Y Nomura

The University of Tokyo, Tokyo, Tokyo-to, Japan

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Publications (153)469.86 Total impact

  • Masaya Segawa, Yoshiko Nomura
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    ABSTRACT: DYT1 and DYT5 are early-onset dominant inherited dystonias. DYT1 is caused by mutations of the TOR1A gene, located on 9q34, which causes dysfunction of the D1 direct pathway or the indirect pathway. Dysfunction of the former causes postural-type and segmental dystonia; the latter causes action-type dystonia. In families with action-type dystonia, there are cases with focal and segmental dystonia. Ages of onset of postural-type dystonia are around 6 years, and 8 to 10 years in cases of action-type dystonia. Focal and segmental dystonia develops in the teens. Mental and psychological functions are preserved. DYT5 is caused by heterozygous mutations of the GCH1 gene, located on 14q22.1-q22.2. Again, mental and psychological functions are preserved. Clinically, there are two types: postural and action. Postural-type dystonia occurs around 6 years of age, with postural dystonia of one leg, and all extremities and trunk muscles are involved by the late teens. Action-type dystonia shows dystonic movements from around 8 to 10 years of age. In both types, all symptoms show diurnal fluctuations that diminish with age and are no longer apparent in the late teens. L-dopa produces dramatic effects, which continue throughout the course of the illness. In both postural and action types, each family or sporadic case has a particular mutation. It remains unclear why specific mutations cause certain age- and gender-specific symptoms.
    Seminars in neurology. 07/2014; 34(3):306-11.
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    ABSTRACT: BACKGROUND: Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.
    Brain & development 05/2013; · 1.74 Impact Factor
  • Masaya Segawa, Yoshiko Nomura, Masaharu Hayashi
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    ABSTRACT: From the characteristics of its clinical features, Segawa disease is considered to be caused by deficiency of the tyrosine hydroxylase (TH) of the nigrostriatal dopamine neurons, which have high TH activities in the terminal but not in the perikaryon. This hypothesis was confirmed by two autopsied cases. However, these cases were younger than 40 years and left a question as to whether these abnormalities turned to those of Parkinson disease in older ages. An autopsy of a 90-year-old woman with Segawa disease confirmed the hypothesis that Segawa disease has a completely different pathophysiology and pathology than Parkinson disease.
    Neuropediatrics 03/2013; · 1.19 Impact Factor
  • Clinical Neurophysiology. 09/2012; 123(9):e89.
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    ABSTRACT: OBJECTIVE: To investigate horizontal saccade changes according to disease stage in patients with progressive supranuclear palsy (PSP). METHODS: We studied visually and memory guided saccades (VGS and MGS) in 36 PSP patients at various disease stages, and compared results with those in 66 Parkinson's disease (PD) patients and 58 age-matched normal controls. RESULTS: Both vertical and horizontal saccades were affected in PSP patients, usually manifesting as "slow saccades" but sometimes as a sequence of small amplitude saccades with relatively well preserved velocities. Disease progression caused saccade amplitude reduction in PSP but not PD patients. In contrast, VGS and MGS latencies were comparable between PSP and PD patients, as were the frequencies of saccades to cue, suggesting that voluntary initiation and inhibitory control of saccades are similar in both disorders. Hypermetria was rarely observed in PSP patients with cerebellar ataxia (PSPc patients). CONCLUSIONS: The progressively reduced accuracy of horizontal saccades in PSP suggests a brainstem oculomotor pathology that includes the superior colliculus and/or paramedian pontine reticular formation. In contrast, the functioning of the oculomotor system above the brainstem was similar between PSP and PD patients. SIGNIFICANCE: These findings may reflect a brainstem oculomotor pathology.
    Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 08/2012; · 3.12 Impact Factor
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    ABSTRACT: We describe a 33-year-old male patient with mental retardation and cerebellar ataxia whose brain magnetic resonance imaging (MRI) showed diffuse central hypomyelination. The associated hypogonadotropic hypogonadism and hypodontia were consistent with the clinical diagnosis of 4H syndrome. Two compound heterozygous mutations in POLR3A were found: p.Met852Val and p.Asn1249His. MRI of the brain showed cerebellar atrophy, atrophy of the corpus callosum, and diffuse hypomyelination extending as far as the U-fibers, with preservation of the basal ganglia. T2 hyperintensity was observed in the bilateral middle cerebellar peduncles. The patient showed almost normal development until 4-5years of age. After 25years of age, the patient showed a gradual but consistent motor and cognitive deterioration. We demonstrated the involvement of the corticospinal tract electrophysiologically, but peripheral nerve conduction was normal. Although this disease may start very early in life, the clinical course in the present case suggests that brains that initially appear to have developed normally may show dysfunction later in life, although the pathophysiological bases for this dysfunction may not be evident on MRIs.
    Journal of the neurological sciences 07/2012; 320(1-2):102-5. · 2.32 Impact Factor
  • Parkinsonism & Related Disorders 07/2011; 17(10):769-70. · 3.27 Impact Factor
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    ABSTRACT: The cardinal pathophysiology of Parkinson's disease (PD) is considered to be the increase in the activities of basal ganglia (BG) output nuclei, which excessively inhibits the thalamus and superior colliculus (SC) and causes preferential impairment of internal over external movements. Here we recorded saccade performance in 66 patients with PD and 87 age-matched controls, and studied how the abnormality changed with disease progression. PD patients were impaired not only in memory guided saccades, but also in visually guided saccades, beginning in the relatively early stages of the disease. On the other hand, they were impaired in suppressing reflexive saccades (saccades to cue). All these changes deteriorated with disease progression. The frequency of reflexive saccades showed a negative correlation with the latency of visually guided saccades and Unified Parkinson's Disease Rating Scale motor subscores reflecting dopaminergic function. We suggest that three major drives converging on SC determine the saccade abnormalities in PD. The impairment in visually and memory guided saccades may be caused by the excessive inhibition of the SC due to the increased BG output and the decreased activity of the frontal cortex-BG circuit. The impaired suppression of reflexive saccades may be explained if the excessive inhibition of SC is "leaky." Changes in saccade parameters suggest that frontal cortex-BG circuit activity decreases with disease progression, whereas SC inhibition stays relatively mild in comparison throughout the course of the disease. Finally, SC disinhibition due to leaky suppression may represent functional compensation from neural structures outside BG, leading to hyper-reflexivity of saccades and milder clinical symptoms.
    Neuropsychologia 03/2011; 49(7):1794-806. · 3.48 Impact Factor
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    ABSTRACT: Eighty cases of idiopathic autism with epilepsy and 97 cases without epilepsy were studied to evaluate the pathophysiology of epilepsy in autism. The initial visit to this clinic ranged 8months-30years 3months of age, and the current ages are 5years 8months-42years 3months, 60% reaching to over 30years of age. The average follow up duration is 22.2years±9.4years. The ages of onset of epilepsy were from 7months to 30years of age, with the two peaks at 3.2years and 16.7years. EEG central focus appeared earlier than frontal focus. Abnormality of locomotion and atonic NREM were observed more frequently in epileptic group. These suggest the neuronal system related to abnormality of locomotion and atonic NREM, which are the hypofunction of the brainstem monoaminergic system, is the pathomechanism underling the epilepsy in autism. By showing the abnormal sleep-wake rhythm and locomotion being the very initial symptoms in autism, we had shown the hypofunction of the brainstem monoaminergic system is the initial pathomechanism of autism. Thus, epilepsy in autism is not the secondary manifestation, but one of the pathognomonic symptoms of autism. The brainstem monoaminergic system project to the wider cortical area, and the initial monoaminergic hypofunction may lead to the central focus which appears earlier. The failure of the monoaminergic (serotonergic) system causes dysfunction of the pedunculo-pontine nucleus (PPN) and induces dysfunction of the dopamine (DA) system, and with development of the DA receptor supersensitivity consequently disinhibits the thalamo-frontal pathway, which after maturation of this pathway in teens cause the epileptogenesis in the frontal cortex.
    Brain & development 11/2010; 32(10):799-804. · 1.74 Impact Factor
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    Y Une, K Shirota, Y Nomura
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    ABSTRACT: A retrospective study was performed on primary cardiac tumors found in 44 cattle during meat inspection in Japan, using histology, immunohistochemistry, and electron microscopy. The age of affected cattle ranged from 10 to 129 months; 82% were less than 3 years old. In 38 hearts, the tumor was solitary; the remaining 6 hearts had multiple masses. All tumors were subendocardial and involved the papillary muscles and/or cardiac valves. Two histologic patterns were recognized; both included giant cells. Pattern 1 was characterized by interlacing fascicles of spindle-shaped cells; pattern 2 resembled cavernous hemangioma. The 2 patterns coexisted and were linked by transitional zones. Given the immunohistochemical reactivity and ultrastructure, the spindle-shaped cells were identified as smooth muscle cells and the giant cells as endothelial cells. Single cell and multicellular angiogenesis by giant cells was observed. The tumors were classified as cardiac angioleiomyoma. Subendocardial multipotential mesenchymal cells, persistent tissue of the endocardial cushion, or valvular interstitial cells were suspected as the origin.
    Veterinary Pathology 09/2010; 47(5):923-30. · 1.93 Impact Factor
  • Clinical Neurophysiology - CLIN NEUROPHYSIOL. 01/2010; 121.
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    ABSTRACT: Japanese childhood onset MG, 226 cases, were evaluated. The highest (50%) onset under age 3 years, the highest frequency of latent general type (50%), and negative to low positive anti-AChR Ab were found. Some showed the increase of the titer around age 20 years. Amblyopia may develop with the cases onset younger than age 3 years. The 75% went into remission with steroid (58.1%) or anticholinesterase (16.2%). General type often needed thymectomy. The total duration and amount of prednisolone revealed the linear correlations with the clinical types and final outcomes. This study in the larger subjects confirmed the previous studies.
    07/2009; 31(5-6):201-205.
  • Clinical Neurophysiology - CLIN NEUROPHYSIOL. 01/2009; 120(5).
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    ABSTRACT: DYTI dystonia (DYT1-D, early-onset torsion dystonia) is caused by a GAG deletion in the DYTI gene. Here we report a girl with child-onset familial DYT1-D showing localized arm involvement. The patient developed postural and action dystonia in the right and left arms at 7 and 9 years, respectively. She was misdiagnosed as hysteria due to lack of abnormalities on laboratory tests. At 11 years of age she was introduced to our clinic. Increased muscle tonus and dystonic discharges seen on surface electromyogram in the right arm and the sternocleidomastoid muscle led to the diagnosis of dystonia. A GAG deletion in the DYTI gene was confirmed in the patient, her healthy father and paternal grandfather with torsion dystonia. Titration of levodopa resulted in the fluctuation of her arm dystonia. Combined therapy by levodopa and trihexyphenidyl relieved postural dystonia in the right arm but not action dystonia in the left. Both types of dystonia in the right and left arms were well ameliorated by the additional increase of levodopa. Somatosensory evoked potentials demonstrated abnormal premovement gating. The latency and accuracy of the amplitude were disturbed in visually guided saccadic eye movement. Now at more than 11 years after onset, the patient has not shown torsion or involvement of the lower extremities. Most DYT1-D patients are refractory to medication and early surgical intervention is recommended. However, the presence of DYT1-D patients showing a milder disease course should also be considered.
    No to hattatsu. Brain and development 12/2008; 40(6):483-6.
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    ABSTRACT: The expression of estrogen receptor-alpha (ER) and progesterone receptor (PR) in normal, hyperplastic, and neoplastic endometrium in rabbits was evaluated by immunohistochemistry. The tissues evaluated were 27 normal uteri, 19 cases with endometrial hyperplasia, and 42 adenocarcinomas. Sixteen of 27 cases of normal uteri (59.3%) and 13 out of 19 hyperplasias (68.4%) stained positive with both ER-alpha and PR. Adenocarcinomas were further subdivided into 26 papillary and 16 tubular/solid adenocarcinomas. Papillary adenocarcinoma infiltrated the myometrium late in the disease and caused attenuation of the myometrium. In contrast, tubular/solid adenocarcinoma invaded into the deep myometrium early in the disease without thinning of the myometrium. Twenty-one cases out of 26 (80.8%) cases of papillary adenocarcinoma were both ER-alpha and PR negative, whereas 15 out of 16 (93.8%) of the tubular/solid adenocarcinomas were positive for ER-alpha, PR, or both. The total immunoreactive scores of ER-alpha, PR, and mode of myometrial invasion were significantly different between histopathologic types. This suggests that there may be 2 different developmental pathways for uterine adenocarcinomas in the rabbit.
    Veterinary Pathology 04/2008; 45(2):217-25. · 1.93 Impact Factor
  • Clinical Neurophysiology. 10/2007; 118(10):e205.
  • Clinical Neurophysiology. 09/2007; 118(9):e196.
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    ABSTRACT: Myasthenia gravis (MG) is an autoimmune disease. AChR-specific autologous helper T (Th) cells are essential to the pathogenesis of MG. Factors correlated with the development of childhood-onset MG are unknown. In longitudinal studies, we found TCR Vbeta 2/5.1/6/7 usage in the development or relapse phases, but not in the remission phase. We also found that TCR Vbeta 8/9/13.1/15/18/20 usage persisted. The polyclonally expanded TCR Vbeta 2/5.1/6/7 by CDR3 spectratyping was found to be associated with the development of disease. These data suggest that in patients with childhood-onset MG, stimuli such as superantigens induced by a preceding infection, which cause development of the polyclonal pattern in TCR Vbeta families, play an important role in the development of the disease.
    Journal of Neuroimmunology 08/2007; 187(1-2):192-200. · 3.03 Impact Factor
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    ABSTRACT: Segawa disease (autosomal dominant guanosine triphosphate cyclohydrolase I [GTP-I] deficiency, DYT5) is a hereditary dopa-responsive generalized dystonia. To investigate the pathophysiologic mechanisms for dystonia in Segawa disease, we studied intracortical inhibition of the primary motor cortex in patients with Segawa disease. We studied 9 patients with Segawa disease (8 genetically confirmed patients and 1 with abnormally low GTP-I activity) and 12 age-matched normal control subjects. We studied the active motor threshold (AMT) using single pulse transcranial magnetic stimulation (TMS) and the short-interval intracortical inhibition (SICI) of the motor cortex using the previously reported paired pulse TMS method. Responses were recorded from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. The AMT was not significantly different between the patients and normal subjects. For both studied muscles, in Segawa disease, normal amount of SICI was evoked at interstimulus intervals (ISIs) of 1 to 4 msec even though they had dystonia in those muscles. Normal SICI of the motor cortex in Segawa disease stands in remarkable contrast to the previously reported reduction of SICI in focal dystonia. This suggests that the gamma-aminobutyric acid A system of the motor cortex is intact in Segawa disease. The pathophysiologic mechanisms for dystonia must be partly different between Segawa disease and focal dystonia.
    Neurology 04/2007; 68(13):1039-44. · 8.30 Impact Factor
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    ABSTRACT: Rett syndrome (RTT) is a major neurodevelopmental disorder, characterized by mental retardation and autistic behavior. Mutation of the MeCP2 gene, encoding methyl CpG-binding protein 2, causes the disease. The pathomechanism by which MeCP2 dysfunction leads to the RTT phenotype has not been elucidated. We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. A chromatin immunoprecipitation assay showed that the IGFBP3 promoter contained an MeCP2 binding site. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. Moreover, mecp2-null mice showed a widely distributed and increased number of IGFBP3-positive cells in the cerebral cortex, whereas wild-type mice at the same age showed fewer IGFBP3-positive cells. These results suggest that IGFBP3 is a downstream gene regulated by MeCP2 and that the previously reported BDNF and DLX5 genes and MeCP2 may contribute directly to the transcriptional expression of IGFBP3 in the brain. Interestingly, the pathologic features of mecp2-null mice have some similarities to those of IGFBP3-transgenic mice, which show a reduction of early postnatal growth. IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation.
    Journal of Neuropathology and Experimental Neurology 03/2007; 66(2):117-23. · 4.35 Impact Factor

Publication Stats

3k Citations
469.86 Total Impact Points

Institutions

  • 2000–2012
    • The University of Tokyo
      • • Department of Neuroscience
      • • Faculty and Graduate School of Pharmaceutical Sciences
      Tokyo, Tokyo-to, Japan
  • 2011
    • Kitasato University
      • Medical Department
      Edo, Tōkyō, Japan
  • 1984–2010
    • Azabu University
      • • School of Veterinary Medicine
      • • Department of Veterinary Medicine
      Sagamihara, Kanagawa-ken, Japan
  • 2004
    • Toho University
      • Department of Pediatrics
      Edo, Tōkyō, Japan
  • 2002–2003
    • Hokkaido Institute of Public Health
      Edo, Tōkyō, Japan
  • 2001–2002
    • Asahikawa Medical University
      • Department of Internal Medicine
      Asakhigava, Hokkaidō, Japan
  • 1998
    • Tokyo Medical and Dental University
      • Department of Pediatrics
      Tokyo, Tokyo-to, Japan
  • 1997
    • Juntendo University
      • Department of Neurosurgery
      Edo, Tōkyō, Japan
  • 1995–1996
    • Niigata University
      • Division of Neuropathology
      Niahi-niigata, Niigata, Japan
  • 1994
    • Fujita Health University
      • Institute for Comprehensive Medical Science (ICMS)
      Nagoya, Aichi, Japan
  • 1990
    • Tokyo Medical University
      Edo, Tōkyō, Japan