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1.
BMC Neurol ; 22(1): 352, 2022 Sep 16.
Article in English | MEDLINE | ID: mdl-36114472

ABSTRACT

BACKGROUND: The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. METHODS: Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. RESULTS: Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. CONCLUSION: The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.


Subject(s)
Epilepsy , Seizures , Adolescent , Adult , Cerebellum/blood supply , Cerebellum/diagnostic imaging , Epilepsy/diagnostic imaging , Female , Humans , Middle Aged , Retrospective Studies , Spin Labels , Young Adult
4.
Brain ; 144(4): 1103-1117, 2021 05 07.
Article in English | MEDLINE | ID: mdl-33791773

ABSTRACT

A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype-phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype-phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.


Subject(s)
DNA Repeat Expansion/genetics , Epilepsies, Myoclonic/genetics , Nerve Tissue Proteins/genetics , Sequence Analysis, DNA/methods , Adult , Aged , Aged, 80 and over , CRISPR-Associated Protein 9 , CRISPR-Cas Systems , Female , Genetic Association Studies , Humans , Male , Microsatellite Repeats , Middle Aged
5.
J Hum Genet ; 66(7): 697-705, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33510365

ABSTRACT

Whole-exome sequencing (WES) can detect not only single-nucleotide variants in causal genes, but also pathogenic copy-number variations using several methods. However, there may be overlooked pathogenic variations in the out of target genome regions of WES analysis (e.g., promoters), leaving many patients undiagnosed. Whole-genome sequencing (WGS) can potentially analyze such regions. We applied long-read nanopore WGS and our recently developed analysis pipeline "dnarrange" to a patient who was undiagnosed by trio-based WES analysis, and identified a heterozygous 97-kb deletion partially involving 5'-untranslated exons of MBD5, which was outside the WES target regions. The phenotype of the patient, a 32-year-old male, was consistent with haploinsufficiency of MBD5. The transcript level of MBD5 in the patient's lymphoblastoid cells was reduced. We therefore concluded that the partial MBD5 deletion is the culprit for this patient. Furthermore, we found other rare structural variations (SVs) in this patient, i.e., a large inversion and a retrotransposon insertion, which were not seen in 33 controls. Although we considered that they are benign SVs, this finding suggests that our pipeline using long-read WGS is useful for investigating various types of potentially pathogenic SVs. In conclusion, we identified a 97-kb deletion, which causes haploinsufficiency of MBD5 in a patient with neurodevelopmental disorder, demonstrating that long-read WGS is a powerful technique to discover pathogenic SVs.


Subject(s)
DNA-Binding Proteins/genetics , Genetic Predisposition to Disease , Neurodevelopmental Disorders/genetics , Adult , Exome/genetics , Haploinsufficiency/genetics , Humans , Male , Mutagenesis, Insertional/genetics , Neurodevelopmental Disorders/pathology , Retroelements/genetics , Whole Genome Sequencing
6.
Neurology ; 88(5): 493-500, 2017 01 31.
Article in English | MEDLINE | ID: mdl-28039312

ABSTRACT

OBJECTIVE: To evaluate the diagnostic value of myxovirus resistance A (MxA) expression in the cytoplasm of myofibers in the diagnosis of dermatomyositis (DM). METHODS: We assessed the sensitivity and specificity of the sarcoplasmic expression of MxA in muscles with DM by immunohistochemistry in consecutive cases of DM (n = 34) and other idiopathic inflammatory myopathies (n = 120: 8 with polymyositis, 16 with anti-tRNA-synthetase antibody-associated myositis, 46 with immune-mediated necrotizing myopathy, and 50 with inclusion body myositis) and compared them with conventional pathologic hallmarks of DM, including perifascicular atrophy (PFA) and membrane attack complex (MAC) deposition on endomysial capillaries. RESULTS: The sensitivity and specificity of sarcoplasmic MxA expression were 71% and 98%, respectively. While the specificity was almost comparable to that of PFA and capillary MAC deposition, the sensitivity was higher, with PFA showing 47% sensitivity and 98% specificity and capillary MAC deposition showing 35% sensitivity and 93% specificity. Of note, in patients with DM with typical skin rash but no PFA, 44% of the samples showed sarcoplasmic MxA expression, which was higher than the 17% sensitivity of capillary MAC deposition in the population. CONCLUSIONS: Sarcoplasmic MxA expression detected by immunohistochemistry is a more sensitive marker of DM than the conventional hallmarks, indicating its practical utility in the diagnosis of DM. It may well be included in the routine immunohistochemistry panel for myositis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that immunohistochemistry-detected sarcoplasmic MxA expression accurately identifies patients with dermatomyositis.


Subject(s)
Dermatomyositis/diagnosis , Dermatomyositis/metabolism , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Myxovirus Resistance Proteins/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Atrophy , Biomarkers/metabolism , Capillaries/metabolism , Capillaries/pathology , Child , Child, Preschool , Complement Membrane Attack Complex/metabolism , Dermatomyositis/pathology , Diagnosis, Differential , Humans , Immunohistochemistry , Infant , Middle Aged , Retrospective Studies , Sensitivity and Specificity , Young Adult
7.
Neuromuscul Disord ; 26(9): 604-9, 2016 09.
Article in English | MEDLINE | ID: mdl-27460346

ABSTRACT

Mutations in the multiple epidermal growth factor-like domains 10 (MEGF10: NM_032446.2) gene are known to cause early-onset myopathy characterized by areflexia, respiratory distress, and dysphagia (EMARDD: OMIM 614399), and a milder phenotype of minicore myopathy. To date, there have been reports of six families with EMARDD and one with a milder disorder. Cysteine mutations in the extracellular EGF-like domain may be responsible for the milder phenotype, but the relationship is not conclusive because of the few reports of this disorder. We here present two Japanese patients with MEGF10 mutations: one with EMARDD phenotype who had a novel homozygous frameshift mutation, c.131_132del, and the other with the milder phenotype who harbored a compound heterozygous mutation, c.2981-2A > G, and a novel missense mutation, p.Cys810Tyr. This is the first report on East Asian patients with MEGF10 myopathy showing two phenotypes, indicating the genotype-phenotype correlation in MEGF10 myopathy.


Subject(s)
Membrane Proteins/genetics , Muscular Diseases/genetics , Muscular Diseases/physiopathology , Mutation , Adolescent , Fatal Outcome , Female , Genetic Association Studies , Humans , Male , Muscular Diseases/pathology , Phenotype
8.
Neurology ; 86(3): 211-7, 2016 Jan 19.
Article in English | MEDLINE | ID: mdl-26683644

ABSTRACT

OBJECTIVE: To clarify whether there is any association between inclusion body myositis (IBM) and hepatitis C virus (HCV) infection. METHODS: We assessed the prevalence of HCV infection in 114 patients with IBM whose muscle biopsies were analyzed pathologically for diagnostic purpose from 2002 to 2012 and in 44 age-matched patients with polymyositis diagnosed in the same period as a control by administering a questionnaire survey to the physicians in charge. We also compared clinicopathologic features including the duration from onset to development of representative symptoms of IBM and the extent of representative pathologic changes between patients with IBM with and without HCV infection. RESULTS: A significantly higher number of patients with IBM (28%) had anti-HCV antibodies as compared with patients with polymyositis (4.5%; odds ratio 8.2, 95% confidence interval 1.9-36) and the general Japanese population in their 60s (3.4%). Furthermore, between patients with IBM with and without HCV infection, we did not find any significant difference in the clinicopathologic features, indicating that the 2 groups have essentially the same disease regardless of HCV infection. CONCLUSION: Our results provide the statistical evidence for an association between IBM and HCV infection, suggesting a possible pathomechanistic link between the 2 conditions.


Subject(s)
Hepatitis C Antibodies/analysis , Hepatitis C/virology , Myositis, Inclusion Body/virology , Polymyositis/virology , Aged , Case-Control Studies , Comorbidity , Female , Hepatitis C/epidemiology , Hepatitis C/pathology , Humans , Japan/epidemiology , Male , Middle Aged , Myositis, Inclusion Body/epidemiology , Myositis, Inclusion Body/pathology , Polymyositis/epidemiology , Polymyositis/pathology , Prevalence
9.
Brain Dev ; 37(1): 145-8, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24582475

ABSTRACT

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) localizes on the outermost surface of the myelin sheath and oligodendrocytes in the central nervous system (CNS). Autoantibodies against MOG are reportedly found in patients with spectrum of inflammatory demyelinating diseases of the CNS, including acute disseminated encephalomyelitis, multiple sclerosis, and neuromyelitis optica. In addition, recent studies have emphasized an association between anti-MOG antibodies and optic neuritis. PATIENT: We present the first case report of a 7-year-old Japanese boy who was positive for anti-MOG antibodies. He experienced four episodes of unilateral optic neuritis and one seizure event. Magnetic resonance imaging revealed T2-hyperintense lesions in the subcortical white matter and midbrain. Although he fulfilled the diagnostic criteria for multiple sclerosis, recombinant interferon beta did not prevent recurrence. Established cell-based immunoassays revealed that he was positive for anti-MOG antibodies and negative for anti-aquaporin 4 antibodies. CONCLUSIONS: Our case report supports the relationship between anti-MOG antibodies and recurrent optic neuritis. Additional studies are needed to establish the clinical significance of anti-MOG antibodies for diagnosis, treatment, and prognosis.


Subject(s)
Autoantibodies/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Optic Neuritis/immunology , Asian People , Autoantibodies/blood , Autoantigens/immunology , Child , Humans , Male , Optic Neuritis/blood , Recurrence
10.
Neuromuscul Disord ; 24(5): 402-8, 2014 May.
Article in English | MEDLINE | ID: mdl-24444550

ABSTRACT

Duchenne muscular dystrophy (DMD) is strongly associated with a unique form of dilated cardiomyopathy. Cardiac complications are the leading cause of death in DMD; thus, longitudinal assessments and early intervention for cardiac dysfunction are necessary to improve prognosis. Two-dimensional echocardiography, which is routinely used for cardiac assessment, has some limitations for quantitative analyses in DMD patients with thoracic deformities and regional wall motion abnormalities in the left ventricle. Recently, real-time three-dimensional echocardiography has emerged as a feasible tool for cardiac assessment in various cardiac diseases. The aim of this study was to examine the utility of this technology in DMD. We evaluated left ventricular ejection fraction (LVEF), a major parameter of left ventricular function, in 17 male DMD patients. LVEF values measured by real-time three-dimensional echocardiography were compared with those determined by two established nuclear cardiology methods: "the first-pass method of radionuclide angiocardiography" and "quantitative electrocardiogram-gated single-photon emission computed tomography". A good correlation was observed for LVEF values, particularly between real-time three-dimensional echocardiography and "the first-pass method of radionuclide angiocardiography" (r=0.90, p<0.05). Thus, real-time three-dimensional echocardiography can provide an accurate measurement of LVEF in DMD patients with echocardiographic limitations.


Subject(s)
Echocardiography, Three-Dimensional/methods , Muscular Dystrophy, Duchenne/diagnostic imaging , Adolescent , Adult , Cardiac-Gated Single-Photon Emission Computer-Assisted Tomography , Feasibility Studies , Gated Blood-Pool Imaging , Humans , Male , Ventricular Function, Left , Young Adult
11.
Brain Dev ; 35(10): 887-93, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24047572

ABSTRACT

The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation.


Subject(s)
Spasms, Infantile/diagnosis , Spectroscopy, Near-Infrared/methods , Tomography, Emission-Computed, Single-Photon/methods , Brain/blood supply , Brain/diagnostic imaging , Brain/pathology , Humans , Infant , Regional Blood Flow , Spasms, Infantile/diagnostic imaging , Spasms, Infantile/pathology
12.
Neuromuscul Disord ; 23(11): 911-6, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23850239

ABSTRACT

Here we report what is to our knowledge the first identified Japanese family afflicted by X-linked myopathy with excessive autophagy. The index case is a 52-year-old man with almost 40years of progressive proximal muscle weakness. High urinary ß2 microglobulin, normal serum ß2 microglobulin, autophagic vacuoles with sarcolemmal features, and a hemizygous c.164-7T>G mutation in the VMA21 gene were found. His two maternal uncles had similar clinicopathological findings. High urinary ß2 microglobulin without obvious renal dysfunction might result from decreased urine acidification in the distal convoluted tubules caused by the VMA21 gene mutation. These findings might prove to be useful as a preliminary marker suggestive of X-linked myopathy with excessive autophagy.


Subject(s)
Genetic Diseases, X-Linked/diagnosis , Muscular Diseases/diagnosis , Vacuolar Proton-Translocating ATPases/genetics , beta 2-Microglobulin/urine , Adult , Asian People , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Humans , Japan , Male , Middle Aged , Muscle Fibers, Skeletal/ultrastructure , Muscular Diseases/genetics , Muscular Diseases/pathology , Mutation , beta 2-Microglobulin/blood
13.
Ann Rheum Dis ; 71(10): 1646-50, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22402141

ABSTRACT

OBJECTIVES: To investigate associations between signal transducer and activator of transcription 4 (STAT4), one of the most commonly acknowledged genes for the risk of multiple autoimmune diseases, with susceptibility to adult-onset polymyositis/dermatomyositis among Japanese individuals. METHODS: A single nucleotide polymorphism of STAT4, rs7574865, was genotyped using TaqMan assay in 1143 Japanese individuals. The first set comprised 138 polymyositis/dermatomyositis patients and 289 controls and the second set comprised 322 patients and 394 controls. 460 patients (273 polymyositis and 187 dermatomyositis patients) and 683 controls were genotyped. RESULTS: rs7574865T conferred a risk of polymyositis/dermatomyositis with an OR of 1.37 (95% CI 1.16 to 1.64; p=4x10(-4); p(corr)=0.0012). Both polymyositis and dermatomyositis exhibited high associations with the rs7574865T allele (polymyositis: OR=1.36, 95% CI 1.11 to 1.67; p=0.0039; p(corr)=0.012; dermatomyositis: OR=1.40, 95% CI 1.10 to 1.78; p=0.0054; p(corr)=0.016). The association between this STAT4 polymorphism and interstitial lung disease (ILD) was also investigated in the first set of polymyositis/dermatomyositis patients (n=138); those with ILD (n=79) bore rs7574865T more frequently compared with controls (OR 1.59, 95% CI 1.10 to 2.28; p=0.013; p(corr)=0.039). CONCLUSION: This is the first study to show a positive association between a STAT4 polymorphism and polymyositis/dermatomyositis, suggesting that polymyositis/dermatomyositis shares a gene commonly associated with the risk of other autoimmune diseases.


Subject(s)
Asian People/genetics , Dermatomyositis/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide , STAT4 Transcription Factor/genetics , Female , Genotype , Humans , Male , Middle Aged , Polymerase Chain Reaction , Risk Factors
14.
Arch Neurol ; 69(6): 728-32, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22332183

ABSTRACT

OBJECTIVE: To characterize the clinical course of myopathy associated with antibodies to signal recognition particle (SRP), or anti-SRP myopathy. DESIGN: Case series. SETTING: Keio University Hospitals and National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. PATIENTS: We reviewed clinical features of 27 patients with anti-SRP myopathy and analyzed disease progression and neurological outcome. MAIN OUTCOME MEASURES: Anti-SRP antibodies in serum were detected by RNA immunoprecipitation assay using extracts of K562 cells. RESULTS: Of the 27 patients, 5 (19%) showed chronic progressive muscle weakness as well as atrophy of limbs and trunk muscles from a younger age with more severe neurological outcomes compared with the other 22 patients(81%) with the subacute form. CONCLUSION: A subset of patients with anti-SRP myopathy can show a chronic progressive form associated with severe clinical deficits.


Subject(s)
Autoantibodies/blood , Muscular Diseases/blood , Muscular Diseases/immunology , Nervous System Diseases/etiology , Signal Recognition Particle/immunology , Adolescent , Adult , Age of Onset , Aged , Aged, 80 and over , Anti-Inflammatory Agents/therapeutic use , Creatine Kinase/blood , Disease Progression , Female , Humans , Immunoprecipitation , Male , Middle Aged , Muscular Diseases/complications , Muscular Diseases/drug therapy , Prednisolone/therapeutic use , Severity of Illness Index , Young Adult
15.
Am J Med Genet A ; 158A(3): 674-7, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22315185

ABSTRACT

Periventricular heterotopia (PH), clumps of neurons mislocated beside the ventricle, is caused by failure to initiate migration during embryogenesis. We report on a 32-month-old Japanese girl with a unique subtype of PH, namely ribbon-like PH. The patient presented with severe psychomotor developmental delay, intractable epilepsy, and congenital cataracts and developed West syndrome phenotype. Brain magnetic resonance imaging revealed a unique undulating form of PH, categorized as ribbon-like PH, and other brain malformations including simplified gyri and dysgenesis of the corpus callosum. There was no evidence of prenatal TORCH infection or associated syndrome. Array-based comparative genomic hybridization revealed no chromosomal rearrangements. Genetic analyses of the FLNA, DCX, ARX, LIS1, and TUBA1A genes showed no mutations. Although little is known about ribbon-like PH, the clinical manifestations in our patient clearly differed from those in other reported patients.


Subject(s)
Cataract/congenital , Periventricular Nodular Heterotopia/complications , Cataract/complications , Cataract/genetics , Child, Preschool , Comparative Genomic Hybridization , Female , Humans , Japan , Mutation , Periventricular Nodular Heterotopia/genetics , Real-Time Polymerase Chain Reaction
16.
Neuromuscul Disord ; 22(5): 389-93, 2012 May.
Article in English | MEDLINE | ID: mdl-22196155

ABSTRACT

Diagnosis of adult-onset Pompe disease is sometimes challenging because of its clinical similarities to muscular dystrophy and the paucity of disease-specific vacuolated fibers in the skeletal muscle pathology. We describe two patients with adult-onset Pompe disease whose muscle pathology showed no typical vacuolated fibers but did show unique globular inclusions with acid phosphatase activity. The acid phosphatase-positive globular inclusions may be a useful diagnostic marker for adult-onset Pompe disease even when typical vacuolated fibers are absent.


Subject(s)
Acid Phosphatase/metabolism , Glycogen Storage Disease Type II/diagnosis , Glycogen Storage Disease Type II/enzymology , Inclusion Bodies/pathology , alpha-Glucosidases/genetics , Acid Phosphatase/genetics , Adult , Age of Onset , DNA Mutational Analysis , Female , Genetic Markers , Humans , Male , Middle Aged , Muscle, Skeletal/pathology , Muscle, Skeletal/ultrastructure , Mutation/genetics
17.
Neuromuscul Disord ; 21(8): 563-8, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21632249

ABSTRACT

Mutations in LMNA cause wide variety of disorders including Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and congenital muscular dystrophy. We recently found a LMNA mutation in a patient who was previously diagnosed as infantile onset inflammatory myopathy. In this study, we screened for LMNA mutations in 20 patients suspected to have inflammatory myopathy with onset at 2years or younger. The diagnosis of inflammatory myopathy was based on muscle pathology with presence of perivascular cuffing and/or endomysial/perimysial lymphocyte infiltration. We identified heterozygous LMNA mutations in 11 patients (55%), who eventually developed joint contractures and/or cardiac involvement after the infantile period. Our findings suggest that LMNA mutation should be considered in myopathy patients with inflammatory changes during infancy, and that this may help avoid life-threatening events associated with laminopathy.


Subject(s)
Inflammation/pathology , Lamin Type A/genetics , Muscular Diseases/genetics , Muscular Diseases/pathology , Adrenal Cortex Hormones/therapeutic use , Child, Preschool , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Muscle, Skeletal/pathology , Muscular Diseases/drug therapy , Mutation , Myositis/drug therapy , Myositis/genetics , Myositis/pathology , Retrospective Studies , Treatment Outcome
18.
Nat Med ; 17(6): 720-5, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21623381

ABSTRACT

Myotonic dystrophy is the most common muscular dystrophy in adults and the first recognized example of an RNA-mediated disease. Congenital myotonic dystrophy (CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by the expression of mutant RNAs containing expanded CUG or CCUG repeats, respectively. These mutant RNAs sequester the splicing regulator Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the alternative splicing of other pre-mRNAs. We found that alternative splicing of the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of membranes and is required for the biogenesis of muscle T tubules, which are specialized skeletal muscle membrane structures essential for excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear myopathy, which shares some histopathological features with myotonic dystrophy. We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative splicing. BIN1 missplicing results in expression of an inactive form of BIN1 lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating activities. Consistent with a defect of BIN1, muscle T tubules are altered in people with myotonic dystrophy, and membrane structures are restored upon expression of the normal splicing form of BIN1 in muscle cells of such individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient to promote T tubule alterations and muscle weakness, a predominant feature of myotonic dystrophy.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alternative Splicing/physiology , Muscle Fibers, Skeletal/physiology , Muscle Weakness/genetics , Myotonic Dystrophy/genetics , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics , Adaptor Proteins, Signal Transducing/physiology , Animals , Cell Line , Exons/genetics , Humans , Mice , Muscle Weakness/physiopathology , Myotonic Dystrophy/physiopathology , Nuclear Proteins/physiology , Protein Isoforms/genetics , Protein Isoforms/physiology , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/physiology , Tumor Suppressor Proteins/physiology
20.
Brain Dev ; 32(5): 409-11, 2010 May.
Article in English | MEDLINE | ID: mdl-19345525

ABSTRACT

Carnitine palmitoyl transferase I (CPT I) deficiency is a rare disorder of long-chain fatty acid oxidation. It is one of the metabolic diseases detectable by tandem mass spectrometry. We report herein a presymptomatic CPT I deficiency detected in a Japanese female newborn by tandem mass spectrometry newborn screening. A mutation analysis of the CPT1A gene revealed two novel mutations, p.R446X and p.G719D.


Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Lipid Metabolism, Inborn Errors/diagnosis , Neonatal Screening/methods , Tandem Mass Spectrometry/methods , DNA Mutational Analysis/methods , Female , Humans , Infant, Newborn , Japan , Lipid Metabolism, Inborn Errors/diet therapy , Lipid Metabolism, Inborn Errors/physiopathology
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