Biomedical subjects
Publications and source records attributed to Ryuji Kaji.
We performed epidemiological studies of primary dystonia in the city of Kyoto. The prevalence was at least 10.1 per 100,000 persons, which was similar to that in Western countries. Facial dystonia was more common than other types, which contrasts with that reported in Europe. Age of onset for both genders was in agreement with that in other countries.
Conduction block is an important functional consequence of demyelination whereby nervous transmission is abolished. Its mechanism has been discussed with respect to the loss of insulation due to disruption of myelin. Recent development of threshold tracking techniques, which enabled noninvasive assessment of axonal membrane potentials and ion channels, has provided evidence that axonal excitability changes significantly and contributes to conduction failure. This view, based upon axo-glial interaction, clarifies the mechanism of muscle fatigue and fasciculation associated with peripheral demyelination and possibly explains selective motor involvement in multifocal motor neuropathy.
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The human leukocyte antigen (HLA) class III region, located on chromosome 6p21, has been regarded as one of the susceptible loci for type 1 diabetes. Because it contains many genes related to inflammatory and immune responses, including tumor necrosis factor (TNF), lymphotoxin-alpha (LT-alpha), and allograft inflammatory factor 1 (AIF-1) genes, it is unclear which gene within the class III region is responsible for the susceptibility to the disease. We sequenced the AIF-1 gene region and detected three novel polymorphisms, all of which were diallelic and localized at introns. Then, we investigated AIF-1, TNF, and LT-alpha gene polymorphisms in 165 patients with type 1 diabetes, consisting of 90 patients with young-onset type 1 diabetes, 75 patients with adult-onset type 1 diabetes, and 200 control patients. We also analyzed TNF receptors type 1 (TNFR1) and type 2 (TNFR2) gene polymorphisms, located on chromosome 12p13 and 1p36, respectively. Although there were significant differences between type 1 diabetes patients and controls in the distributions of TNF promoter polymorphisms at position -1031 and -857, and LT-alpha gene NcoI polymorphism, none of them was independently associated with the disease after two-locus analysis with HLA class II alleles. We detected the significantly increased frequency of the -383C allele, located in the TNFR-1 promoter region, in both young-onset and adult-onset diabetes patients compared with controls. In addition, the -383C allele was found to be associated with higher expression of the TNFR1 gene than that of -383A allele in in vitro expression. These results suggest that the TNFR1 gene region might be a susceptible locus to type 1 diabetes in Japanese.
Human T-cell leukemia virus type I (HTLV-I) provirus load differs more than 100-fold among carriers and a high provirus load in the peripheral blood mononuclear cells (PBMCs) is regarded as a risk factor for both preleukemic states and inflammatory diseases including HTLV-I-associated myelopathy (HAM). We examined polymorphisms in the genes for tumor necrosis factor (TNF), TNF receptor type 1 and 2, lymphotoxin (LT)-alpha, interleukin (IL)-1beta, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, and mannose binding protein (ManBP) in 143 HTLV-I carriers whether these polymorphisms affect the provirus load in the PBMCs of carriers. No significant association was observed between these polymorphisms and the provirus load. Homozygotes for a ManBP-variant allele, however, showed a tendency for the decreased number of provirus load. When combined, the data on the alleles of LT-alpha and MCP-1, HTLV-I carriers having high producer alleles of both genes showed a trend for increased provirus load. These data suggest that inflammation or an active immune response may induce an increased amount of HTLV-I-infected T cells, leading to a high provirus load.
In search of a gene polymorphism that may contribute to the development of partial epilepsy, we focused on brain-derived neurotrophic factor (BDNF), since the functional effects of insult-induced neurotrophin changes are reported to be protection against neuronal damage and stimulation of synaptic reorganization. Two hundred nineteen patients with partial epilepsy were selected for study and 311 individuals were used as healthy controls. A single base pair (bp) polymorphism at position 240 in the non-coding region of the BDNF gene and at position 480 within the proBDNF sequence were analyzed, and the frequency of the 240T allele was found to be significantly increased in partial epilepsy patients as compared with the controls (chi(2)=8.59, P=0.0034). In contrast, no significant differences were found between the two groups in any combination of the G480A BDNF gene polymorphism. Our results suggest that the 240T allele in the BDNF gene may be a genetic marker that indicates an enhanced susceptibility to seizures, setting up a cascade leading eventually to chronic partial epilepsy in patients with such a genetic predisposition.
PURPOSE: To confirm the high frequency of interleukin (IL)-1beta-511T allele occurrence in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS), with special attention given to the impact of prolonged febrile convulsions (PFCs) on IL-1beta genotype distribution. METHODS: Patients with evidence of unilateral HS on magnetic resonance (MR) images were chosen as study subjects (TLE+HS; n = 66). Other patients with essentially normal MRI findings or only foreign tissue (TLE without HS; TLE-HS; n = 64), and those with symptomatic localization-related epilepsy but without TLE (SLE; n = 89) were selected as disease controls. A single base pair polymorphism at position 2511 in the promoter region of the IL-1beta gene was analyzed. RESULTS: The distribution of IL-1beta-511 genotypes as well as allele frequency was significantly different between TLE+HS patients and controls. In contrast, no difference was found between TLE-HS patients and controls or between SLE patients and controls. Further, in the group of patients with TLE+HS, the frequency of the IL-1beta-511T allele tended to increase as a function of febrile convulsions [0.531 without either PFC or simple febrile convulsion (SFC); 0.633 with SFC; 0.686 with PFC]. Although no statistically significant difference was noted between patients without PFC and the controls, a chi2 analysis of allele distribution revealed a significant difference between those with PFC and the controls. CONCLUSIONS: PFC proved to be a potent determinant of IL-1beta-511T allele frequency; thus a discrepancy of PFC incidence should be considered an explanation of recent conflicting results regarding the association between the gene polymorphisms of IL-1beta-511 and TLE+HS.
Three genes commonly causing Charcot-Marie-Tooth disease (CMT) encode myelin-related proteins: peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32). Demyelinating versus axonal phenotypes are major issues in CMT associated with mutations of these genes. We electrophysiologically, pathologically and genetically evaluated demyelinating and axonal features of 205 Japanese patients with PMP22 duplication, MPZ mutations or Cx32 mutations. PMP22 duplication caused mainly demyelinating phenotypes with slowed motor nerve conduction velocity (MCV) and demyelinating histopathology, while axonal features were variably present. Two distinctive phenotypic subgroups were present in patients with MPZ mutations: one showed preserved MCV and exclusively axonal pathological features, while the other was exclusively demyelinating. These axonal and demyelinating phenotypes were well concordant among siblings in individual families, and MPZ mutations did not overlap among these two subgroups, suggesting that the nature and position of the MPZ mutations mainly determine the axonal and demyelinating phenotypes. Patients with Cx32 mutations showed intermediate slowing of MCV, predominantly axonal features and relatively mild demyelinating pathology. These axonal and demyelinating features were present concomitantly in individual patients to a variable extent. The relative severity of axonal and demyelinating features was not associated with particular Cx32 mutations. Median nerve MCV and overall histopathological phenotype changed little with disease advancement. Axonal features of diminished amplitudes of compound muscle action potentials (CMAPs), axonal loss, axonal sprouting and neuropathic muscle wasting all changed as disease advanced, especially in PMP22 duplication and Cx32 mutations. Median nerve MCVs were well maintained independently of age, disease duration and the severity of clinical and pathological abnormalities, confirming that median nerve MCV is an excellent marker for the genetically determined neuropathic phenotypes. Amplitude of CMAPs was correlated significantly with distal muscle strength in PMP22 duplication, MPZ mutations and Cx32 mutations, while MCV slowing was not, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. Thus, the three major myelin-related protein mutations induced varied degrees of axonal and demyelinating phenotypic features according to the specific gene mutation as well as the stage of disease advancement, while clinically evident muscle wasting was attributable to loss of functioning large axons.
We report a case of amyotrophic lateral sclerosis (ALS) with IgM antibody against gangliosides GM2 and GD2. A 57-year-old woman presented with slowly progressive muscular weakness of the upper extremities and dysarthria. She fulfilled the clinical and electrophysiological criteria of ALS, and died from sudden suffocation about 3 years after the onset of illness. The patient's serum IgM antibody was shown to recognize the structure shared by GM2 and GD2. Since anti-GM2 antibodies have been implicated in motor neuropathy or motor neuron syndrome, this rare case might contribute to the understanding of the immunological aspects of ALS.
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We studied genetic polymorphisms in the promoter region at position -511 of the interleukin (IL) -1beta gene (IL-1B-511) and at position -889 of the IL-1alpha gene (IL-1A-889), in 111 Japanese patients with multiple system atrophy (MSA) and 160 controls. The distribution of IL-1B-511 was significantly different between MSA patients and controls, because of the under-representation of patients with homozygotes for allele 2 (IL-1B-511*2), a high producer of IL-1beta. The frequency of IL-1A-889*2, a high secretor of IL-1alpha, was also decreased in MSA patients. Our findings suggest that abnormal cytokine expression may be implicated in the pathogenesis of MSA.
We studied a polymorphism in the dopamine transporter (DAT) gene in 236 Japanese patients with Parkinson's disease (PD) and compared the results with 220 controls. The 1215A/G genotype of the DAT gene was significantly different between PD patients and controls, suggesting a possible involvement of DAT in genetic susceptibility to PD.
A Japanese patient with congenital end-plate acetylcholinesterase (AChE) deficiency developed severe proximal and truncal muscle weakness with preservation of distal strength. Electrophysiological studies included a train of stimuli at 3 HZ, which induced a marked decremental response in the deltoid but not in the first dorsal interosseous (FDI) muscle. Single fiber electromyography (EMG) revealed a high blocking rate (23.1 +/- 30.5%, n = 13) with a markedly increased jitter (mean consecutive difference [MCD] 297 +/- 218 micros) in the deltoid, but a low blocking rate (6.2 +/- 7.4%, n = 16) despite an equally increased jitter (MCD 227 +/- 147 micros) in the FDI. In vitro microelectrode study and computer simulation suggested that the combination of a large jitter and a low blocking rate may be ascribed to a reduced end-plate potential (EPP) amplitude with an abnormally prolonged decay time constant (tau). These characteristics may constitute the primary underlying pathophysiologic mechanism in our patient and in similar cases of congenital myasthenic syndrome.
We studied cytokine gene polymorphisms in the promoter region, including interleukin (IL)-6, IL-1beta, and IL-10, in Japanese patients with human T-cell leukemia virus type I (HTLV-I) associated myelopathy (HAM) (n = 65), asymptomatic HTLV-I carriers (n = 143), and HTLV-I seronegative, normal controls (n = 160). There was a significant difference between HAM patients and HTLV-I carriers in the distribution of IL-6 promoter polymorphism at position -634 (chi(2) = 9.90, p = 0.0071). The IL-6 genotype was also significantly different between HAM patients and normal controls (chi(2) = 11.53, p = 0.0033), while a similar distribution was observed in IL-1beta and IL-10 polymorphisms among HAM patients, carriers, and normal controls. The results suggest that IL-6 gene region may contribute to susceptibility to HAM, and that aberrant cytokine productions could be involved in the development of HAM.
Multiple nerve excitability measurements were used to investigate axonal membrane properties of patients diagnosed with multifocal motor neuropathy (MMN). Six patients were selected, all with evidence of distal focal motor conduction block involving the median nerve in the forearm. In all patients, the median nerve was stimulated at the wrist, just distal to the site of block, and the resulting compound muscle action potentials were recorded from abductor pollicis brevis. Stimulus-response behaviour, the strength--duration time constant, threshold electrotonus to 100 ms polarizing currents, a current-threshold relationship and the recovery of excitability following supramaximal activation were recorded using a protocol described recently. When compared with control values, patients demonstrated significantly greater superexcitability, a 'fanning out' of threshold electrotonus recordings, and a significant change in the slope of the current--threshold relationship. These abnormalities in axonal membrane excitability parameters closely resembled those in normal axons hyperpolarized following release from ischaemia. To test for axonal hyperpolarization, DC depolarizing currents were applied to the nerves of three patients, and all the excitability parameters were normalized by depolarization. Attempts to trace excitability measures proximally towards the site of block were unsuccessful, as the nerve became inexcitable in all cases. It is suggested that the distal hyperpolarization is probably linked to focal depolarization and that the clinical features of MMN are consistent with a depolarizing/hyperpolarizing lesion.