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Nagasaki-shi, Japan

Higuchi O.,Tokyo Medical University | Higuchi O.,Nagasaki Kawatana Medical Center | Yamanashi Y.,Tokyo Medical University
Brain and Nerve | Year: 2011

The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle. The contraction of skeletal muscle is controlled by the neurotransmitter acetylcholine (ACh), which is released from the motor nerve terminal. To achieve efficient neuromuscular transmission, acetylcholine receptors (AChRs) must be densely clustered on the muscle membrane of the NMJ. Failure of AChR clustering is associated with disorders of neuromuscular transmission such as congenital myasthenic syndromes (CMS) and myasthenia gravis (MG). Motoneuronal agrin and muscle-specific receptor tyrosine kinase (MuSK) are known to play essential roles in the formation and maintenance of NMJs in the central region of each muscle. However, it had been unclear how agrin activates MuSK. Recent studies have elucidated the roles of several key molecules, including the cytoplasmic adaptor protein Dok-7 and LDL receptor-related protein 4 (Lrp4), in agrin-induced MuSK activation. Moreover, new evidence indicates that cyclin-dependent kinase 5 (Cdk5) regulates postsynaptic differentiation. In this review, we summarize the latest developments in molecular mechanisms underlying NMJ formation in vertebrates.

Higuchi O.,Nagasaki Kawatana Medical Center
Clinical and Experimental Neuroimmunology | Year: 2013

Myasthenia gravis (MG) is an autoimmune disorder characterized by skeletal muscle fatigability and muscle weakness resulting from inhibition of neuromuscular transmission by autoantibodies against synaptic apparatus in the neuromuscular junction (NMJ). MG is probably classified into three groups: anti-acetylcholine receptor (AChR) antibody-positive MG; antimuscle-specific kinase (MuSK) antibody-positive MG; and seronegative MG, which is negative for both antibodies. In patients with seronegative MG, pathogenic factors remain elusive. Recently, a new autoantibody against low-density lipoprotein receptor-related protein 4 (Lrp4), which is one of the postsynaptic apparatus and indispensable for the formation of the NMJ, has been identified and has attracted attention as a third MG-related autoantibody. In the present review, we discuss the role of Lrp4 in the formation of NMJ, and the molecular mechanism(s) of pathogenesis for anti-Lrp4 antibody-positive MG. © 2013 Japanese Society for Neuroimmunology.

Kinoshita T.,Shinshu University | Abe R.-T.,Shinshu University | Hineno A.,Shinshu University | Tsunekawa K.,Shinshu University | And 2 more authors.
Internal Medicine | Year: 2014

Objective To investigate the causes of neurological manifestations in girls immunized with the human papillomavirus (HPV) vaccine.Methods During the past nine months, 44 girls visited us complaining of several symptoms after HPV vaccination. Four patients with other proven disorders were excluded, and the remaining forty subjects were enrolled in this study.Results The age at initial vaccination ranged from 11 to 17 years, and the average incubation period after the first dose of the vaccine was 5.47±5.00 months. Frequent manifestations included headaches, general fatigue, coldness of the legs, limb pain and weakness. The skin temperature examined in 28 girls with limb symptoms exhibited a slight decrease in the fingers (30.4±2.6°C) and a moderate decrease in the toes (27.1±3.7°C). Digital plethysmograms revealed a reduced height of the waves, especially in the toes. The limb symptoms of four girls were compatible with the Japanese clinical diagnostic criteria for complex regional pain syndrome (CRPS), while those in the other 14 girls were consistent with foreign diagnostic criteria for CRPS. The Schellong test identified eight patients with orthostatic hypotension and four patients with postural orthostatic tachycardia syndrome. The girls with orthostatic intolerance and CRPS commonly experienced transient violent tremors and persistent asthenia. Electron-microscopic examinations of the intradermal nerves showed an abnormal pathology in the unmyelinated fibers in two of the three girls examined.Conclusion The symptoms observed in this study can be explained by abnormal peripheral sympathetic responses. The most common previous diagnosis in the studied girls was psychosomatic disease. The social problems of the study participants remained unresolved in that the severely disabled girls stopped going to school. © 2014 The Japanese Society of Internal Medicine.

Matsuo H.,Nagasaki Kawatana Medical Center
Clinical Neurology | Year: 2012

Plasmapheresis (PP) and intravenous immunoglobulin (IVIG) are both effective for treatment of crisis and acute exacerbation of myasthenia gravis. The 1st clinical problem is that effect oi both treatments usually lasts for only 2-3 weeks. Additional immunosuppressive treatments may be necessary for prevention of the relapse. The 2nd problem is adverse effects and complications associated with each treatment. Hypotension, including shock, thromboembolism, and opportunistic infections are major adverse events of PP. Awareness of these complications and careful practice should be solutions. IVIG complicates less adverse effects than PP. The cost of each treatment, which is expensive particularly in IVIG use, may become the 3rd problem. It should be important to clarify the appropriate number of PP and the dose of IVIG to improve myasthenic crisis.

Motomura M.,Nagasaki University | Higuchi O.,Nagasaki Kawatana Medical Center
Clinical Neurology | Year: 2012

Myasthenia gravis (MG) is caused by the failure of neuromuscular transmission mediated by pathogenic autoantibodies (Abs) against acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK). The seropositivity rates for routine AChR binding Ab and MuSK Ab in MG are 80-85% and 5-10% for MG patients in Japan, respectively. The autoimmune target in the remaining patients is unknown. In 2011, autoantibodies against low-density lipoprotein receptor-related protein 4 (Lrp4) were identified in Japanese MG patients and thereafter have been reported in Germany and the USA. We developed a simple technique termed Gaussia luciferase immunoprecipitation for detecting antibodies to Lrp4. As a result, nine generalized MG patients from 300 lacking AChR Ab are positive for Lrp4 antibodies. Thymoma was not observed in any of these patients. These antibodies inhibit binding of Lrp4 to its ligand and are predominantly of the IgGl subclass. In other reports of Lrp4 ab, Lrp4 ab positive sera inhibited agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that Lrp4 is a third autoantigen in patients with MG, and anti-Lrp4 autoantibodies may be pathogenic. Further studies including neuromuscular junction biopsy are needed to clarify the pathomechanism of Lrp4 ab positive MG.

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