Publications by authors named "Satoshi Kuru"

41 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

[Fifity years after the identification of the cause of SMON].

Authors:
Satoshi Kuru

Rinsho Shinkeigaku 2021 Feb 26;61(2):109-114. Epub 2021 Jan 26.

Department of Neurology, National Hospital Organization Suzuka Hospital.

SMON (subacute myelo-optico-neuropathy) is toxic neurological disease which had a profound impact on the population in Japan in 1960's. The clinical characteristics of SMON includes an ascending sensory disturbance, spasticity, and visual impairment typically following abdominal symptoms. Infection was first suspected as an underlying cause of this epidemic. The disorder was ultimately attributed to the overuse of clioquinol, based on the analysis of green urine from affected patients and confirmed by the epidemiological surveys and experimental animal studies. The factors that contributed to the prevalence of SMON which remains the worst example of drug-associated toxicity in Japan to date include the conversion of clioquinol from a purely topical agent to an orally-administered drug, dogma associated with drug safety, relatively limited regulation of drug use, an increase in the number of prescriptions due to the availability of universal insurance, as well as the complexity of the associated abdominal symptoms. Periodical examination of the patients diagnosed with SMON continues to this day. As such, it is important to have a better understanding of clioquinol-induced neurotoxicity together with the mechanisms underlying drug susceptibility; we should not permit the memory of this severe and prominent drug-associated toxicity fade from view.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001500DOI Listing
February 2021

The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy.

Neurobiol Aging 2021 Apr 14;100:120.e1-120.e6. Epub 2020 Nov 14.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address:

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.028DOI Listing
April 2021

Cardiac Conduction Disorders as Markers of Cardiac Events in Myotonic Dystrophy Type 1.

J Am Heart Assoc 2020 09 19;9(17):e015709. Epub 2020 Aug 19.

Department of Neurology National Hospital Organization Osaka Toneyama Medical Center 5-1-1 Toyonaka Japan.

Background Myotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1. Methods and Results This study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine-thymine-guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow-up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow-up period of 87 months (Q1-Q3, 37-138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22-15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9-7.19, <0.05) or QRS duration ≥120 ms (HR, 9.41; 95% CI, 2.62-33.77, < 0.01) were independent factors associated with a higher occurrence of cardiac events than those observed with a PQ interval <240 ms or QRS duration <120 ms; these cardiac conduction parameters were not related to sudden death. Conclusions Cardiac conduction disorders are independent markers associated with cardiac events. Further investigation on the prediction of occurrence of sudden death is warranted.
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http://dx.doi.org/10.1161/JAHA.119.015709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660777PMC
September 2020

Repetitive Transcranial Magnetic Stimulation for Dysesthesia Caused by Subacute Myelo-Optico-Neuropathy: A Case Report.

Case Rep Neurol 2020 May-Aug;12(2):169-174. Epub 2020 Jun 9.

Department of Neurology, National Hospital Organization Suzuka National Hospital, Suzuka, Japan.

Subacute myelo-optico-neuropathy (SMON) is caused by the ingestion of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline), which is an intestinal antibacterial drug. Patients with SMON typically suffer from abnormal dysesthesia in the lower limbs, which cannot explain the mechanism only in pathology and electrophysiology. Neuromodulation therapies are increasingly being investigated as a means of alleviating abnormal sensory disturbances. We report here the response to repetitive transcranial magnetic stimulation (rTMS) for dysesthesia in a patient with SMON. The patient underwent rTMS treatment once per week for 12 weeks. rTMS was administered at 10 Hz, 90% of the resting motor threshold over the bilateral primary motor cortex foot area, for a total of 1,500 stimuli per day. After the treatment had finished at 12 weeks, the abnormal dysesthesia gradually declined. At first, there were improvements only in the area with a feeling of adherence. Later, this sensation was eliminated. Three months following the application, most of the feeling of adherence had disappeared and the feeling of tightness was slightly reduced. In contrast, the throbbing feeling had not changed during this period. Dysesthesia may indicate a process of central sensitization, which would contribute to chronic neuromuscular dysfunction. This case suggests that rTMS is a promising therapeutic application for dysesthesia.
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http://dx.doi.org/10.1159/000507650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315208PMC
June 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

[Study of care practices for patients with myotonic dystrophy in Japan-Nationwide patient survey].

Rinsho Shinkeigaku 2020 Feb 18;60(2):130-136. Epub 2020 Jan 18.

Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center.

We conducted a comprehensive anonymous questionnaire survey on medical care and treatment for patients with myotonic dystrophy, who registered in the Japanese national registry (Remudy) or were undergoing care in seven hospitals specializing neuromuscular diseases. The questionnaire consisted of 49 questions were distributed to 813 patients, and 342 valid responses were collected. Most prevalent symptoms or complaints were dysfunction of fingers and fatigue. One-third of the adult patients left the job, half of which was due to the disease. Twelve percent of the patients did not visit the specialist regularly, the main reason being distance. The most common reason that the patients did not follow the advice of using a ventilator by medical professionals was lack of feeling the need. One-fourth of the adult female patients had infertility treatment, 80% of which was before a diagnosis of this disorder. This first-time nationwide survey revealed the actual condition of Japanese patients with myotonic dystrophy and raised various care-related issues.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001349DOI Listing
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

Assessment of muscle involvement in patients with Duchenne muscular dystrophy via segmental multifrequency bioelectrical analysis.

Neuromuscul Disord 2019 09 21;29(9):671-677. Epub 2019 Aug 21.

Department of Neurology, Yokohama Rosai Hospital, Yokohama, Japan.

We investigated the usefulness of segmental multifrequency bioelectrical impedance analyses (MBIA) for assessing muscle involvement in Duchenne muscular dystrophy (DMD) patients. Bioelectrical impedance data of the upper arm, thigh, and lower leg were obtained from 29 boys with DMD (ages 2-17 years old; mean 10.8 ± 3.9 years) at three institutions along with 41 healthy controls (ages 3-16; mean 9.8 ± 3.5 years). Then the muscle density index (MDI: 1- Z/Z) was calculated using segmental MBIA and compared between groups. The MDI was lower in boys with DMD, relative to controls, with older DMD patients exhibiting a significant decrease in MDI. The MDI of patient thighs was significantly correlated with the percent muscle volume index (%MVI), as measured using computed tomography (r = 0.79). MDI values for the upper arm, thigh, and lower leg were all significantly correlated with the Brooke and the Vignos scales, respectively, with correlation coefficients of 0.56-0.77. Finally, MDI was significantly greater in the glucocorticoid-treated group, relative to the untreated group in all regions. Taken together, these data show that segmental MBIA is feasible for evaluating muscle involvement and might serve as an outcome measure in DMD.
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http://dx.doi.org/10.1016/j.nmd.2019.08.006DOI Listing
September 2019

Automatic calculation of Mercuri grades from CT and MR muscle images.

Brain Dev 2019 Nov 12;41(10):870-877. Epub 2019 Jul 12.

Department of Neurology, NHO Suzuka National Hospital, Japan.

Background: Mercuri grading of muscle images is a useful method to evaluate the progression of muscular dystrophies. However, because Mercuri grading is skill-based, few competent experts are available. We therefore developed an automated method for Mercuri grade calculations.

Methods: We used computed tomography (CT) and magnetic resonance (MR) images of the thigh and lower leg muscles taken from a Japanese limb-girdle muscular dystrophy patient database. We calculated muscle impairment ratios based on the CT images, and then converted the ratios to revised Mercuri grades. This method was also applied to T1-weighted MR images. Additionally, radiation absorption doses in muscle and chest CT images from a separate patient group were also analyzed.

Results: We observed a close correlation between our automatically calculated Mercuri grades and skill-based visually determined Mercuri grades in both CT and MR images. The radiation absorption, measured by total dose length product, was lower in muscle CT (121.8 mGy-cm) than in chest CT (524.1 mGy-cm).

Conclusions: We developed a new automatic Mercuri grading method using values obtained from CT images. This method was also applied to calculate the Mercuri grade of T1-weighted MR images. In addition, the radiation doses from muscle CT were observed to be lower than those from chest CT.
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http://dx.doi.org/10.1016/j.braindev.2019.06.008DOI Listing
November 2019

Characteristic findings of skeletal muscle MRI in caveolinopathies.

Neuromuscul Disord 2018 10 31;28(10):857-862. Epub 2018 Jul 31.

Department of Pediatrics, School of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, Japan. Electronic address:

Caveolinopathies, caused by CAV3 mutations, can include several phenotypes such as rippling muscle disease, limb-girdle muscular dystrophy type 1C, distal myopathy, familial hypertrophic cardiomyopathy, and idiopathic hyperCKemia. Here we present characteristic skeletal muscle imaging findings in four patients with genetically defined childhood-onset RMD caused by CAV3 mutations and in one patient with congenital generalized lipodystrophy type 4 with muscular dystrophy due to polymerase I and transcript release factor (PTRF) mutations, which may have caused secondary deficiency of caveolin-3. Muscle MRI revealed that the rectus femoris and semitendinosus muscles were most commonly affected in the rippling muscle disease patients. Peripheral changes in the rectus femoris were specific and observed even in one of the younger patients in this study. Furthermore, muscle involvement extended to the semitendinosus muscles, biceps femoris, and gracilis with disease progression or increase in its severity. Similar patterns of involvement were observed on reviewing skeletal muscle images of various previously reported phenotypes of caveolinopathy; interestingly, patients with secondary deficiency of caveolin due to PTRF mutations revealed the same pattern. Thus, primary caveolinopathies and secondary deficiency of caveolin demonstrated specific findings on skeletal muscle imaging, regardless of the broad phenotypic spectrum of these two conditions.
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http://dx.doi.org/10.1016/j.nmd.2018.07.010DOI Listing
October 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

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

Muscle development in healthy children evaluated by bioelectrical impedance analysis.

Brain Dev 2017 Feb 21;39(2):122-129. Epub 2016 Sep 21.

Department of Neurology, NHO Suzuka Hospital, Japan.

Objectives: This study aimed to use bioelectrical impedance analysis (BIA) to generate a new muscle density index (MDI), the MDI_BIA, to evaluate muscle development, and to demonstrate the changes that occur in the BIA-based muscle cross-sectional area index (MCAI_BIA) that accompany growth. We also sought to determine the traceability of chronological changes in the MDI_BIA and MCAI_BIA.

Methods: Healthy children (n=112) aged 8.68±3.16years (0.33-14.00years) underwent bioelectrical impedance (BI) measurements of their upper arms, thighs, and lower legs. The MDI_BIA and MCAI_BIA were calculated, and cross-sectional investigations were conducted into the changes in these indices that accompanied growth. Data collected after 1.10±0.08years from 45 participants determined the traceability of the chronological changes in the MDI_BIA and MCAI_BIA.

Results: The MDI_BIA and MCAI_BIA were significantly positively correlated with age and height at all locations (P<0.01). The relationships between the locations and the MDI_BIA and MCAI_BIA differed, indicating that these indices evaluated the muscles from different perspectives. Except for the upper arm MDI_BIA, both indices at all locations regardless of age, showed significant chronological increases after an average period of 1.10years.

Conclusions: The MDI_BIA and MCAI_BIA were significantly correlated with age and height in healthy children, and they showed significant chronological increases. Hence, these indices could be used to represent muscle development and muscle mass increases. BIA is non-invasive, convenient, and economical and it may be useful in evaluating muscle development and muscle cross-sectional areas in children.
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http://dx.doi.org/10.1016/j.braindev.2016.08.013DOI Listing
February 2017

Milder forms of muscular dystrophy associated with POMGNT2 mutations.

Neurol Genet 2015 Dec 10;1(4):e33. Epub 2015 Dec 10.

Department of Neuromuscular Research (Y.E., M.D., S. Noguchi, M.O., Y.K.H., I. Nonaka, I. Nishino), National Institute of Neuroscience; and Department of Genome Medicine Development (Y.E., S. Noguchi, I. Nishino), Medical Genome Center, NCNP, Tokyo, Japan; Department of Neurology (M.D.), China-Japan Friendship Hospital, Beijing, China; Department of Pathophysiology (Y.K.H.), Tokyo Medical University; National Hospital Organization Suzuka National Hospital (S.K.), Mie, Japan; Department of Pediatrics (K.S.), Local Independent Administrative Institution, Mie Prefectural General Medical Center; Department of Child Neurology (S. Nagai), Shikoku Medical Center for Children and Adults, Kagawa, Japan; and Department of Pediatrics (S.O.), Kumamoto University, Kumamoto, Japan.

Objective: To determine the genetic variants in patients with dystroglycanopathy (DGP) and assess the pathogenicity of these variants.

Methods: A total of 20 patients with DGP were identified by immunohistochemistry or Western blot analysis. Whole-exome sequencing (WES) was performed using patient samples. The pathogenicity of the variants identified was evaluated on the basis of the phenotypic recovery in a knockout (KO) haploid human cell line by transfection with mutated POMGNT2 cDNA and on the basis of the in vitro enzymatic activity of mutated proteins.

Results: WES identified homozygous and compound heterozygous missense variants in POMGNT2 in 3 patients with the milder limb-girdle muscular dystrophy (LGMD) and intellectual disability without brain malformation. The 2 identified variants were located in the putative glycosyltransferase domain of POMGNT2, which affected its enzymatic activity. Mutated POMGNT2 cDNAs failed to rescue the phenotype of POMGNT2-KO cells.

Conclusions: Novel variants in POMGNT2 are associated with milder forms of LGMD. The findings of this study expand the clinical and pathologic spectrum of DGP associated with POMGNT2 variants from the severest Walker-Warburg syndrome to the mildest LGMD phenotypes. The simple method to verify pathogenesis of variants may allow researchers to evaluate any variants present in all of the known causative genes and the variants in novel candidate genes to detect DGPs, particularly without using patients' specimens.
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http://dx.doi.org/10.1212/NXG.0000000000000033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811383PMC
December 2015

Slowly progressing lower motor neuron disease caused by a novel duplication mutation in exon 1 of the SOD1 gene.

Neurobiol Aging 2014 Oct 19;35(10):2420.e7-2420.e12. Epub 2014 Apr 19.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine l, Matsumoto Japan.

Familial amyotrophic lateral sclerosis accounts for about 5% of all cases of the neurodegenerative disorder amyotrophic lateral sclerosis. Genetic mutations in Cu/Zn superoxide dismutase (SOD1) have been associated with one kind of familial amyotrophic lateral sclerosis (ALS1). We identified a novel duplication mutation in exon 1 of the SOD1 gene in a Japanese family whose members had lower motor neuron diseases. The patients showed slow disease progression, with the onset of lower limb muscle weakness and exertional dyspnea. Some patients had mild motor and sensory neuropathy and/or bladder dysfunction, which is further evidence that SOD1 mutation results in a predominantly lower motor neuron phenotype.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.04.012DOI Listing
October 2014

Immunohistochemical localization of spatacsin in α-synucleinopathies.

Neuropathology 2014 Apr 22;34(2):135-9. Epub 2013 Sep 22.

Department of Neurology, National Organization Suzuka Hospital, Suzuka, Japan.

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP-TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α-synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti-spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin-positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α-synuclein-containing inclusions suggests that spatacsin may be involved in the pathogenesis of α-synucleinopathies.
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http://dx.doi.org/10.1111/neup.12069DOI Listing
April 2014

Analysis using histograms of muscle CT images in patients with Duchenne muscular dystrophy.

BMJ Case Rep 2013 May 31;2013. Epub 2013 May 31.

Department of Neurology, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan.

We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with Duchenne muscular dystrophy, and this shape of the histogram will employ a new analytical method. CT images of the middle part of the thigh were acquired in a patient with Duchenne muscular dystrophy once a year from 6 to 11 years of age. Regions apparently corresponding to subcutaneous fat, bone and bone marrow were manually excluded, and the CT values were calculated to prepare histograms. His motor disability was also evaluated employing Vignos functional rating scale. A single peak was noted in the muscle CT value range in the histogram at the youngest age. The muscle-to-fat ratio in muscle decreased with the worsening of his disease disability level and the peak of the histogram shifted from the muscle to the fat CT value.
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http://dx.doi.org/10.1136/bcr-2013-009301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3670016PMC
May 2013

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

J Neurol Neurosurg Psychiatry 2013 Apr 15;84(4):433-40. Epub 2012 Dec 15.

Department of Neurology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai 980-8574, Japan.

Objective And Methods: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed.

Results And Conclusions: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.
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http://dx.doi.org/10.1136/jnnp-2011-301339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595148PMC
April 2013

[Complete atrioventricular block in Duchenne muscular dystrophy].

Rinsho Shinkeigaku 2012 ;52(9):685-7

Department of Neurology, Suzuka National Hospital.

We report a case of complete atrioventricular (AV) block in a 40-year-old patient with Duchenne muscular dystrophy (DMD). While he was bed-ridden and required mechanical ventilation, his cardiac involvement was mild. He had the deletion of exon 45-52 in the dystrophin gene. He underwent transient complete AV block and came to require pacemaker implantation due to recurrence of complete AV block ten days after the first attack. Electrophysiological study revealed mild prolonged AH and HV interval. Although DMD patients with AV block have been rarely reported so far, attention should be paid to AV block for patients who prolonged their lives.
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http://dx.doi.org/10.5692/clinicalneurol.52.685DOI Listing
December 2013

[Respiratory management in muscular dystrophies].

Authors:
Satoshi Kuru

Brain Nerve 2011 Nov;63(11):1229-36

Department of Neurology, Suzuka National Hospital, Suzuka-shi, Mie, Japan.

Respiratory failure is a major contributor to immobility and mortality in progressive muscular dystrophies. The severity of pulmonary impairment and the stage at which it develops differ according to the type of muscular dystrophy. Appropriate respiratory management for each type should be considered. In Duchenne muscular dystrophy (DMD), respiratory impairment manifests in the late teens, and assisted mechanical ventilation is administered. Noninvasive positive-pressure ventilation (NIPPV) has increased the median survival of patients with DMD by 10 year and improved quality of life. In myotonic dystrophy (MyD), the causes of respiratory failure can involve both the central and the peripheral nervous systems in addition to respiratory muscles. Nocturnal desaturation is more severe in MyD than in other muscular dystrophies with similar degrees of respiratory muscle weakness. Cognitive impairment should be taken into account in the management of MyD patients. NIPPV does not appear to improve survival of MyD. Guidelines for DMD have been published. Respiratory function should be assessed serially by measuring forced vital capacity, oxyhemoglobin saturation, peak cough flow, and end-tidal CO2 level. A respiratory action plan should be enacted with increasing disease severity. Therapeutic measures comprise airway clearance, respiratory muscle training, noninvasive nocturnal ventilation, daytime noninvasive ventilation, and continuous invasive ventilation. At the advanced stage of respiratory failure, attention should be paid to complications related to long-term mechanical ventilation, such as pneumothorax and tracheal hemorrhage. Discussing about end-of-life care among the patient, family, and physician is important before mechanical ventilatory support is required.
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November 2011

[Evaluation of neurological symptoms related to hip fracture in a 29-year longitudinal study of subacute myelo-optic-neuropathy (SMON)].

Nihon Ronen Igakkai Zasshi 2010 ;47(5):445-51

Department of Neurology, National Hospital Organization Suzuka Hospital.

Aim: Hip fracture in elderly people is a major risk factor in the deterioration of activities of daily living (ADL). The aim of this study was to investigate the incidence of hip fractures and the neurological symptoms contributing to hip fracture in patients with subacute myelo-optic-neuropathy (SMON), a drug-induced neurological disease manifesting various symptoms.

Methods: We investigated the incidence of hip fracture in 3,269 SMON patients with 24,187 medical check-ups from 1979 through 2007 by the SMON Research Committee in Japan. Neurological symptoms were evaluated in 80 patients who had undergone clinical examinations within 2 years before the fracture (hip-fracture group: age at examination = 75.7 ± 8.8 years (mean ± SD)), and the control group (160 SMON patients without a history of hip fracture; 76.5 ± 10.4) were matched for age, gender, and duration of illness. Incidence of hip fracture in SMON as well as severity of visual acuity, motor and sensory symptoms, and ADL were investigated.

Results: A total 230 hip fractures occurred in 208 patients (6.4%) with a men-to-women ratio of 21 : 187. In comparison with the Japanese general population, SMON patients showed a statistically high incidence of hip fracture in the 50s and 60s age groups in women (p < 0.002 in both), and in those under 40 (p < 0.02) and in their 50s (p < 0.002) in men. In those with neurological symptoms related to gait, the percentage of subjects who could walk with crutches was significantly higher in the hip-fracture group (43.8%) than in the control group (28.1%) (p < 0.05). Analysis of the vibratory sensation revealed that the hip-fracture group showed a significantly higher percentage of severe impairment (51.9%) than the control group (32.0%) (p < 0.025). There were no significant differences in variance between the two groups in other clinical symptoms or ADL.

Conclusions: Impairment of vibration sense, a deep sensation, is more likely to be associated with falling and hip fracture than visual acuity or other neurological symptoms in SMON patients. Those persons with vibration sense disturbance, such as elderly or patients with neurological diseases, should be particularly cautious of falling.
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http://dx.doi.org/10.3143/geriatrics.47.445DOI Listing
May 2011

Carvedilol can prevent cardiac events in Duchenne muscular dystrophy.

Intern Med 2010 15;49(14):1357-63. Epub 2010 Jul 15.

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

Objective: Heart failure is one of the most serious complications in Duchenne muscular dystrophy (DMD). Beta-blocker medication is known to improve the prognosis of chronic heart failure of adults, but its efficacy and safety for DMD patients has not been fully assessed. Thus we conducted a multicenter open trial.

Methods: Fifty-four DMD patients participated; 41 received carvedilol (BB group) and 13 did not (non BB group). All patients with an ejection fraction of less than 50% received angiotensin-converting enzyme inhibitor. Then, patients in BB group were started on carvedilol. The mean maintenance dose of carvedilol in BB group was 7.85+/-2.80 mg/day. Clinical signs and cardiac function were monitored regularly and statistical analysis was done.

Results: The survival rate free from primary endpoints (death, deterioration of heart failure and severe arrhythmia) was higher in the BB group. The survival rate free from all-cause death was also higher in the BB group, although not significantly higher. Patients with primary endpoints received lower maintenance doses of carvedilol and presented higher mean heart rates (HR) during the observation period. In the BB group, mean HR at enrollment and the reduction of mean HR were correlated with the change of ejection fraction. Although serious adverse events were rare during the introduction of carvedilol, patients with advanced cardiac dysfunction required a longer period for up-titration and frequently presented with minor complaints.

Conclusion: The present study suggests that carvedilol is relatively safe and can prevent cardiac events even in patients with DMD.
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http://dx.doi.org/10.2169/internalmedicine.49.3259DOI Listing
April 2011

XPA gene mutations resulting in subtle truncation of protein in xeroderma pigmentosum group A patients with mild skin symptoms.

J Invest Dermatol 2010 Oct 24;130(10):2481-8. Epub 2010 Jun 24.

Innovative Beauty Science Laboratory, Kanebo Cosmetics, Odawara, Japan.

Comparisons of the clinical manifestations with gene mutations in patients with xeroderma pigmentosum group A (XPA) have suggested that those with mutations closer to the C-terminal coding region of the XPA gene have milder neurological and cutaneous symptoms. Here we report on four middle-aged, newly diagnosed Japanese XPA patients whose unusually mild symptoms, especially those affecting the skin, implicate a reduced association of a subtle defect in the C-terminus of XPA protein with skin lesions. All patients had a heterozygous G → C transversion at the splice acceptor site of XPA intron 3. We identified previously unreported heterozygous mutations in exon 6: a single-base insertion (690insT) in one patient and a four-base insertion (779insTT and 780insTT) in the other patients. These mutations led to the frameshift that created new premature termination codons, resulting in the production of truncated XPA proteins. They were longer than any previously reported truncated XPA protein, suggesting that the minimal cutaneous symptoms in these patients are due to a higher residual level of XPA protein activity and that the subtle defect in the C-terminus of XPA protein is more closely related to neurological impairment than to cutaneous abnormalities.
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http://dx.doi.org/10.1038/jid.2010.137DOI Listing
October 2010

An autopsy case of spinal muscular atrophy type III (Kugelberg-Welander disease).

Neuropathology 2009 Feb 11;29(1):63-7. Epub 2008 Apr 11.

Department of Neurology, Suzuka National Hospital, Suzuka-shi, Mie, Japan.

We report an autopsy case of a 67-year-old man clinicogenetically diagnosed as having spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease), showing slowly progressive muscle wasting and weakness of the extremities. His brother showed similar manifestations. Autopsy revealed neuronal loss and severe gliosis in the anterior horns of the spinal cord, a marked neurogenic change of skeletal muscles and mild degeneration of cardiomyocytes. Chromatolytic change was seen in the anterior horn, but not in the Clarke's and thalamic nuclei. The anterior spinal roots were atrophic, and there was loss of myelinated fibers with abundant glial bundles. In addition, degeneration was also observed in the posterior column and dentate nucleus. The pathological features were essentially similar to those of SMA I. Chronic change was prominent while acute change was mild in degree, corresponding to a very long clinical course.
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http://dx.doi.org/10.1111/j.1440-1789.2008.00910.xDOI Listing
February 2009

[Two cases of Duchenne muscular dystrophy complicated with dilated cardiomyopathy and cerebral infarction].

No To Shinkei 2006 Mar;58(3):250-5

Department of Internal Medicine, Suzuka National Hospital, Mie, Japan.

We report two cases of Duchenne muscular dystrophy (DMD) complicated with dilated cardiomyopathy (DCM), who were affected with cerebral infarction. Case 1 suddenly developed dysarthria and right facial weakness at age 21. Cranial CT study disclosed a low density area in the left basal ganglia and internal capsule. Case 2 had a history of transient ischemic attack (TIA) at age 21. Five months after the TIA, he developed right hemiplegia and dysarthria, and a low density area in the corona radiate in left cerebral hemisphere was observed in cranial CT. These two cases showed the radiographic cardiomegaly with cardio thoracic ratio (CTR) of 72.8% and 66.6%, the decreased echocardiographic left ventricular ejection fraction below 20%, and the elevated titer of thrombin-anti-thrombin III complex (TAT) and D-dimer. The autopsy of Case 2 at age 26 disclosed the remarkable degeneration and fibrosis of myocardium and old ischemic lesion in the left cerebral frontal cortex. Despite the negative finding of the emboli in the left heart, cardiogenic cerebral infarction secondary to DCM was strongly suspected in both cases.
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March 2006

[Siblings with xeroderma pigmentosum group A showing mild cutaneous and various neurological manifestations].

Rinsho Shinkeigaku 2006 Feb;46(2):134-9

Department of Neurology, Suzuka National Hospital.

We report siblings with xeroderma pigmentosum group A (XP-A) showing mild cutaneous and late-onset severe neurological manifestations. The elder brother first noticed unstability in walking at 16 years of age. Subsequently slowly progressive mental deterioration developed with cerebellar ataxia, spasticity, sensory disturbance, urinary dysfunction and vocal cord paralysis. His younger sister presented with dysarthria at 18 years of age. She showed manifestations similar to her brother's. Both of them suffered from sensitivity to the sun but no malignant skin tumor. They were diagnosed as XP-A by the measurement of unscheduled DNA synthesis and complementation analysis. Gene analyses revealed compound heterozygote for G-->C substitution at the 3' splicing acceptor site of intron 3 and insertion of 4 bases in exon 6 of XPA gene. It is suggested that transcription-coupled repair is dominantly affected with relative sparing of global genome repair in these siblings.
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February 2006

Autopsy case of hereditary spastic paraplegia with thin corpus callosum showing severe gliosis in the cerebral white matter.

Neuropathology 2005 Dec;25(4):346-52

Department of Neurology, Suzuka National Hospital, Kasado, Suzuka-shi, Mie, Japan.

We report an autopsy case of a 51-year-old man clinically diagnosed with a complicated type of hereditary spastic paraplegia. His sister showed similar manifestations. Gait disturbance was manifested at 14 years of age. Subsequently, slowly progressive spastic tetraplegia developed with mental deterioration, neuropathy and amyotrophy. Marked cerebral atrophy with thin corpus callosum was shown by cranial MRI. Autopsy revealed a severely atrophic brain with extreme thinning of the whole corpus callosum. Microscopically, neurodegeneration was found in the corticospinal tract, thalamus, cerebral white matter and substantia nigra, as well as in the anterior horn and posterior column of the spinal cord. The remaining neurons contained large amounts of lipofuscin and eosinophilic granules. Unique to this patient was the severe gliosis in the cerebral white matter and substantia nigra, suggesting that sufficient development had been established when the degenerative process occurred. The predominant feature of the present case is the neurodegeneration process rather than hypoplasia.
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http://dx.doi.org/10.1111/j.1440-1789.2005.00620.xDOI Listing
December 2005