ABSTRACT
INTRODUCTION/AIMS: Myotonic dystrophy (DM) is a systemic disease with multiple organ complications, making the standardization of medical care a challenge. We analyzed data from Japan's national registry to clarify the current treatment patterns and demographic features of Japanese DM patients. METHODS: Using the Japanese National Registry of Muscular Dystrophy (Remudy), we analyzed medical care practice for the multisystemic issues associated with adult DM type 1 patients, excluding congenital DM. RESULTS: We included 809 patients with a median age of 44.2 years. Among these patients, 15.8% used ventilators; 31.7% met the index considered at risk for sudden death due to cardiac conduction defects (PR interval over 240 milliseconds or QRS duration over 120 milliseconds) and 2.8% had implanted cardiac devices. Medication for heart failure was prescribed to 9.6% of patients. Overall, 21.2% of patients had abnormal glucose metabolism, of whom 42.9% were treated with oral medications. Among the oral medications, dipeptidyl peptidase-4 inhibitors were the most common. Cancers were observed in 3.7% of the patients, and endometrial and breast cancers were dominant. Mexiletine was prescribed for myotonia in 1.9% of the patients, and only 1% of the patients received medication for daytime sleepiness. DISCUSSION: This study shows difference in treatment patterns for DM1 in Japan compared with other countries, such as lower rates of use of implantable cardiac devices and higher rates of ventilator use. These data may be useful in discussions aimed at standardizing medical care for patients with DM.
Subject(s)
Muscular Dystrophies , Myotonia , Myotonic Dystrophy , Adult , Humans , Myotonic Dystrophy/epidemiology , Myotonic Dystrophy/therapy , Myotonic Dystrophy/complications , Japan/epidemiology , Muscular Dystrophies/complications , RegistriesABSTRACT
The identification of causative genetic variants for hereditary diseases has revolutionized clinical medicine and an extensive collaborative framework with international cooperation has become a global trend to understand rare disorders. The Initiative on Rare and Undiagnosed Diseases (IRUD) was established in Japan to provide accurate diagnosis, discover causes, and ultimately provide cures for rare and undiagnosed diseases. The fundamental IRUD system consists of three pillars: IRUD diagnostic coordination, analysis centers (IRUD-ACs), and a data center (IRUD-DC). IRUD diagnostic coordination consists of clinical centers (IRUD-CLs) and clinical specialty subgroups (IRUD-CSSs). In addition, the IRUD coordinating center (IRUD-CC) manages the entire IRUD system and temporarily operates the IRUD resource center (IRUD-RC). By the end of March 2021, 6301 pedigrees consisting of 18,136 individuals were registered in the IRUD. The whole-exome sequencing method was completed in 5136 pedigrees, and a final diagnosis was established in 2247 pedigrees (43.8%). The total number of aberrated genes and pathogenic variants was 657 and 1718, among which 1113 (64.8%) were novel. In addition, 39 novel disease entities or phenotypes with 41 aberrated genes were identified. The 6-year endeavor of IRUD has been an overwhelming success, establishing an all-Japan comprehensive diagnostic and research system covering all geographic areas and clinical specialties/subspecialties. IRUD has accurately diagnosed diseases, identified novel aberrated genes or disease entities, discovered many candidate genes, and enriched phenotypic and pathogenic variant databases. Further promotion of the IRUD is essential for determining causes and developing cures for rare and undiagnosed diseases.
Subject(s)
Undiagnosed Diseases , Humans , Japan/epidemiology , Pedigree , Rare Diseases/diagnosis , Rare Diseases/epidemiology , Rare Diseases/genetics , Exome SequencingABSTRACT
Clioquinol (5-chloro-7-indo-8-quinolinol), a chelator and ionophore of copper/zinc, was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). SMON is characterized by the subacute onset of sensory and motor disturbances in the lower extremities with occasional visual impairments, which are preceded by abdominal symptoms. Although pathological studies demonstrated axonopathy of the spinal cord and optic nerves, the underlying mechanisms of clioquinol toxicity have not been elucidated in detail. In the present study, a reporter assay revealed that clioquinol (20-50 µM) activated metal response element-dependent transcription in human neuroblastoma SH-SY5Y cells. Clioquinol significantly increased the cellular level of zinc within 1 h, suggesting zinc influx due to its ionophore effects. On the other hand, clioquinol (20-50 µM) significantly increased the cellular level of copper within 24 h. Clioquinol (50 µM) induced the oxidation of the copper chaperone antioxidant 1 (ATOX1), suggesting its inactivation and inhibition of copper transport. The secretion of dopamine-ß-hydroxylase (DBH) and lysyl oxidase, both of which are copper-dependent enzymes, was altered by clioquinol (20-50 µM). Noradrenaline levels were reduced by clioquinol (20-50 µM). Disruption of the ATOX1 gene suppressed the secretion of DBH. This study suggested that the disturbance of cellular copper transport by the inactivation of ATOX1 is one of the mechanisms involved in clioquinol-induced neurotoxicity in SMON.
Subject(s)
Clioquinol/toxicity , Copper Transport Proteins/metabolism , Copper/metabolism , Dopamine beta-Hydroxylase/metabolism , Molecular Chaperones/metabolism , Neurons/drug effects , Norepinephrine/biosynthesis , Toxic Optic Neuropathy/etiology , Cell Line, Tumor , Copper Transport Proteins/genetics , Humans , Molecular Chaperones/genetics , Neurons/enzymology , Oxidation-Reduction , Protein-Lysine 6-Oxidase/metabolism , Secretory Pathway , Toxic Optic Neuropathy/enzymology , Zinc/metabolismABSTRACT
BACKGROUND: Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is characterized by adult onset, a slowly progressive course and autosomal dominant inheritance. It remains unclear whether myopathic changes occur histopathologically. METHODS: We encountered 2 patients in a family with a heterozygous p.P285L mutation in TRK-fused gene (TFG), which is known to cause HMSN-P. The affected individuals developed proximal-dominant muscle weakness in their 40s, which slowly progressed to a motor neuron disease-like phenotype. RESULTS: Muscle biopsy showed myopathic pathology including fiber size variability, increased internal nuclei, fiber splitting, and core-like structures, associated with neurogenic changes: large groups of atrophic fibers and fiber type-grouping. Immunohistochemistry revealed sarcoplasmic aggregates of TFG, TDP-43, and p62 without congophilic material. CONCLUSIONS: The present study demonstrates myopathic changes in HMSN-P. Although the mechanisms underlying the skeletal muscle involvement remain to be elucidated, immunohistochemistry suggests that abnormal protein aggregation may be involved in the myopathic pathology.
Subject(s)
Hereditary Sensory and Motor Neuropathy/pathology , Muscle Fibers, Skeletal/pathology , Muscle, Skeletal/pathology , Action Potentials , DNA-Binding Proteins/metabolism , Female , Fluorescent Antibody Technique , Hereditary Sensory and Motor Neuropathy/diagnostic imaging , Hereditary Sensory and Motor Neuropathy/genetics , Hereditary Sensory and Motor Neuropathy/physiopathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Muscle, Skeletal/diagnostic imaging , Muscular Atrophy/pathology , Neural Conduction , Pedigree , Proteins/genetics , RNA-Binding Proteins/metabolism , Sarcoplasmic Reticulum/metabolism , SiblingsABSTRACT
Duchenne muscular dystrophy is a lethal X-linked muscle disorder. We have already reported that osteopontin (OPN), an inflammatory cytokine and myogenic factor, is expressed in the early dystrophic phase in canine X-linked muscular dystrophy in Japan, a dystrophic dog model. To further explore the possibility of OPN as a new biomarker for disease activity in Duchenne muscular dystrophy, we monitored serum OPN levels in dystrophic and wild-type dogs at different ages and compared the levels to other serum markers, such as serum creatine kinase, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1. Serum OPN levels in the dystrophic dogs were significantly elevated compared with those in wild-type dogs before and 1 hour after a cesarean section birth and at the age of 3 months. The serum OPN level was significantly correlated with the phenotypic severity of dystrophic dogs at the period corresponding to the onset of muscle weakness, whereas other serum markers including creatine kinase were not. Immunohistologically, OPN was up-regulated in infiltrating macrophages and developmental myosin heavy chain-positive regenerating muscle fibers in the dystrophic dogs, whereas serum OPN was highly elevated. OPN expression was also observed during the synergic muscle regeneration process induced by cardiotoxin injection. In conclusion, OPN is a promising biomarker for muscle regeneration in dystrophic dogs and can be applicable to boys with Duchenne muscular dystrophy.
Subject(s)
Muscle, Skeletal/physiology , Muscular Dystrophy, Duchenne/physiopathology , Osteopontin/metabolism , Regeneration/physiology , Age Factors , Animals , Biomarkers/metabolism , Cobra Cardiotoxin Proteins/toxicity , Diaphragm/metabolism , Dogs , Male , Matrix Metalloproteinase 9/metabolism , Muscle, Skeletal/metabolism , Muscular Dystrophy, Animal/physiopathology , Phenotype , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
INTRODUCTION: We conducted a study to reveal trends in steroid prescription for Duchenne muscular dystrophy (DMD) patients in Japan. METHODS: We asked patients (ages 5-20 years) identified in the patient registry and their clinicians about steroid therapy experiences. Regimen, dose, and starting age were compared among 3 subgroups according to prednisolone initiation year (2000-2004, 2005-2009, and 2010-2013). RESULTS: Among 157 prednisolone users, 4 different regimens were used. Dose frequencies were: every other day (98 patients), daily (44 patients), 10 days on 20 days off (14 patients), and weekly (1 patient). Median starting age was 6 years, and median dose was 0.42 mg/kg/day. There was an increase in daily regimen use from 2005-2009 (n = 9, 16%) to 2010-2013 (n = 33, 36%). CONCLUSIONS: This study revealed a transition over time in steroid use from expert opinion to evidence-based recommendation. Clinical research should be encouraged to optimize medication worldwide. Muscle Nerve 54: 673-680, 2016.
Subject(s)
Glucocorticoids/therapeutic use , Muscular Dystrophy, Duchenne/drug therapy , Muscular Dystrophy, Duchenne/epidemiology , Prednisolone/therapeutic use , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Humans , Japan/epidemiology , Male , Muscular Dystrophy, Duchenne/diagnosis , Surveys and Questionnaires , Young AdultABSTRACT
INTRODUCTION: We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. METHODS: Subjects included 48 patients who underwent respiratory evaluation (n = 47), electrocardiography (n = 46), and echocardiography (n = 23). RESULTS: Of the 47 patients, 10 had reduced percent forced vital capacity (%FVC), and 4 required non-invasive positive pressure ventilation. %FVC was significantly correlated with disease duration, and mean %FVC was significantly lower in non-ambulatory patients, as well as in those aged ≥65 years with normal creatine kinase levels. On electrocardiography, QRS complex duration was prolonged in 19 patients, although no significant association with age, disease duration, or respiratory function was found. Echocardiography indicated no left ventricular dysfunction in any patient. Histopathology of autopsied cases revealed mild cardiomyopathy and moderate diaphragm involvement. CONCLUSION: Patients with dysferlinopathy may develop severe respiratory failure and latent cardiac dysfunction. Both respiratory and cardiac function should be monitored diligently.
Subject(s)
Heart Diseases/etiology , Muscular Dystrophies, Limb-Girdle/complications , Respiration Disorders/etiology , Adult , Age Factors , Aged , Autopsy , Creatine Kinase/blood , Dysferlin , Electrocardiography , Female , Heart Diseases/diagnosis , Humans , Japan , Male , Membrane Proteins/genetics , Middle Aged , Muscle Proteins/genetics , Muscular Dystrophies, Limb-Girdle/blood , Muscular Dystrophies, Limb-Girdle/genetics , Mutation/genetics , Respiration Disorders/diagnosis , Retrospective Studies , Tomography, X-Ray Computed , Vital Capacity , Young AdultABSTRACT
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.
Subject(s)
Biomedical Research/organization & administration , Clinical Trials as Topic/organization & administration , Muscular Dystrophies/drug therapy , Rare Diseases/drug therapy , Registries , Cooperative Behavior , Hospitals , Humans , Japan , Male , Orphan Drug Production , Patient SelectionABSTRACT
Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
Subject(s)
Databases, Genetic , Dystrophin/genetics , Muscular Dystrophy, Duchenne/genetics , Mutation , Humans , RegistriesABSTRACT
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry.
Subject(s)
Databases, Factual , Muscular Dystrophy, Duchenne , Registries , Databases, Factual/economics , Geography, Medical , Global Health , Humans , Muscular Dystrophy, Duchenne/economics , Muscular Dystrophy, Duchenne/epidemiologyABSTRACT
INTRODUCTION: Several studies have shown a significant amplitude decrement in compound muscle action potentials (CMAPs) on repetitive nerve stimulation (RNS) of muscles involved in amyotrophic lateral sclerosis (ALS). In ALS, muscle wasting preferentially affects the thenar muscles (APB) rather than the hypothenar muscles (ADM). METHODS: We performed RNS studies in the APB and ADM muscles of 32 ALS patients to determine whether the effect of RNS differs between the median and ulnar nerves. RESULTS: The decremental responses to RNS were greater in the APB than in the ADM. Reduced CMAP amplitude was negatively correlated with CMAP decrement in median but not in ulnar nerves. CONCLUSIONS: The greater CMAP decrement in median nerve is attributable to preferential involvement of the APB in the pathophysiology of ALS or some underlying difference in the biology of the two muscles/nerves. Further investigations will better our understanding of the pathophysiology of ALS.
Subject(s)
Action Potentials/physiology , Amyotrophic Lateral Sclerosis/pathology , Biophysical Phenomena/physiology , Median Nerve/physiopathology , Muscle, Skeletal/physiopathology , Ulnar Nerve/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Electric Stimulation , Female , Humans , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
The purpose of this report was to investigate predictive factors that necessitate intensive care in myasthenic crisis (MC). We retrospectively reviewed MC patients at our institution and compared ICU and ward management groups. Higher MG-ADL scale scores, non-ocular initial symptoms, infection-triggered findings, and higher MGFA classification were observed more frequently in the ICU group. In patients with these prognostic factors, better outcomes may be obtained with early institution of intensive care.
Subject(s)
Intensive Care Units , Myasthenia Gravis/therapy , Respiratory Insufficiency/therapy , Respiratory Therapy , Aged , Aged, 80 and over , Disease Management , Female , Humans , Male , Middle Aged , Myasthenia Gravis/complications , Respiratory Insufficiency/etiology , Retrospective Studies , Treatment OutcomeABSTRACT
Duchenne muscular dystrophy (DMD) is an inherited severe muscle wasting disorder with, thus far, no effective therapy. DMD causes respiratory and cardiac failure as well as muscle wastage. Among the various symptoms, respiratory insufficiency is a major cause of death in DMD patients at about 20 years of age. So, naturally, the improvement of respiratory function will extend the patient's life. We report here, for the first time, a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected in the utrophin/dystrophin double knockout mouse (dko mouse), showing quite similar systemic symptoms to human DMD including restrictive ventilatory impairment. Furthermore, we show that a highly efficient dystrophin-transduction to the dko's diaphragm--achieved by simple intraperitoneal injection of a helper-dependent adenovirus vector (HDAdv) containing the full-length dystrophin expression cassette--provided beneficial results. In spite of dystrophin expression only in the diaphragm, this focal gene transfer could result in the rescue from ventilatory impairment (increased tidal volume (TV) and improvement of compensatory hyperpnea). Our result suggests that a DMD patient's mortal ventilatory impairment may be improved via technically easy means through the intraperitoneal injection of HDAdv.
Subject(s)
Diaphragm/metabolism , Dystrophin/genetics , Dystrophin/metabolism , Peritoneal Cavity , Transduction, Genetic/methods , Utrophin/genetics , Animals , COS Cells , Cell Line , Chlorocebus aethiops , Genetic Therapy/methods , Genetic Vectors , HEK293 Cells , Humans , Mice , Mice, Knockout , Muscular Dystrophy, Animal/therapyABSTRACT
We present two Parkinson's disease (PD) patients, who experienced heatstroke. Both patients manifested central nervous system dysfunction with elevated core temperature. Despite adequate lowering of the body temperature, multiorgan-dysfunction syndrome including encephalopathy, rhabdomyolysis, acute renal failure, acute respiratory failure, and disseminated intravascular coagulopathy was noted in one patient, leading to permanent neurologic damage. Because the ensuing multiorgan dysfunction could determine the functional prognosis in heatstroke patients, it is important to provide information about the prevention of heatstroke to patients, who are isolated or are severely disabled in the advanced stages of PD.
Subject(s)
Heat Stroke/complications , Parkinson Disease/complications , Aged , Body Temperature/physiology , Dementia/complications , Female , Heat Stroke/diagnosis , Humans , Hypothermia, Induced/methods , Male , Middle AgedABSTRACT
BACKGROUND: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. METHODS: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). RESULTS: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). CONCLUSION: ADT might be useful as an initial treatment option for polymyositis.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Polymyositis/drug therapy , Prednisolone/therapeutic use , Adult , Aged , Diabetes Mellitus/chemically induced , Drug Administration Schedule , Female , Humans , Longitudinal Studies , Male , Middle Aged , Survival Rate , Treatment OutcomeABSTRACT
We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy, she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy. However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions.
Subject(s)
Carcinoma, Papillary/pathology , Dermatomyositis/pathology , Thyroid Neoplasms/pathology , Aged , Carcinoma, Papillary/complications , Carcinoma, Papillary/surgery , Dermatomyositis/complications , Dermatomyositis/drug therapy , Female , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Humans , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Prednisolone/administration & dosage , Prednisolone/therapeutic use , Pulse Therapy, Drug , Thyroid Neoplasms/complications , Thyroid Neoplasms/surgery , Thyroidectomy , Treatment OutcomeABSTRACT
Myotonic dystrophies (DM) are inherited autosomal dominant disorders affecting multiple organs. Currently available therapeutics for DM are limited; therefore, a patient registry is essential for therapeutic development and success of clinical trials targeting the diseases. We have developed a nationwide DM registry in Japan under the Registry of Muscular Dystrophy (Remudy). The registration process was patient-initiated; however, physicians certified the clinical information. The dataset includes all Naarden and TREAT-NMD core datasets and additional items covering major DM clinical features. As of March 2020, we enrolled 976 patients with genetically confirmed DM. The majority (99.9%) of these patients had DM1, with 11.4% having the congenital form. However, 1 patient had DM2. Upon classifying 969 symptomatic DM1 patients based on their age at onset, an earlier onset was associated with a longer CTG repeat length. Myotonia was the most frequent symptom, followed by hand disability, fatigue, and daytime sleepiness. The frequency of hand disabilities, constipation, and visual disturbances was higher for patients with congenital DM. According to a multiple regression analysis of objective clinical measurements related to prognosis and activities of daily living, CTG repeat length strongly influenced the grip strength, forced vital capacity, and QRS time in an electrocardiogram. However, the grip strength was only modestly related to disease duration. This report will shed light on the Japanese national DM registry, which has recruited a significant number of patients. The registry will provide invaluable data for planning clinical trials and improving the standard of care for patients.
Subject(s)
Myotonic Dystrophy , Activities of Daily Living , Fatigue , Humans , Japan/epidemiology , Myotonic Dystrophy/epidemiology , Myotonic Dystrophy/genetics , RegistriesABSTRACT
A 56-year-old man noticed discomfort in his left lower limb, followed by convulsion and numbness in the same area. Magnetic resonance imaging (MRI) showed white matter lesions in the right parietal lobe accompanied by leptomeningeal or leptomeningeal and cortical post-contrast enhancement along the parietal sulci. The patient also exhibited higher brain dysfunction corresponding with the lesions on MRI. Histological pathology disclosed ß-amyloid in the blood vessels and perivascular inflammation, which highlights the diagnosis of cerebral amyloid angiopathy (CAA)-related inflammation. Pulse steroid therapy was so effective that clinical and radiological findings immediately improved.CAA-related inflammation is a rare disease, defined by the deposition of amyloid proteins within the leptomeningeal and cortical arteries associated with vasculitis or perivasculitis. Here we report a patient with CAA-related inflammation who showed higher brain dysfunction that improved with steroid therapy. In cases with atypical radiological lesions like our case, cerebral biopsy with histological confirmation remains necessary for an accurate diagnosis.
Subject(s)
Cerebral Amyloid Angiopathy/drug therapy , Cerebral Amyloid Angiopathy/pathology , Cerebral Amyloid Angiopathy/physiopathology , Encephalitis/drug therapy , Encephalitis/pathology , Encephalitis/physiopathology , Steroids/therapeutic use , Cerebral Amyloid Angiopathy/complications , Encephalitis/etiology , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
To explore whether stable transduction of myogenic stem cells using lentiviral vectors could be of benefit for treating dystrophic muscles, we generated vectors expressing a functional microdystrophin/enhanced green fluorescence protein fusion (microDys/eGFP) gene. Lentiviral vector injection into neonatal mdx(4cv) muscles resulted in widespread and stable expression of dystrophin for at least 2 years. This expression resulted in a significant amelioration of muscle pathophysiology as assessed by a variety of histological and functional assays. To assess whether this long-term expression was accompanied by stable transduction of satellite cells, we harvested muscle mononuclear cells 1 year after vector injection. Up to 20% of the cultured myoblast colonies expressed the microDys/eGFP transgene following myotube formation. Furthermore, transplantation of the muscle mononuclear cells into secondary mdx(4cv) recipients showed their ability to regenerate dystrophin-expressing myofibers in vivo. The ability to isolate myogenic cells able to form dystrophin-positive myotubes or myofibers in vitro and in vivo >1 year postinjection indicates that the vectors stably transduced muscle satellite cells, or a progenitor of such cells, in neonatal mdx(4cv) muscles. These studies suggest that integrating lentiviral vectors have potential utility for gene therapy of muscular dystrophy.
Subject(s)
Dystrophin/physiology , Genetic Vectors/genetics , Lentivirus/genetics , Muscles/metabolism , Muscular Dystrophy, Animal/therapy , Animals , Cell- and Tissue-Based Therapy/methods , Cells, Cultured , Dystrophin/genetics , Dystrophin/metabolism , Genetic Vectors/administration & dosage , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Inbred mdx , Muscle Cells/metabolism , Muscle Cells/transplantation , Muscles/pathologyABSTRACT
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults, affecting multiple organs, including the eyes, heart, endocrine system, and central nervous system. The broad spectrum of DM1 symptoms has been attributed to the aberrant pre-mRNA splicing of various genes due to an abnormal expansion of the CTG repeat in the 3' untranslated region of the DMPK gene. The current challenge in the clinical care of DM1 is the lack of well-established protocols for the management of each organ disorder or symptom. Moreover, the current status of clinical management has not been adequately explored. Metabolic disturbance in DM1 has been less explored among the DM1 manifestations, even though impaired glucose tolerance is a widely known metabolic disorder associated with DM1. We investigated the metabolic disturbance related to DM1 using the national registry of neuromuscular diseases in Japan, Registry of Muscular Dystrophy (Remudy), and assessed the metabolic complications in DM1 and the current treatments. We obtained comprehensive information on the current status of liver dysfunction and dyslipidemia in a sizeable DM1 cohort (~300). We confirmed that the incidence of liver dysfunction and dyslipidemia, particularly hypertriglyceridemia, as well as impaired glucose tolerance, were significantly higher in DM1 patients. Furthermore, the majority of DM1 patients with dyslipidemia were not receiving pharmacotherapy. Our data highlight the current status of DM1 patients in Japan, which can guide the establishment of the standard of care for metabolic issues consequent to DM1.