Norio Ohkoshi

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.

Japanese families with autosomal dominant pure cerebellar ataxia map to chromosome 19p13.1-p13.2 and are strongly associated with mild CAG expansions in the spinocerebellar ataxia type 6 gene in chromosome 19p13.1.

Autosomal dominant cerebellar ataxia is a group of clinically and genetically heterogeneous disorders. We carried out genomewide linkage analysis in 15 families with autosomal dominant pure cerebellar ataxia (ADPCA). Evidence for linkage to chromosome 19p markers was found in nine families, and combined multipoint analysis refined the candidate region to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of CAG-repeat expansion in the alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 19p13.1, recently identified among 8 small American kindreds with ADPCA (spinocerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 families studied had similar, very small expansion in this gene: all affected individuals had larger alleles (range of CAG repeats 21-25), compared with alleles observed in neurologically normal Japanese (range 5-20 repeats). Inverse correlation between the CAG-repeat number and the age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable within each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied. We conclude that more than half of Japanese cases of ADPCA map to 19p13.1-p13.2 and are strongly associated with the mild CAG expansion in the SCA6/CACNL1A4 gene.

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.

Multiple deletions in mitochondrial DNA at direct repeats of non-D-loop regions in cases of familial mitochondrial myopathy

Muscle mitochondrial DNAs from two brothers with mitochondrial myopathy associated with peripheral neuropathy had multiple deletions, most of which started in non-D-loop regions, unlike in an autosomal dominant mitochondrial myopathy (Zeviani, M. et al., Nature 339, 309 (1989)). The non-D-loop regions with deletions were amplified by the polymerase chain reaction and the resulting fragments were subcloned and then sequenced. At least 12 deletions of different lengths in different sites were found. However, all the deletions were flanked by short direct repeats (4-12 base pairs).

Distal myopathy with rimmed vacuoles: Novel mutations in the GNE gene

Abstract—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.

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

Recent studies suggest that Parkinsons disease (PD) is associated with particular personality traits. Using Cloningerss 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.

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.

Wernicke’s Encephalopathy Induced by Hyperemesis gravidarum, Associated with Bilateral Caudate Lesions on Computed Tomography and Magnetic Resonance Imaging

The case of an 18-year-old woman with Wernickes encephalopathy induced by hyperemesis gravidarum is reported. She had severe vomiting and received antiemetic therapy and intravenous administration of glucose and low-dose insulin solution without thiamine. She developed coma, nystagmus, ataxia and polyneuropathy. CT and MR imaging showed bilateral caudate lesions as well as symmetrical periventricular lesions of the thalamus and hypothalamus and periaqueductal gray matter. Caudate lesions are quite rare in Wernickes encephalopathy.

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.

Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease.

Parkinsons disease (PD) is characterized by major alterations of neurotransmitter activity due to damage of the substantia nigra. Changes in neuropeptide concentration within the basal ganglia may play an important role in the putative dopaminergic–peptidergic interactions associated with the disease. Cholecystokinin (CCK) modulates the release of dopamine in the mesolimbic pathway and affects dopamine‐related behavior.We analyzed genetic variations in the CCK gene, in both the coding and promoter region, in order to investigate the role of polymorphism in idiopathic PD. Four polymorphic sites of the CCK gene (‐196G/A, ‐45C/T, 1270C/G, 6662C/T) were found in PD patients and controls. Complete linkage disequilibrium was observed between the ‐45 locus and the 1270 locus, and also a possible linkage disequilibrium was found between the ‐45 and ‐196 loci. A significant difference was found in the distributions of three identified genotypes at the ‐45 locus between 116 PD patients and 95 age‐matched control subjects (χ2=7.95, p=0.018, Bonferroni correction; p=0.054). In addition, a significant difference was obtained amongst the three genotypic groups at the ‐45 locus when compared between PD patients who experienced hallucinations (n=23) and those (n=93) who did not (χ2=8.08, p=0.018, Bonferroni correction; p=0.126).Our data suggested that mutations at the ‐45 locus in the promoter region of the CCK gene may influence vulnerability to hallucinations in PD patients treated with l‐dopa.