Publications by authors named "Katsuhisa Ogata"

34 Publications

[Changing medical care for amyotrophic lateral sclerosis patients and cause of death - review of muscular dystrophy wards (1999-2013)].

Rinsho Shinkeigaku 2021 Mar 23;61(3):161-165. Epub 2021 Feb 23.

Department of Neurology, National Hospital Organization Higashisaitama National Hospital.

We analyzed the records of inpatients with amyotrophic lateral sclerosis (ALS) treated at 27 specialized institutions for muscular dystrophy in Japan from 1999 to 2013 registered in a database on October 1 of each year. The total number of ALS inpatients in 1999 was 29, then that showed rapid increases in 2006 and 2007, and reached 164 in 2013. Age regardless of year was predominantly greater than 50 years. In 1999, the respirator dependent rate was 68.9% and then increased to 92.7% in 2013, while the oral nutritional supply rate was 41.4% in 1999 and decreased to 10.4% in 2013. The number of deaths from 2000 to 2013 was 118. Cause of death was respiratory failure in 26 of 30 patients who maintained voluntary respiration at the time of death and in 5 of 6 with non-invasive ventilation. On the other hand, the main cause of death in patients with tracheostomy invasive ventilation was respiratory infection, which was noted in 26 of 82, while other causes varied. It is expected that the number of ALS patients admitted to specialized institutions with muscular dystrophy wards will continue to increase.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001536DOI Listing
March 2021

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Brain Commun 2020 14;2(1):fcz048. Epub 2020 Jan 14.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation ( = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425345PMC
January 2020

[Pitfalls in Diagnostic Evaluation of Muscle Diseases].

Authors:
Katsuhisa Ogata

Brain Nerve 2020 Apr;72(4):371-380

Institute of Clinical Research/Department of Neurology, National Hospital Organization Higashisaitama National Hospital.

Diagnostic procedures for muscle diseases provide confirmation of the presence of muscle disorder, and their etiological assessments and precise classification, including the molecular analysis. It is important to understand the correlation between structural changes observed in muscle pathology and functional changes with electrophysiological tests to avoid pitfalls in the diagnostic evaluation of muscle diseases. Here, I present two cases with difficulties in differentiating between inflammatory and hereditary muscle diseases, and discuss pitfalls in the diagnostic process.
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http://dx.doi.org/10.11477/mf.1416201535DOI Listing
April 2020

Early phase 2 trial of TAS-205 in patients with Duchenne muscular dystrophy.

Ann Clin Transl Neurol 2020 02 20;7(2):181-190. Epub 2020 Jan 20.

National Center of Neurology and Psychiatry, Tokyo, Japan.

Objective: Duchenne muscular dystrophy (DMD) is a progressive muscular disease characterized by chronic cycles of inflammatory and necrotic processes. Prostaglandin D (PGD ) is produced by hematopoietic PGD synthase (HPGDS), which is pathologically implicated in muscle necrosis. This randomized, double-blind, placebo-controlled early phase 2 study (NCT02752048) aimed to assess the efficacy and safety of the novel selective HPGDS inhibitor, TAS-205, with exploratory measures in male DMD patients aged ≥5 years.

Methods: Patients were randomized 1:1:1 to receive low-dose TAS-205 (6.67-13.33 mg/kg/dose), high-dose TAS-205 (13.33-26.67 mg/kg/dose), or placebo. The primary endpoint was the change from baseline in a 6-minute walk distance (6MWD) at Week 24.

Results: Thirty-six patients were enrolled, of whom 35 patients were analysed for safety. The mean (standard error) changes from baseline to Week 24 in 6MWD were -17.0 (17.6) m in the placebo group (n = 10), -3.5 (20.3) m in the TAS-205 low-dose group (n = 11), and -7.5 (11.2) m in the TAS-205 high-dose group (n = 11). The mean (95% confidence interval) difference from the placebo group was 13.5 (-43.3 to 70.2) m in the TAS-205 low-dose group and 9.5 (-33.3 to 52.4) m in the TAS-205 high-dose group. No obvious differences were observed in the incidences of adverse events between treatment groups. No adverse drug reactions specific to TAS-205 treatment were observed.

Interpretation: The HPGDS inhibitor TAS-205 showed a favorable safety profile in DMD patients. Further research is required to examine the effectiveness of TAS-205 in a larger trial.
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http://dx.doi.org/10.1002/acn3.50978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034509PMC
February 2020

[Inpatients with facioscapulohumeral muscular dystrophy in specialized institutions in Japan from 1999 to 2013-Clinical condition changes and causes of death].

Rinsho Shinkeigaku 2019 Nov 26;59(11):716-722. Epub 2019 Oct 26.

Department of Neurology, National Hospital Organization Higashisaitama Hospital.

We analyzed the registration data of inpatients with facioscapulohumeral muscular dystrophy (FSHD) receiving care at 27 specialized institutions for muscular dystrophy in Japan from 1999 to 2013 using data from October 1 of each year. The number of inpatients of each year ranged from 63 to 72 (67.1 ± 3.3) throughout the study period. Those aged over 50 years gradually increased during the study period, while the oldest inpatient was 82.8 years old. Most could not walk. The rate of respirator dependency increased from 21.0% in 1999 to 71.0% in 2013, while the rate of patients receiving oral nutrition was 98.4% in 1999 and then reduced to 75.4% in 2013. There were 36 death cases reported in the database, including 15 patients with respiratory failure and 4 with heart failure. Our findings indicate that FSHD patients in a severe condition are impacted by respiratory and nutritional problems and their prognosis for survival is related to respiratory failure.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001229DOI Listing
November 2019

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Nat Genet 2019 08 22;51(8):1222-1232. Epub 2019 Jul 22.

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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http://dx.doi.org/10.1038/s41588-019-0458-zDOI Listing
August 2019

Novel pathogenic gene mutations in Japanese patients with chorea-acanthocytosis.

Neurol Genet 2019 Jun 1;5(3):e332. Epub 2019 May 1.

Kagoshima University Graduate School of Medical and Dental Sciences (Y.N., M.N., Y.U., K. Kasamo, H.H., I.Y., A.S.), Department of Psychiatry, Kagoshima, Japan; Epilepsy Center (M.M.), Department of Neurology, Nakamura Memorial Hospital, Hokkaido, Japan; Department of Psychiatry and Neurology (K. Sakurai.), Hokkaido University Graduate School of Medicine, Hokkaido, Japan; Department of Neurology (Y.O., Y.M.), Kochi Medical School, Kochi, Japan; Shinjyuku Neuro Clinic (M.W.), Tokyo, Japan; Department of Neurology (K. Yoshida and K. Yamane), Neurological Institute, Ohta-Atami Hospital, Fukushima, Japan; Department of Neurology (N.M., R.O.), Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; Division of Neurology (T.U., H.T.), Kobe University Graduate School of Medicine, Hyogo, Japan; Department of Neurology (N.W., Y.S., T.S., Y.T., M.A.), National Center of Neurology and Psychiatry Hospital, Tokyo, Japan; Department of Neurology (K. Shibano), Akita Red Cross Hospital, Japan; Amagasaki General Medical Center (A.H.), Hyogo, Japan; Department of Neurology (K.M., K.O.), National Hospital Organization Higashisaitama National Hospital, Saitama, Japan; Department of Neurology (K. Kakuda, H.M.), Graduate School of Medicine, Osaka University, Japan; Ikebe Clinic (T.A.), Shizuoka, Japan; Department of Psychiatry (T.F.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology (K.T., H.S.-T.), Tenri Hospital, Nara, Japan; and Department of Neurology (K.T., H.S.-T.), Graduate School of Medicine, Kyoto University, Japan.

Objective: To identify mutations in () for Japanese patients with suspected chorea-acanthocytosis (ChAc).

Methods: We performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis of the gene, and chorein Western blotting of erythrocyte ghosts. As the results of the analysis, 17 patients were molecularly diagnosed with ChAc. In addition, we investigated the distribution of gene mutations and clinical symptoms in a total of 39 molecularly diagnosed Japanese patients with ChAc, including 22 previously reported cases.

Results: We identified 11 novel pathogenic mutations, including 1 novel CNV. Excluding 5 patients with the unknown symptoms, 97.1% of patients displayed various neuropsychiatric symptoms or forms of cognitive dysfunction during the course of disease. The patients carrying the 2 major mutations representing over half of the mutations, exon 60-61 deletion and exon 37 c.4411C>T (R1471X), were localized in western Japan.

Conclusions: We identified 13 different mutations in , including 11 novel mutations, and verified the clinical manifestations in 39 Japanese patients with ChAc.
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http://dx.doi.org/10.1212/NXG.0000000000000332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515943PMC
June 2019

The myotonic dystrophy health index: Japanese adaption and validity testing.

Muscle Nerve 2019 05 8;59(5):577-582. Epub 2019 Feb 8.

Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.

Introduction: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific, patient-reported outcome measure. The objective of this study was to translate, evaluate, and validate a Japanese version of the MDHI (MDHI-J).

Methods: We utilized forward and backward translations and qualitative interviews with 11 myotonic dystrophy type 1 (DM1) participants. We subsequently tested the internal consistency, test-retest reliability, concurrent validity against muscle strength, and 3 quality-of-life measures, and the known-groups validity of the MDHI-J with 60 adult patients.

Results: The MDHI-J was found to be culturally appropriate, comprehensive, and clinically relevant. The MDHI-J and its subscales had high internal consistency (mean Cronbach's α = 0.91), test-retest reliability (intraclass coefficient 0.678-0.915), and concurrent validity (Spearman's ρ - 0.869 to 0.904). MDHI-J scores were strongly associated with employment, duration of symptoms, and modified Rankin Scale.

Discussion: The MDHI-J is suitable and valid to measure patient-reported disease burden in adult Japanese patients with DM1. Muscle Nerve 59:577-577, 2019.
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http://dx.doi.org/10.1002/mus.26422DOI Listing
May 2019

Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations.

J Hum Genet 2018 Apr 5;63(4):417-423. Epub 2018 Feb 5.

Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.
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http://dx.doi.org/10.1038/s10038-017-0408-5DOI Listing
April 2018

Validation of The Individualized Neuromuscular Quality of Life in Japanese patients with myotonic dystrophy.

Muscle Nerve 2018 Jan 17. Epub 2018 Jan 17.

Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan.

Introduction: The Individualized Neuromuscular Quality of Life (INQoL) is used to measure the quality of life (QoL) of patients with neuromuscular disease. We conducted this study to translate and validate the Japanese version of the INQoL in patients with myotonic dystrophy.

Methods: Forward and backward translation, patient testing, and psychometric validation were performed. We used the 36-Item Short Form Health Survey (SF-36) and the modified Rankin scale for concurrent validation.

Results: The Japanese INQoL was administered to 90 adult patients. The coefficients for internal consistency and test-retest reliability were adequately high in most domains (Cronbach α 0.88-0.96 and intraclass coefficient 0.64-0.99). INQoL domains were moderately to strongly associated with relevant SF-36 subscales (Spearman's ρ -0.23 to -0.74). Symptom severity, disease duration, employment status, and use of a ventilator influenced overall QoL.

Discussion: The INQoL is a reliable and validated measure of QoL for Japanese patients with myotonic dystrophy. Muscle Nerve, 2018.
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http://dx.doi.org/10.1002/mus.26071DOI Listing
January 2018

Screening of autoantibodies associated with necrotizing myopathy among undiagnosed chronic myopathy.

Rinsho Shinkeigaku 2017 10 28;57(10):562-566. Epub 2017 Sep 28.

Department of Neurology, National Hospital Organization Toneyama Hospital.

We screened anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies among 42 patients who had undiagnosed chronic myopathy from six national hospitals. Anti-SRP and anti-HMGCR antibodies were determined by RNA immuneprecipitation and enzyme-linked immune-sorbent assay (ELISA), respectively. We identified two patients with anti-SRP antibodies (4.7%) and, two with anti-HMGCR antibodies (4.7%). Both of anti-SRP-positive patients showed dysphagia with a high level of creatine kinase. Anti-HMGCR antibodies were associated with mild muscle weakness with a relatively late disease onset. Our study suggests the importance of autoantibody testing among undiagnosed chronic myopathy.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001075DOI Listing
October 2017

A Japanese male with a novel ANO5 mutation with minimal muscle weakness and muscle pain till his late fifties.

Neuromuscul Disord 2017 May 18;27(5):477-480. Epub 2017 Jan 18.

Department of Neurology, National Hospital Organization Higashisaitama Hospital, Saitama, Japan.

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with anoctamin 5 (ANO5) gene mutation, mainly reported from Northern and Central Europe. We report the case of a Japanese male patient with a novel homozygous mutation of c.2394dup, p.Arg799Thrfs in ANO5 gene, the second patient in the Asian population. He had had marked elevation of creatine kinase (CK) level for more than 10 years with minimal muscular symptoms consisting of muscle stiffness and occasional cramps, preceding the onset of proximal limb weakness. Calf hypertrophy and selective fatty replacement of the adductor magnus and gastrocnemius muscles were prominent clinical and muscle imaging features. This case suggests that LGMD2L may affect a broader population than has been previously thought, physicians should consider the possibility of ANO5 mutation even in patients showing elevated CK level with no apparent muscle weakness but muscle stiffness or cramps.
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http://dx.doi.org/10.1016/j.nmd.2017.01.012DOI Listing
May 2017

Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.

Am J Hum Genet 2017 Jan 22;100(1):169-178. Epub 2016 Dec 22.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan. Electronic address:

Nemaline myopathy (NM) is a common form of congenital nondystrophic skeletal muscle disease characterized by muscular weakness of proximal dominance, hypotonia, and respiratory insufficiency but typically not cardiac dysfunction. Wide variation in severity has been reported. Intranuclear rod myopathy is a subtype of NM in which rod-like bodies are seen in the nucleus, and it often manifests as a severe phenotype. Although ten mutant genes are currently known to be associated with NM, only ACTA1 is associated with intranuclear rod myopathy. In addition, the genetic cause remains unclear in approximately 25%-30% of individuals with NM. We performed whole-exome sequencing on individuals with histologically confirmed but genetically unsolved NM. Our study included individuals with milder, later-onset NM and identified biallelic loss-of-function mutations in myopalladin (MYPN) in four families. Encoded MYPN is a sarcomeric protein exclusively localized in striated muscle in humans. Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness. Walking difficulties were recognized around their forties. Decreased respiratory function, cardiac involvement, and intranuclear rods in biopsied muscle were observed in two individuals. MYPN was localized at the Z-line in control skeletal muscles but was absent from affected individuals. Homozygous knockin mice with a nonsense mutation in Mypn showed Z-streaming and nemaline-like bodies adjacent to a disorganized Z-line on electron microscopy, recapitulating the disease. Our results suggest that MYPN screening should be considered in individuals with mild NM, especially when cardiac problems or intranuclear rods are present.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223057PMC
January 2017

Study of Duchenne muscular dystrophy long-term survivors aged 40 years and older living in specialized institutions in Japan.

Neuromuscul Disord 2017 Feb 25;27(2):107-114. Epub 2016 Nov 25.

Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Osaka, Japan.

The national muscular dystrophy wards database of Japan lists 118 long-term Duchenne muscular dystrophy (DMD) patients who were at least 40 years old as of October 1, 2013. To elucidate the clinical features of DMD patients aged 40 years and older, we obtained gene analysis and muscle biopsy findings, as well as medical condition information. Ninety-four of the registered patients consented to participate, of whom 55 meeting genetic or biochemical criteria confirming DMD were analyzed. The mean age at the time of the study was 43.6 ± 3.0 years, while at the time of independent ambulation loss it was 10.6 ± 1.5 years and at mechanical ventilation introduction it was 24.1 ± 5.5 years. All were receiving continuous ventilation support, 27 with non-invasive positive pressure ventilation and 28 with tracheal intermittent positive pressure ventilation. Thirty-eight were receiving β-blockers or a renin-angiotensin system inhibitor, while 9 were free from those agents. Forty had maintained oral nutrition. The 55 analyzed patients had survived into their 40s by receiving multidisciplinary intervention. Our findings emphasize the need of future studies to investigate disease modifiers and the mechanism of long-term survival. In addition, establishment of a worldwide care standard with focus on quality of life for adult males with DMD is important.
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http://dx.doi.org/10.1016/j.nmd.2016.11.012DOI Listing
February 2017

Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

BMC Health Serv Res 2016 07 11;16:241. Epub 2016 Jul 11.

Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan.

Background: Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases.

Methods: To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation.

Results: Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time.

Conclusion: Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to an improvement of neuromuscular disease treatment in Japan.
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http://dx.doi.org/10.1186/s12913-016-1477-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939632PMC
July 2016

[Vasculitic Peripheral Neuropathies: Clinical Features and Diagnostic Laboratory Tests].

Authors:
Katsuhisa Ogata

Brain Nerve 2016 Mar;68(3):205-11

Institute of Clinical Research, National Hospital Organization Higashisaitama Hospital.

Vasculitic peripheral neuropathy (VPN) occurs due to ischemic changes of peripheral nerves, resulting from a deficit of vascular blood supply due to damaged vasa nervorum leading to vasculitis. VPN usually manifests as sensorimotor or sensory disturbances accompanied by pain, presenting as a type of multiple mononeuropathy, with a scattered distribution in distal limbs. VPN may also present as a mononeuropathy, distal symmetric polyneuropathy, plexopathy, or radiculopathy. The rapidity of VPN is variable, ranging from days to months, with symptoms occasionally changing with the appearance of new lesions. Careful history taking and neurological examination provides an exact diagnosis. The most common cause of VPN is primary vasculitis predominantly affecting small vessels, including vasa nervorum, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and polyarteritis nodosa. Similar vasculitic processes can also result from a systemic collagen disorder or secondary vasculitis. Electrophysiological studies and pathological investigation of biopsied peripheral nerves and muscles are important for diagnosis of vasculitis. Serological tests, including ANCA, are useful for diagnosis of vasculitis. Accurate neurological examinations are essential for diagnosis and evaluation of clinical course.
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http://dx.doi.org/10.11477/mf.1416200379DOI Listing
March 2016

Necklace cytoplasmic bodies in hereditary myopathy with early respiratory failure.

J Neurol Neurosurg Psychiatry 2015 May 24;86(5):483-9. Epub 2014 Sep 24.

Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan Department of Neuromuscular Research, National Institute of Neuroscience, NCNP, Tokyo, Japan.

Background: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown.

Objective: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs).

Methods: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM.

Results: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort.

Conclusions: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.
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http://dx.doi.org/10.1136/jnnp-2014-309009DOI Listing
May 2015

A novel SACS mutation in an atypical case with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).

Intern Med 2012 15;51(16):2221-6. Epub 2012 Aug 15.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disorder with symptoms of spastic ataxia, neuropathy, pyramidal sign, finger and foot deformities, and hypermyelination of retinal nerve fibers. SACS is mutated in ARSACS. The clinical diversity of ARSACS is recognized, which sometimes makes its diagnosis difficult. By using homozygosity mapping, we identified a novel homozygous c.12020C > T missense mutation in a consanguineous Japanese family with atypical clinical features. In addition to the absence of spasticity and hypermyelinated retinal nerve fibers, the present case had urinary dysfunction, impotence, and severe constipation, indicating the possibility of autonomic dysfunction. Furthermore, we showed the diagnostic usefulness of MRI even for the case of atypical clinical features. It had been considered that cases without obvious spasticity were very rare, however recent reports on atypical cases as well as our case indicate that ARSACS cases without obvious spasticity might be more frequent than previously thought. We should be aware of atypical features of ARSACS for the correct diagnosis.
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http://dx.doi.org/10.2169/internalmedicine.51.7374DOI Listing
November 2012

Selective muscle involvement in a family affected by a second LIM domain mutation of fhl1: an imaging study using computed tomography.

J Neurol Sci 2012 Jul 27;318(1-2):163-7. Epub 2012 Apr 27.

Department of Neurology, Dokkyo Medical University, Tochigi, Japan.

Mutations in the four-and-a-half LIM domains 1 gene (fhl1) are associated with various phenotypes of hereditary myopathies, including reducing body myopathy. We describe here a mother, daughter and son suffering from FHL1 myopathy with a mutation in the second LIM domain of fhl1. We investigated whether there is a characteristic muscle involvement in both sexes. Despite the variety of symptoms exhibited by the male and female patients, the systemic imaging studies showed a similar pattern: the flexor muscles of the brachium and thigh were affected earlier than the extensor muscle with a profound degeneration of the paraspinal muscles. These findings may include one of the characteristic clinical features for suspecting a mutation in the second LIM domain.
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http://dx.doi.org/10.1016/j.jns.2012.04.007DOI Listing
July 2012

Misfolded SOD1 forms high-density molecular complexes with synaptic molecules in mutant SOD1-linked familial amyotrophic lateral sclerosis cases.

J Neurol Sci 2012 Mar 14;314(1-2):92-6. Epub 2011 Nov 14.

Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we report identification of various synaptic molecules forming molecular complexes with misfolded SOD1 in mutant SOD1-associated FALS patient tissues as well as in cellular FALS models. In the FALS cellular model system, we found that membrane depolarization that mimics synaptic hyperactivation/excitotoxicity could cause misfolding of mutant SOD, as well as acceleration of misfolded SOD1-synaptic protein complex formation. These results suggest that inhibition of synaptic release mechanism by association of misfolded SOD1 with synaptic molecules plays a role in the dysfunction of FALS.
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http://dx.doi.org/10.1016/j.jns.2011.10.017DOI Listing
March 2012

Decreased resting energy expenditure in patients with Duchenne muscular dystrophy.

Brain Dev 2012 Mar 31;34(3):206-12. Epub 2011 May 31.

Department of Child Neurology, National Center Hospital of Neurology and Psychiatry, National Center of Neurology and Psychiatry, Japan.

Background: Skeletal muscle metabolism is a major determinant of resting energy expenditure (REE). Although the severe muscle loss that characterizes Duchenne muscular dystrophy (DMD) may alter REE, this has not been extensively investigated.

Methods: We studied REE in 77 patients with DMD ranging in age from 10 to 37 years using a portable indirect calorimeter, together with several clinical parameters (age, height, body weight (BW), body mass index (BMI), vital capacity (VC), creatine kinase, creatinine, albumin, cholinesterase, prealbumin), and assessed their influence on REE. In addition, in 12 patients maintaining a stable body weight, the ratio of energy intake to REE was calculated and defined as an alternative index for the physical activity level (aPAL).

Results: REE (kcal/day, mean±SD) in DMD patients was 1123 (10-11 years), 1186±188 (12-14 years), 1146±214 (15-17 years), 1006±136 (18-29 years) and 1023±97 (≥30 years), each of these values being significantly lower than the corresponding control (p<0.0001). VC (p<0.001) was the parameter most strongly associated with REE, followed by BMI (p<0.01) and BW (p<0.05). The calculated aPAL values were 1.61 (10-11 years), 1.19 (12-14 years), 1.16 (15-17 years), and 1.57 (18-29 years).

Conclusion: The REE in DMD patients was significantly lower than the normal value in every age group, and strongly associated with VC. Both the low REE and PAL values during the early teens, resulting in a low energy requirement, might be related to the obesity that frequently occurs in this age group. In contrast, the high PAL value in the late stage of the disease, possibly due to the presence of respiratory failure, may lead to a high energy requirement, and thus become one of the risk factors for development of malnutrition.
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http://dx.doi.org/10.1016/j.braindev.2011.05.005DOI Listing
March 2012

Brain volume analyses and somatosensory evoked potentials in multiple system atrophy.

J Neurol 2010 Mar 30;257(3):419-25. Epub 2009 Sep 30.

Department of Neurology, Higashi-Saitama National Hospital, Hasuda, Saitama, Japan.

We investigated a progression of brain atrophy and somatosensory system dysfunction in multiple system atrophy (MSA). Subjects were 21 MSA patients [12 MSA-C (cerebellar type) and 9 MSA-P (parkinsonism type)]. The relative volumes of cerebrum, brainstem and cerebellum to the intracranial volume were obtained from three-dimensional computed tomography (3D-CT) of the brain. The median nerve somatosensory evoked potentials (SEPs) were recorded, and the latencies and amplitudes of N9, N11, P13/14, N20 and P25 components were measured. We studied correlations between brain volumes, SEP and clinical features. The brainstem and cerebellar atrophies were aggravated with progression of the disease. The central sensory conduction time (CSCT) was progressively prolonged in parallel with the disease duration irrespective of the actual age of the patients. In MSA patients, the volume reductions of cerebellum and brainstem could be one of structural markers of disease progression, and the sensory pathway is progressively involved with the progression of disease processes.
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http://dx.doi.org/10.1007/s00415-009-5338-5DOI Listing
March 2010

Heart rate variability and hypercapnia in Duchenne muscular dystrophy.

Intern Med 2008 4;47(21):1893-7. Epub 2008 Nov 4.

Department of Neurology, Higashi-Saitama National Hospital, Hasuda.

Objective: To investigate the relationship between heart rate variability and hypercapnia.

Patients And Methods: We measured the coefficient of variation of R-R interval (CVrr) and arterial blood gas pressures in 73 patients with Duchenne muscular dystrophy.

Results: CVrr was negatively correlated with arterial partial pressure of carbon dioxide (PaCO(2)). In patients whose CVrr was larger than 5%, 84% of them had no hypercapnia while the other 16% had hypercapnia (PaCO(2) >45 mmHg). In contrast, 27% of those with CVrr smaller than 3% had no hypercapnia, 73% had hypercapnia and 47% had severe hypercapnia (PaCO(2) >50 mmHg).

Conclusion: We first showed that CVrr was negatively correlated with PaCO(2), and propose that abnormally low CVrr indicates respiratory insufficiency in patients with Duchenne muscular dystrophy.
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http://dx.doi.org/10.2169/internalmedicine.47.1118DOI Listing
June 2009

Mental retardation and lifetime events of Duchenne muscular dystrophy in Japan.

Intern Med 2008 1;47(13):1207-10. Epub 2008 Jul 1.

Department of Neurology, Higashi-Saitama National Hospital, Hasuda, Japan.

Objective: This study investigated the relationship between mental retardation and lifetime events in patients with Duchenne muscular dystrophy (DMD).

Methods: The data on mental retardation and ages of lifetime events (first walking, loss of ambulation, introductions of ventilator support and tube nutrition and death) were collected retrospectively, and the relationships between the factors were analyzed.

Patients: Among 194 DMD patients admitted to our hospital between 1995 and 2007, 74 patients underwent evaluation of their intelligence quotient (IQ).

Results: Twenty-eight patients (38%) demonstrated mental retardation (IQ<70). DMD patients with mental retardation started walking later, required ventilator and tube nutrition support earlier, and died earlier than those without mental retardation.

Conclusions: Since the prognosis of DMD patients with mental retardation was worse than that of those without mental retardation, more careful treatment is necessary for DMD patients with mental retardation.
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http://dx.doi.org/10.2169/internalmedicine.47.0907DOI Listing
August 2008

[Case of suspected multiple sclerosis with transcallosal lesions involving the upper surface of the corpus callosum].

Rinsho Shinkeigaku 2008 May;48(5):321-7

Department of Neurology, Graduate School of Medicine, Kobe University.

A 26-year-old woman noticed gradually progressive, right lower leg weakness over a 1.5-month period. Neurological examination revealed right hemiparesis with slightly increased deep tendon reflexes, Babinski's sign on the right side, loss of position sense in the right leg, and slight loss of superficial sensation in the right toes. MR FLAIR images showed a high intensity area measuring 5 x 2 x 3 cm in the left frontal lobe, extending to the outer surface of the body of the corpus callosum and the adjacent right cingulate gyrus. Gadolinium enhancement was seen along the cortex and the outer surface of the body of the corpus callosum. CSF findings showed no pleocytosis, a protein content of 32 mg/dl, a sugar level of 85 mg/dl, and an IgG index of 0.46. The biopsy specimen obtained from the superior frontal gyrus showed perivascular cuffing of T-lymphocytes and some B-lymphocytes, as well as multiple small foci of demyelination. Starting on the second day of admission, the patient was treated with methylprednisolone pulse therapy (1,000 mg/day for 3 days); she was then switched to oral prednisolone (20 mg/day). Thereafter, the patient had two clinical relapses: one was due to a lesion in the dorsal part of the medulla oblongata associated with a disturbance of deep sensation in both hands, and the other was due to a lesion involving the right internal capsule, the globus pallidus, and the caudate nucleus associated with left facial nerve palsy. Visual evoked potentials suggested a demyelinating lesion in the right optic nerve. We suspected a diagnosis of multiple sclerosis based on the presence of more than two clinical episodes of neurological deficits with identifiable lesions on MRI. Multiple sclerosis should be considered in the differential diagnosis of lesions located in the outer part of the corpus callosum and transcallosal bilateral hemispheres on MRI, even though inner callosal lesions are common in multiple sclerosis.
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http://dx.doi.org/10.5692/clinicalneurol.48.321DOI Listing
May 2008

Asymptomatic sporadic dysferlinopathy presenting with elevation of serum creatine kinase. Typical distribution of muscle involvement shown by MRI but not by CT.

Intern Med 2008 15;47(4):305-7. Epub 2008 Feb 15.

Department of Neurology, Higashisaitama Hospital, National Hospital Organization, Hasuda, Japan.

We report an 18-year-old man with elevation of the creatine kinase (CK) level to 11,068 IU/L. There was no muscle atrophy or fat replacement on CT while muscles in the posterior compartment of lower legs showed high T2 signal intensity on MRI. We performed muscle biopsy from the gastrocnemius muscle. Immunohistochemical analysis demonstrated an absence of dysferlin leading to a diagnosis of preclinical dysferlinopathy. Typical distribution of muscle involvement was demonstrated not by CT but by MRI which may have contributed to facilitating diagnosing the earliest stage of preclinical dysferlinopathy, presenting with asymptomatic elevation of serum creatine kinase.
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http://dx.doi.org/10.2169/internalmedicine.47.0519DOI Listing
April 2008

[Videofluorographic evaluation of dysphagia in a patient with myasthenia gravis].

Rinsho Shinkeigaku 2007 Oct;47(10):669-71

Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry.

A 64-year-old woman with myasthenia gravis (MG) presented with isolated bulbar symptoms. Two years earlier, she had developed neck weakness, diplopia, and ptosis and was diagnosed with MG. Extensive thymectomy was performed, and she was treated with predonisolone (PSL). The neck weakness, diplopia, and ptosis improved over a 2-year period. However, dysphagia developed, and her voice took on a nasal tone that did not improve subjectively even after administration of 10 mg of edrophonium chloride (EC). We then performed videofluorography (VF). After consumption of 10 ml of liquid barium and 8 g of corned beef hash, she attempted to swallow, but the residue remained in the valleculae and the piriform fossa. After the EC injection, her dysphagia on ingestion of corned beef hash improved; however, there was slight subjective improvement in swallowing. Drinking of liquid barium resulted in some residue with slight improvement of dysphagia. After treatment with 70 mg of PSL for 4 weeks, VF showed improvement of dysphagia. Thus, VF, particularly during consumption of solid food, with EC administration is helpful in evaluating bulbar symptoms in patients with MG.
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October 2007

Multiplex families with multiple system atrophy.

Arch Neurol 2007 Apr;64(4):545-51

Departments of Neurology, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan.

Background: Multiple system atrophy (MSA) has been considered a sporadic disease, without patterns of inheritance.

Objective: To describe the clinical features of 4 multiplex families with MSA, including clinical genetic aspects.

Design: Clinical and genetic study.

Setting: Four departments of neurology in Japan. Patients Eight patients in 4 families with parkinsonism, cerebellar ataxia, and autonomic failure with age at onset ranging from 58 to 72 years. Two siblings in each family were affected with these conditions.

Main Outcome Measures: Clinical evaluation was performed according to criteria by Gilman et al. Trinucleotide repeat expansion in the responsible genes for the spinocerebellar ataxia (SCA) series and for dentatorubral-pallidoluysian atrophy (DRPLA) was evaluated by polymerase chain reaction. Direct sequence analysis of coding regions in the alpha-synuclein gene was performed.

Results: Consanguineous marriage was observed in 1 of 4 families. Among 8 patients, 1 had definite MSA, 5 had probable MSA, and 2 had possible MSA. The most frequent phenotype was MSA with predominant parkinsonism, observed in 5 patients. Six patients showed pontine atrophy with cross sign or slitlike signal change at the posterolateral putaminal margin or both on brain magnetic resonance imaging. Possibilities of hereditary ataxias, including SCA1 (ataxin 1, ATXN1), SCA2 (ATXN2), Machado-Joseph disease/SCA3 (ATXN1), SCA6 (ATXN1), SCA7 (ATXN7), SCA12 (protein phosphatase 2, regulatory subunit B, beta isoform; PP2R2B), SCA17 (TATA box binding protein, TBP) and DRPLA (atrophin 1; ATN1), were excluded, and no mutations in the alpha-synuclein gene were found.

Conclusions: Findings in these multiplex families suggest the presence of familial MSA with autosomal recessive inheritance and a genetic predisposition to MSA. Molecular genetic approaches focusing on familial MSA are expected to provide clues to the pathogenesis of MSA.
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http://dx.doi.org/10.1001/archneur.64.4.545DOI Listing
April 2007

[Long-term treatment of diabetes mellitus in myotonic dystrophy with pioglitazone].

Rinsho Shinkeigaku 2005 Apr;45(4):287-92

Department of Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders.

We report beneficial effects of pioglitazone on insulin resistance in diabetes mellitus accompanied with myotonic dystrophy (DM1). We studied eight DM1 patients with diabetes mellitus aged 32 to 60 (mean age 52.1 +/- 8.6 years). Three of them were under glibenclamide treatment, but their plasma glucose control was poor because of occasional hypoglycemia; others had not been treated with any hypoglycemic drugs. We administered a daily dose of 15 mg pioglitazone for 6-36 months (mean period 14.8 +/- 9.1 months). Plasma glucose control improved in all patients. In a 75 g oral glucose tolerance test, plasma glucose level at 120 min dropped from 203.3 +/- 41.7 mg/dl to 153.9 +/- 39.5 mg/dl (p = 0.04); the area under the insulin curve up to 120 min (sigma IRI) dropped from 236.9 +/- 170.2 microU x hr/ml to 169.6 +/- 81.3 microU x hr/ml (p = 0.12). Sigma IRI decreased in four patients with pretreatment sigma IRI > or = 250 microU x hr/ml; it slightly increased in other patients with pretreatment sigma IRI < or = 150 microU x hr/ml. The homeostasis model assessment-insulin resistance (HOMA-IR) improved from 2.1 +/- 1.0 to 1.1 +/- 0.4 (p = 0.04). Impairment of liver functions, cardiac failure, or hypoglycemia was not observed. Pioglitazone treatment is useful to improve insulin resistance and glucose control in DM1 patients with diabetes mellitus, especially patients with reactive hyperinsulinemia to glucose loading.
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April 2005

[Validation of the Japanese-translated version Multiple Sclerosis Quality of Life-54 instrument].

Rinsho Shinkeigaku 2004 Jul;44(7):417-21

Department of Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders.

The Multiple Sclerosis Quality of Life-54 instrument (MSQOL-54) is a specific quality of life (QOL) scale in English for multiple sclerosis (MS). It is composed of 54 items, and is a combination of the 36-item short form health survey (SF-36) and 18 disease-specific questions, such as fatigue, mental sexual and cognitive dysfunction. We developed the Japanese-translated version of MSQOL-54. The SF-36 has been previously validated and published in Japanese; therefore the translation work was performed mainly on the 18 MS specific items. The Japanese-translated version MSQOL-54 was examined in 62 Japanese patients with MS. The mean age of the patients was 42.8 years; mean expanded disability status scale (EDSS) score was 3.0. The ratio of respondents was almost complete for all scales except for those within the sexual scales. Internal consistency reliability estimates for the 11 multi-item scales ranged from 0.65 to 0.93 in 62 patients. Test-retest intraclass correlation coefficients ranged from 0.61 to 0.95 in 20 patients. Compared to the previous reported mean scores of general Japanese population of SF-36, the mean scores of patients with MS had lower scores in all scales. In comparison with an original article in English, the validation of the Japanese-translated version MSQOL-54 may be acceptable. There were no correlations between the results of the Japanese-translated version MSQOL-54 and EDSS except for physical function and physical health composite score. The Japanese-translated version of MSQOL-54 may provide unique information not readily evaluated by EDSS, and may be useful as clinical outcome measures in patients with MS.
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July 2004