Distal Myopathy With Rimmed Vacuoles Research Articles

Efficacy of Aceneuramic Acid for Distal Myopathy with Rimmed Vacuoles

Distal myopathy with rimmed vacuoles (DMRV), also known as GNE myopathy, is a rare disease affecting the distal muscles, such as the tibialis anterior muscle. The GNE gene, which codes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in a homozygous or compound heterozygous manner, and the lack of sialic acid in skeletal muscle is the critical underlying mechanism in DMRV pathogenesis. DMRV mouse models were established, and supplementation with sialic acid improved the phenotypes of the models. A phase 1 clinical trial using aceneuramic acid was conducted at Tohoku University Hospital, Japan, followed by trials using a slow-release product. A phase II/III study, subsequent extended trial, and confirmatory trial were also conducted. Regulatory approval is currently under review.

Distal myopathy with rimmed vacuoles: Spectrum of GNE gene mutations in seven Chinese patients

Distal myopathy with rimmed vacuoles (DMRV) is a rare, autosomal, recessive inherited disease caused by mutations in the GNE gene. DMRV is an adult-onset disorder characterized by progressive muscle atrophy and weakness, which initially involves the distal muscles with quadriceps sparing. To date, >150 GNE mutations have been reported in different populations from around the world. The present study investigated the clinical, pathological and genetic characteristics of seven unrelated DMRV patients from China. Genetic analysis in these patients revealed three novel mutations (c.455_456insC, p.P421L, and p.A287T) and five previously reported mutations (p.D207V, p.C44S, p.G576R, p.A669P, and p.D218G). In addition, the literature on DMRV was reviewed to provide an overview of the disease and broaden the mutational spectrum of the GNE gene in China.

P.074 Clinical features of a family with distal myopathy and rimmed vacuoles due to a digenic interaction

Background: The interaction between mutations in two or more genes is increasingly recognised as an important contributor to the phenotypic variability in genetic disorders. Co-occurrence of variants in SQSTM1 and TIA1 is reported as a cause of myopathy in 3 prior cases, but limited clinical data were presented. We present detailed clinical features of a family with two siblings having a distal myopathy with rimmed vacuoles (DMRV), and genetic variants in SQSTM1 and TIA1. Methods: Clinicopathologic study of a family with DMRV to describe clinical features, laboratory and neurophysiology studies, neuroimaging, and genetic sequencing. Results: Two siblings with variants in SQSTM1 and TIA1 developed myopathy in their early 60’s, with early involvement of ankle dorsiflexors and finger extensors. A decade after onset, patients remain ambulatory and have not developed cardiac or respiratory complications. MRI of the legs showed selective involvement of adductor magnus, vastus lateralis, and in lower legs the anterior compartment and medial gastrocnemius. Muscle pathology demonstrated rimmed vacuoles, disrupted myofibrillar architecture, and mislocalised TDP43. Two unaffected family members had one genetic variant but not both. Conclusions: We describe a fourth family with co-occurrence of TIA1 and SQSTM1 genetic variants and describe their detailed phenotype. Future study should address the mechanism of the interaction between these two variants.

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n=43), polymyositis (PM) (inflammatory pathology; n=24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n=31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from dysferlinopathy (Dysfy), polymyositis (PM), and distal myopathy with rimmed vacuoles (DMRV) displayed morphological and biochemical evidences of mitochondrial dysfunction. Proteomic analysis revealed down-regulation of electron transport chain (ETC) subunits, assembly factors, and tricarboxylic acid (TCA) cycle enzymes, with 80 proteins common among the three pathologies. Mitochondrial proteins from muscle pathologies also displayed higher Trp oxidation that could alter the local structure. Cover image for this issue: doi: 10.1111/jnc.13324.

Three novel serum biomarkers, miR-1, miR-133a, and miR-206 for Limb-girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, and Becker muscular dystrophy.

Muscular dystrophies are a clinically and genetically heterogeneous group of inherited myogenic disorders. In clinical tests for these diseases, creatine kinase (CK) is generally used as diagnostic blood-based biomarker. However, because CK levels can be altered by various other factors, such as vigorous exercise, etc., false positive is observed. Therefore, three microRNAs (miRNAs), miR-1, miR-133a, and miR-206, were previously reported as alternative biomarkers for duchenne muscular dystrophy (DMD). However, no alternative biomarkers have been established for the other muscular dystrophies. We, therefore, evaluated whether these miR-1, miR-133a, and miR-206 can be used as powerful biomarkers using the serum from muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay. Statistical analysis indicated that all these miRNA levels in serum represented no significant differences between all muscle disorders examined in this study and controls by Bonferroni correction. However, some of these indicated significant differences without correction for testing multiple diseases (P < 0.05). The median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively. Similarly, those of miR-133a and miR-206 levels in the serum of BMD patients were about 2.5 and 2.1 compared to those in controls, 1.03 and 1.32, respectively. Taken together, our data demonstrate that levels of miR-1, miR-133a, and miR-206 in serum of BMD and miR-1 in sera of LGMD and FSHD patients showed no significant differences compared with those of controls by Bonferroni correction. However, the results might need increase in sample sizes to evaluate these three miRNAs as variable biomarkers.

Rimmed vacuole을 가진 원위부 근육병증의 전체 엑솜 서열분석을 이용한 유전적 원인 규명

Distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy 2 is an autosomal recessive muscular disorder characterized by early adult-onset weakness of distal muscles and rimmed vacuoles in muscle biopsy. Mutations in the UDP-N-acetylglucosamine 2-epimerase/N-ace-tylmannosamine kinase (GNE) gene are associated with the development of DMRV. In this study, whole exome sequencing (WES) revealed compound heterozygous GNE mutations of p.Asp176Val and p.Val572Leu in a patient with distal limb weakness. Three hundred healthy controls did not show these mutations. All other variants found in distal myopathy-relevant genes were polymorphic. These findings confirmed that the patient had DMRV. This work underscores the usefulness of WES in improving the molecular diagnosis of myopathy.

GNE myopathy: New name and new mutation nomenclature

The recessively inherited, adult onset, quadriceps sparing myopathy with a predilection for distal muscles has received multiple historic names. The disorder was described in 1981 in Japanese patients and termed Nonaka Distal Myopathy [1], later commonly referred to as Distal Myopathy with Rimmed Vacuoles (DMRV) (OMIM#605820). In 1984, the disorder was described as vacuolar myopathy sparing the quadriceps in Iranian-Jewish patients [2], later commonly referred to as Inclusion Body Myopathy 2 (IBM2) or Hereditary Inclusion Body Myopathy (HIBM) (OMIM#600737).

Molecular markers for granulovacuolar degeneration are present in rimmed vacuoles.

BackgroundRimmed vacuoles (RVs) are round-oval cytoplasmic inclusions, detected in muscle cells of patients with myopathies, such as inclusion body myositis (IBM) and distal myopathy with RVs (DMRV). Granulovacuolar degeneration (GVD) bodies are spherical vacuoles containing argentophilic and hematoxyphilic granules, and are one of the pathological hallmarks commonly found in hippocampal pyramidal neurons of patients with aging-related neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. These diseases are common in the elderly and share some pathological features. Therefore, we hypothesized that mechanisms of vacuolar formation in RVs and GVD bodies are common despite their role in two differing pathologies. We explored the components of RVs by immunohistochemistry, using antibodies for GVD markers.MethodsSubjects included one AD case, eight cases of sporadic IBM, and three cases of DMRV. We compared immunoreactivity and staining patterns for GVD markers. These markers included: (1) tau-modifying proteins (caspase 3, cyclin-dependent kinase 5 [CDK5], casein kinase 1δ [CK1δ], and c-jun N-terminal kinase [JNK]), (2) lipid raft-associated materials (annexin 2, leucine-rich repeat kinase 2 [LRRK2], and flotillin-1), and (3) other markers (charged multi-vesicular body protein 2B [CHMP2B] and phosphorylated transactive response DNA binding protein-43 [pTDP43]) in both GVD bodies and RVs. Furthermore, we performed double staining of each GVD marker with pTDP43 to verify the co-localization.ResultsGVD markers, including lipid raft-associated proteins and tau kinases, were detected in RVs. CHMP2B, pTDP43, caspase 3, LRRK2, annexin 2 and flotillin-1 were detected on the rim and were diffusely distributed in the cytoplasm of RV-positive fibers. CDK5, CK1δ and JNK were detected only on the rim. In double staining experiments, all GVD markers colocalized with pTDP43 in RVs.ConclusionsThese results suggest that RVs of muscle cells and GVD bodies of neurons share a number of molecules, such as raft-related proteins and tau-modifying proteins.

P.3.3 MUC1 is associated with the pathogenesis of GNE-myopathy

Distal myopathy with rimmed vacuoles (DMRV) is a genetic myopathy characterized clinically by distal muscle weakness, pathologically by the formation of inclusions and rimmed vacuoles. DMRV is caused by mutations of GNE, which regulates the synthesis of a sialic acid. Pathological findings of DMRV have already been reported to be improved by treatment with sialic acid metabolites. MUC1, which is one of transmembrane mucins, is associated with cell cycle, autophagy, and exocytosis. In this study, we examined MUC1 expression in DMRV and other neuromuscular disorders by immunohistochemical analysis and western blot analysis. The muscle biopsy specimens from DMRV (n = 6), sporadic inclusion body myositis (sIBM; n = 10), polymyositis (PM: n = 8), and normal control (NC: n = 5) were examined. These specimens were subjected to immunohistochemistry, immunofluorescent technique, and western blot, using antibodies against MUC1, and Aβ. In DMRVs, inclusions and RVs were immunopositive for MUC1 and Aβ, but the sarcolemma was not. On the other hand, the sarcolemma was also immunopositive for MUC1 in sIBM. In PM and NC, the pale immunoreactivity for MUC1 was observed only in the sarcolemma. Western blot indicated the decrease of MUC1 in DMRV. This study suggests that the decrease of MUC1 is implicated in the formation of aggregates and RVs in DMRV. The decrease of MUC1 might be associated with a hypoglycosylation due to decreased sialic acid synthesis.

Limb-girdle phenotype is frequent in patients with myopathy associated with GNE mutations

The gene GNE encodes a bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Its mutations are found in distal myopathy with rimmed vacuoles (DMRV) and hereditary inclusion body myopathy (HIBM). Those disorders are characterized clinically by predominant anterior tibial muscle weakness and atrophy, and pathologically by rimmed vacuoles on muscle biopsy. We analyzed 11 Korean patients with GNE mutations. The mutations showed ethnic similarity to those of Japanese patients, showing the highest frequency with V572L. Another mutation of C13S was also found recurring in our patient group. Interestingly, about half of the patients showed limb-girdle myopathy rather than distal myopathy. This was further represented by limb muscle CT scans revealing atrophic hamstring and relatively spared anterior tibial muscle. However, quadriceps muscles were consistently spared both in distal and limb-girdle phenotypes. In conclusion, this study demonstrates a phenotypic diversity associated with GNE mutations. Recognizing a wider clinical spectrum of GNE mutations will help benefit more patients with imminent new therapy.

Localization of O-GlcNAc-modified proteins in neuromuscular diseases

O-linked N-acetylglucosamine (O-GlcNAc) is a ubiquitous post-translational modification of nucleocytoplasmic proteins that induces the attachment of N-acetylglucosamine to serine or threonine residues of a protein. In contrast to other protein glycosylations, this modification is highly reversible and, similar to phosphorylation, it plays important roles in various cell signals. Here, we immunolocalized O-GlcNAc-modified proteins in muscle biopsy specimens from 40 patients with neuromuscular diseases and controls. In normal muscle fibers, O-GlcNAc was found along plasma membranes and in nuclei. Diffuse and increased cytoplasmic staining of O-GlcNAc was detected in (1) regenerating muscle fibers in muscular dystrophy, myositis, and rhabdomyolysis; (2) a proportion of atrophic fibers in myositis, such as those found in perifascicular regions in dermatomyositis; and (3) vacuolated fibers in sporadic inclusion body myositis (s-IBM) and distal myopathy with rimmed vacuoles (DMRV). Target formations in neurogenic muscular atrophy were O-GlcNAc positive. Increase of O-GlcNAc glycosylation could be associated with the stress response, as these lesions have been shown to be positive for several stress markers. Vacuolar rims in s-IBM and DMRV were sometimes sharply lined by O-GlcNAc-positive deposits, which reflects myonuclear breakdown occurring from the disease.

Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations

BackgroundGlucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, also called distal myopathy with rimmed vacuoles (DMRV) or hereditary inclusion body myopathy (HIBM), is a rare, progressive autosomal recessive disorder caused by mutations in the GNE gene. Here, we examined the relationship between genotype and clinical phenotype in participants with GNE myopathy. MethodsParticipants with GNE myopathy were asked to complete a questionnaire regarding medical history and current symptoms. ResultsA total of 71 participants with genetically confirmed GNE myopathy (27 males and 44 females; mean age, 43.1±13.0 (mean±SD) years) completed the questionnaire. Initial symptoms (e.g., foot drop and lower limb weakness) appeared at a mean age of 24.8±8.3years. Among the 71 participants, 11 (15.5%) had the ability to walk, with a median time to loss of ambulation of 17.0±2.1years after disease onset. Participants with a homozygous mutation (p.V572L) in the N-acetylmannosamine kinase domain (KD/KD participants) had an earlier disease onset compared to compound heterozygous participants with mutations in the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase and N-acetylmannosamine kinase domains (ED/KD participants; 26.3±7.3 vs. 21.2±11.1years, respectively). KD/KD participants were more frequently non-ambulatory compared to ED/KD participants at the time of survey (80% vs. 50%). Data were verified using medical records available from 17 outpatient participants. ConclusionsHomozygous KD/KD participants exhibited a more severe phenotype compared to heterozygous ED/KD participants.

Glycoprotein Hyposialylation Gives Rise to a Nephrotic-Like Syndrome That Is Prevented by Sialic Acid Administration in GNE V572L Point-Mutant Mice

Mutations in the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetyl-mannosamine kinase, result in distal myopathy with rimmed vacuoles (DMRV)/hereditary inclusion body myopathy (HIBM) in humans. Sialic acid is an acidic monosaccharide that modifies non-reducing terminal carbohydrate chains on glycoproteins and glycolipids, and it plays an important role in cellular adhesions and interactions. In this study, we generated mice with a V572L point mutation in the GNE kinase domain. Unexpectedly, these mutant mice had no apparent myopathies or motor dysfunctions. However, they had a short lifespan and exhibited renal impairment with massive albuminuria. Histological analysis showed enlarged glomeruli with mesangial matrix deposition, leading to glomerulosclerosis and abnormal podocyte foot process morphologies in the kidneys. Glycan analysis using several lectins revealed glomerular epithelial cell hyposialylation, particularly the hyposialylation of podocalyxin, which is one of important molecules for the glomerular filtration barrier. Administering Neu5Ac to the mutant mice from embryonic stages significantly suppressed the albuminuria and renal pathology, and partially recovered the glomerular glycoprotein sialylation. These findings suggest that the nephrotic-like syndrome observed in these mutant mice resulted from impaired glomerular filtration due to the hyposialylation of podocyte glycoproteins, including podocalyxin. Furthermore, it was possible to prevent the nephrotic-like disease in these mice by beginning Neu5Ac treatment during gestation.

Peracetylated N-Acetylmannosamine, a Synthetic Sugar Molecule, Efficiently Rescues Muscle Phenotype and Biochemical Defects in Mouse Model of Sialic Acid-deficient Myopathy

Distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy (DMRV/hIBM), characterized by progressive muscle atrophy, weakness, and degeneration, is due to mutations in GNE, a gene encoding a bifunctional enzyme critical in sialic acid biosynthesis. In the DMRV/hIBM mouse model, which exhibits hyposialylation in various tissues in addition to muscle atrophy, weakness, and degeneration, we recently have demonstrated that the myopathic phenotype was prevented by oral administration of N-acetylneuraminic acid, N-acetylmannosamine, and sialyllactose, underscoring the crucial role of hyposialylation in the disease pathomechanism. The choice for the preferred molecule, however, was limited probably by the complex pharmacokinetics of sialic acids and the lack of biomarkers that could clearly show dose response. To address these issues, we screened several synthetic sugar compounds that could increase sialylation more remarkably and allow demonstration of measurable effects in the DMRV/hIBM mice. In this study, we found that tetra-O-acetylated N-acetylmannosamine increased cell sialylation most efficiently, and in vivo evaluation in DMRV/hIBM mice revealed a more dramatic, measurable effect and improvement in muscle phenotype, enabling us to establish analysis of protein biomarkers that can be used for assessing response to treatment. Our results provide a proof of concept in sialic acid-related molecular therapy with synthetic monosaccharides.

Distal myopathy with rimmed vacuoles and inflammation: A genetically proven case

Distal myopathy with rimmed vacuoles (DMRV) is a major entity of distal myopathy. It is an autosomal recessive disorder and is due to mutations in the GNE gene that regulates the synthesis of sialic acid. Although reported predominantly from Japan, cases have been reported from other parts of the world. We report the first genetically proven case of DMRV from India in a 23-year-old male with gradual onset, progressive distal weakness of both lower limbs with features of inflammation in muscle biopsy.

Distal myopathy with rimmed vacuoles: clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients

Objectives: Distal myopathy with rimmed vacuoles (DMRV) is a typical autosomal recessive hereditary inclusion body myopathy, characterized by slowly progressive distal muscle weakness with relative sparing of the quadriceps. This study aimed to investigate the variability of clinical and morphological presentation and the spectrum of Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) mutations in Chinese DMRV patients.Methods: We retrospectively reviewed the medical records of 37 patients with DMRV in PLA General Hospital from 1986 to 2011, and further conducted a review of 16 reported Chinese DMRV patients from other hospitals. We systematically analyzed the clinical, muscle morphological features and GNE gene mutation status of all DMRV patients.Results: A total of 53 DMRV patients were studied. Fourteen cases had family history and other 39 cases were sporadic. Fifteen cases showed atypical pathological presentation as mononuclear cell invasion into necrotic or non-necrotic muscle fibers. Rare initial symptom, earlier age of onset and more dysmorphic presentations were shown in sporadic patients. Eighteen mutations in GNE gene were identified. c.317T>C (p.I106T) was a novel GNE gene mutation. c.1892C>T (p.A631V), c.527A>T (p.D176V) and c.1523T>C (p.L508S) were the common GNE mutations in Chinese DMRV patients.Discussion: The clinical, pathological and genetic characteristics of DMRV are distinct in Chinese patients.

Clinical and molecular genetic analysis in Chinese patients with distal myopathy with rimmed vacuoles

Distal myopathy with rimmed vacuoles (DMRVs) is an autosomal recessive vacuolar myopathy that has been reported in different ethnic populations with the common mutations of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. We presented the clinical, pathological and genetic characteristics of eight Chinese DMRV patients from six unrelated families. Six previously reported Chinese DMRV patients from four unrelated families were also reviewed for comparison in GNE mutations. In the present eight patients with DMRV, direct sequencing analysis revealed one homozygous mutation of c.1760T>C (p.I587T) and seven compound heterozygous mutations in the GNE gene. The latter included two known mutations, c.1892C>T (p.A631V) and c.527A>T (p.D176V), and three novel mutations, c.1523T>C (p.L508S), c.103G>A (p.E35K) and c.153A>G (p.I51M). The allelic frequency of c.1523T>C (p.L508S) was 25% in the Chinese patients with DMRV. Our findings expand the genetic spectrum of DMRV and indicate that the common mutations of GNE gene in DMRV may be variable among different ethnic populations.

Hereditary inclusion‐body myopathy associated with cardiomyopathy: Report of two siblings

Hereditary inclusion-body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps-sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20-26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy.

P2.05 Long-term measurement of muscle strength in distal myopathy with rimmed vacuoles (DMRV)

Distal myopathy with rimmed vacuoles (DMRV), also called Nonaka myopathy (OMIM #605820) or hereditary inclusion body myopathy, which is caused by UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene mutations, is a disorder of sialylation and can potentially be treated by giving sialic acids. We previously reported the outcome of trial of β2 adrenergic agonist clenbuterol in adult muscular dystrophy patients (Rinsho Shinkeigaku 2001), and we treated also patients with DMRV. We measured isometric muscle strength with a hand-held dynamometer (HHD) as well as grip and pinch strength.

P2.04 DMRV and GNE mutations: genotype–phenotype correlation in 100 Japanese patients

Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder with preferential involvement of the distal muscles in lower extremities at young adulthood and spares quadriceps muscles. In DMRV patients, we previously identified homogeneous and compound heterozygous mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene that is the causative gene in hereditary inclusion body myopathy (hIBM). Purpose: To investigate the correlation between phenotypes and genotypes in DMRV, we analyzed the information of 100 cases of this disease in Japan.