analyzed using a microsatellite marker located in a different chromosome. To our knowledge, this is the first report of a sporadic case of Huntington's disease in a non-caucasian population in which the disease prevalence is much lower than that in the caucasian population. A new mutation in the current Japanese population which shares the same mechanism as de novo mutation in Caucasians may have contributed to the frequency of HD in Japan at the present time.

Horner's syndrome associated with mononeuritis multiplex due to cytomegalovirus as the initial manifestation in a patient with AIDS.

We report on a 60-year-old male with AIDS who presented Horner's syndrome that was associated with mononeuritis multiplex due to cytomegalovirus (CMV) infection. This is the first case who presented Homer's syndrome in the course of AIDS. Horner's syndrome associated with mononeuritis multiplex in this patient was the initial manifestation without any opportunistic infections. Since Horner's syndrome and mononeuritis multiplex in the present case were both improved by ganciclovir, it is important to consider CMV infection when Horner's syndrome or mononeuritis multiplex is observed in immunocompromised patients, such as those with HIV-1 infection or AIDS, even if they do not show any other opportunistic infections.

Calbindin-D 28k immunoreactivity in the cerebellum of spinocerebellar degeneration.

We studied immunoreactivity for calbindin-D 28k (CaBP), an intracellular calcium-binding protein, in the cerebellum of control subjects and of patients with spinocerebellar degeneration (SCD) including sporadic olivopontocerebellar atrophy and familial cortical cerebellar atrophy. In the cerebellum, CaBP immunoreactivity was seen exclusively in the Purkinje cell in both SCD and control groups. However, the number of CaBP-immunoreactive Purkinje cells was significantly reduced in SCD. CaBP immunohistochemistry also disclosed abnormal morphological changes of Purkinje cells, which was not visualized on conventional strains or not clearly demonstrated on immunohistochemistry for neurofilaments. Moreover, reduced CaBP immunoreactivity was observed even in some remaining Purkinje cells of SCD suggesting that loss of CaBP precedes neuronal loss of Purkinje cell. We conclude that CaBP is a useful marker for Purkinje cell degeneration, and that reduced CaBP expression might have some association with the mechanism of the Purkinje cell degeneration in SCD.

Effects of acute treatment and long-term treatment with MK-801 against amygdaloid kindled seizures in rats.

Effects of both acute and long-term treatments with a non-competitive NMDA-antagonist, MK-801, were studied in rats in order to investigate whether NMDA receptors would be involved in the maintenance of kindling. Intraperitoneally administered MK-801 at doses of 0.5, 1.0 and 2.0 mg/kg inhibited fully amygdaloid kindled seizures (stage 5) behaviorally and significantly reduced the duration of after discharge and postictal spikes in a dose-dependent manner. Long-term (28 days) administration of MK-801 at three dosages neither abolished behavioral kindled seizures nor significantly altered generalized seizure thresholds. However the after discharge duration and postictal spikes were significantly reduced in rats treated with MK-801 at doses of 0.5 and 1.0 mg/kg, while no significant alterations were observed in rats treated with saline or MK-801 at a dose of 2.0 mg/kg. Acute effects of MK-801 suggested that NMDA receptors were involved in the maintenance of kindling. On the other hand, long-term treatments with MK-801 remained to show such an unequivocal effect.

Effect of riluzole on the acquisition and expression of amygdala kindling.

PURPOSE: Riluzole possesses various synaptic effects including an inhibitory action on glutamate release. The drug has been shown to inhibit kindled seizures, while its effect on the acquisition of kindling has not been reported. We investigated effects of riluzole on the kindling development in addition to effects on kindled seizures. METHODS: A bipolar electrode was implanted in the right amygdala of rats. Riluzole was injected intraperitoneally 30 min before kindling stimulation. To investigate effects of riluzole on the kindling development, rats were stimulated once daily for the drug session of 14 days at a current of 200 microA, 60 Hz, 1 ms for 2 s and thereafter stimulated without drugs (drug-free session) until completion of kindling. Seizure ranks and after discharge duration were observed every day. To investigate effects of riluzole on kindled seizures, fully-kindled rats were stimulated at the current of generalized seizure threshold (GST) before and after the administration of riluzole. Seizure ranks and after discharge duration were measured. GST after the treatment was also determined. RESULTS: The number of stimuli required for the first appearance of stage five seizure was significantly larger in rats treated with 8 mg/kg of riluzole than in vehicle controls. Riluzole at a dose of 8 mg/kg significantly retarded the development of seizure stages in the drug session. By comparison, effects on the duration of after discharge was relatively mild, though significantly different from the vehicle control. Riluzole at a dose of either 4 or 8 mg/kg markedly inhibited behavioral seizures and reduced the duration of after discharge in kindled seizures provoked by GST. The drug also significantly increased GST at both doses, suggesting that the anticonvulsant effects were attributed to the increase in GST. CONCLUSION: It was demonstrated that inhibitory effects of riluzole on both kindled seizures and the development of behavioral seizures in kindling acquisition with relatively mild correlation to afterdischarge duration. These effects might be attributed to inhibitory actions of riluzole on glutamate release and NMDA-receptor mediated events.

Degeneration of the thalamus and inferior olives associated with spongiform encephalopathy of the cerebral cortex.

We describe a 37-year-old man with a 30-month history of progressive dementia, myoclonus and prominent ataxia with the additional clinical features of dysautonomia and delirious psychomotor excitement and with relatively preserved verbal responses. The pathological changes include 1) severe neuronal loss and gliosis without spongiform change of the thalamus and inferior olives associated with gliosis of the midbrain tegmentum, and demyelination and gliosis of the central tegmental tract, olivo-cerebellar fibers and spino-olivary tract, and 2) mild spongiform encephalopathy of the cerebral cortex. Although the latter implies that the present case may be an example of the rare thalamic form of Creutzfeld-Jakob disease, the preferential and severe involvement of the thalamus and inferior olives without spongiform change as well as the clinical features are quite reminiscent of primary thalamic degeneration [Stern 1939]. This case draws further attention to the relationship between spongiform encephalopathy and degeneration without spongiform change of the thalamus and olivary system.

Sensory ataxic dominant neuropathy associated with polyarteritis nodosa.

A 68-year-old man with sensory ataxic dominant neuropathy associated with polyarteritis nodosa (PAN) had deep sensory disturbance with unsteady gait and absence of the Achilles tendon reflex. Examination revealed weight loss, elevated CRP level, negative antineutrophil cytoplasm antibodies, decreased M-wave amplitude in the peroneal motor nerve and absence of action potentials in the sural sensory nerve. Sural nerve biopsy revealed a marked loss of myelinated fibers, myelin ovoid formation and necrotizing angiitis of large epineurial arterioles. Renal biopsy revealed global and/or segmental necrotizing angiitis in glomeruli, but not in the arcuate artery. These pathological findings were distinct from those of PAN, particularly microscopic polyangiitis (MPA). Treatment with a steroid improved the deep sensory disturbance, unsteady gait, and CRP level. This case is similar to ataxic neuropathy which can arise from various disorders. This is the first report of a case of sensory ataxic dominant neuropathy associated with MPA in PAN.

Cortical auditory disorder caused by bilateral temporal infarctions.

We present a 55-year-old man who suddenly became afflicted with a bilateral auditory disturbance. Auditory acuity was preserved relatively well. Brainstem auditory evoked potentials (BAEPs) were normal. Middle latency auditory evoked potentials (MLAEPs) revealed the total absence of all waves. Brain computed tomography (CT) showed infarctions of the temporal lobes bilaterally, involving the superior temporal and transverse temporal gyri. The recognition of verbal and nonverbal sounds was also impaired. Brain CT, MLAEPs and auditory recognition tests were useful in diagnosing the cortical auditory disorder.