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1.
Neurology ; 95(11): e1512-e1527, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32796131

RESUMO

OBJECTIVE: To clarify the prevalence, long-term natural history, and severity determinants of SEPN1-related myopathy (SEPN1-RM), we analyzed a large international case series. METHODS: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades. RESULTS: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 SEPN1 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity (p = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, SEPN1 mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification. CONCLUSION: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.


Assuntos
Genótipo , Proteínas Musculares/genética , Doenças Musculares/diagnóstico por imagem , Doenças Musculares/genética , Selenoproteínas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/patologia , Estudos Retrospectivos , Adulto Jovem
2.
Acta Neuropathol ; 137(3): 501-519, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30701273

RESUMO

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.


Assuntos
Actinina/genética , Músculo Esquelético/patologia , Miotonia Congênita/genética , Miotonia Congênita/patologia , Animais , Feminino , Humanos , Masculino , Camundongos , Mutação , Peixe-Zebra
3.
Muscle Nerve ; 59(1): 137-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30025162

RESUMO

INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Músculo Esquelético/patologia , Mutação/genética , Atrofias Olivopontocerebelares/genética , Atrofias Olivopontocerebelares/patologia , Proteínas de Ligação a RNA/genética , Sarcoma/patologia , Biópsia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Recém-Nascido , Masculino , Músculo Esquelético/ultraestrutura , Miopatias da Nemalina , Sarcoma/ultraestrutura
5.
Acta Neuropathol ; 133(4): 517-533, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28012042

RESUMO

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.


Assuntos
Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Miotonia Congênita/genética , Miotonia Congênita/metabolismo , Adolescente , Adulto , Cálcio/metabolismo , Canais de Cálcio Tipo L , Células Cultivadas , Criança , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Musculares/metabolismo , Células Musculares/patologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação , Miotonia Congênita/diagnóstico por imagem , Miotonia Congênita/patologia , Fenótipo , Homologia de Sequência de Aminoácidos , Adulto Jovem
7.
Ann Clin Transl Neurol ; 3(4): 248-65, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27081656

RESUMO

OBJECTIVE: Limb-girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium-dependent cysteine protease of the skeletal muscle. METHODS: In this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14-65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients. RESULTS: Our study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis. INTERPRETATION: All the generated data will help to determine the endpoints for further clinical studies.

9.
J Neuromuscul Dis ; 2(2): 175-180, 2015 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-27858728

RESUMO

Oculopharyngeal muscular dystrophy (OPMD) is mainly characterized by ptosis and dysphagia. The genetic cause is a short expansion of a (GCN)10 repeat encoding for polyalanine in the poly(A) binding protein nuclear 1 (PABPN1) gene to (GCN)12-17 repeats. The (GCN)11/Ala11 allele has so far been described to be either a polymorphism or a recessive allele with no effect on the phenotype in the heterozygous state. Here we report the clinical and histopathological phenotype of a patient carrying a single (GCN)11/Ala11 heterozygous allele and presenting an atypical form of OPMD with dysphagia and late and mild oculomotor symptoms. Intranuclear inclusions were observed in his muscle biopsy. This suggests a dominant mode of expression of the (GCN)11/Ala11 allele associated with a partial penetrance of OPMD.

10.
J Med Genet ; 51(12): 824-33, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25326555

RESUMO

BACKGROUND: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double-walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene. METHODS: The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum. RESULTS: We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EF-hand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adult-onset myalgia without muscle weakness and normal CK levels. CONCLUSIONS: The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.


Assuntos
Proteínas de Membrana/genética , Músculo Esquelético/patologia , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/genética , Fenótipo , Adulto , Idoso , Sequência de Aminoácidos , Animais , Biópsia , Cálcio/metabolismo , Linhagem Celular , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Proteínas de Membrana/química , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Miopatias Congênitas Estruturais/metabolismo , Proteínas de Neoplasias/química , Linhagem , Conformação Proteica , Alinhamento de Sequência , Molécula 1 de Interação Estromal
11.
Brain ; 137(Pt 12): 3160-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25260562

RESUMO

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação/genética , Miopatias Congênitas Estruturais/genética , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idade de Início , Dinamina II/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo
12.
Neuromuscul Disord ; 24(11): 993-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25070542

RESUMO

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.


Assuntos
Aminoacil-tRNA Sintetases/genética , Fusos Musculares/patologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Mutação/genética , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Imageamento por Ressonância Magnética
13.
Acta Neuropathol Commun ; 2: 44, 2014 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-24725366

RESUMO

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3.In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation between clinical severity on the one hand and the degree of sarcomeric dissociation and contractility efficiency on the other. By contrast the percentage of fibres occupied by rods, as well as the quantity and the sub sarcolemmal position of rods, appears to inversely correlate with severity. Based on our observations, we propose myofibrillar dissociation and changes in contractility as an important cause of muscle weakness in NEB-mutated NM patients.


Assuntos
Proteínas Musculares/genética , Músculos/patologia , Músculos/ultraestrutura , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia Eletrônica , Contração Muscular/genética , Debilidade Muscular/etiologia , Miopatias da Nemalina/complicações , Cadeias Pesadas de Miosina/metabolismo , Miosinas/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
14.
Neuromuscul Disord ; 23(12): 998-1009, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24011702

RESUMO

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.


Assuntos
Junção Neuromuscular/patologia , Osteocondrodisplasias/patologia , Nervos Periféricos/fisiopatologia , Adulto , Proteínas de Ligação ao Cálcio/metabolismo , Eletromiografia , Humanos , Masculino , Proteína Básica da Mielina/metabolismo , Condução Nervosa/fisiologia , Proteínas de Neurofilamentos/metabolismo , Junção Neuromuscular/metabolismo , Junção Neuromuscular/fisiopatologia , Junção Neuromuscular/ultraestrutura , Nervos Periféricos/metabolismo , Nervos Periféricos/patologia , Nervos Periféricos/ultraestrutura , Receptores Proteína Tirosina Quinases/metabolismo , Receptor ErbB-3/metabolismo , Receptores Colinérgicos/metabolismo , Proteínas S100/metabolismo
15.
J Neuropathol Exp Neurol ; 72(9): 833-45, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23965743

RESUMO

FHL1 mutations have been associated with various disorders that include reducing body myopathy (RBM), Emery-Dreifuss-like muscular dystrophy, isolated hypertrophic cardiomyopathy, and some overlapping conditions. We report a detailed histochemical, immunohistochemical, electron microscopic, and immunoelectron microscopic analyses of muscle biopsies from 18 patients carrying mutations in FHL1: 14 RBM patients (Group 1), 3 Emery-Dreifuss muscular dystrophy patients (Group 2), and 1 patient with hypertrophic cardiomyopathy and muscular hypertrophy (Group 2). Group 1 muscle biopsies consistently showed RBs associated with cytoplasmic bodies. The RBs showed prominent FHL1 immunoreactivity whereas desmin, αB-crystallin, and myotilin immunoreactivity surrounded RBs. By electron microscopy, RBs were composed of electron-dense tubulofilamentous material that seemed to spread progressively between the myofibrils and around myonuclei. By immunoelectron microscopy, FHL1 protein was found exclusively inside RBs. Group 2 biopsies showed mild dystrophic abnormalities without RBs; only minor nonspecific myofibrillar abnormalities were observed under electron microscopy. Molecular analysis revealed missense mutations in the second FHL1 LIM domain in Group 1 patients and ins/del or missense mutations within the fourth FHL1 LIM domain in Group 2 patients. Our findings expand the morphologic features of RBM, clearly demonstrate the localization of FHL1 in RBs, and further illustrate major morphologic differences among different FHL1-related myopathies.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Musculares/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação/genética , Adolescente , Adulto , Distrofia Muscular de Emery-Dreifuss Autossômica , Biópsia , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Criança , Conectina , Proteínas do Citoesqueleto/metabolismo , Análise Mutacional de DNA , Desmina/metabolismo , Feminino , Humanos , Masculino , Proteínas dos Microfilamentos , Microscopia Eletrônica , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Doenças Musculares/classificação , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patologia , Adulto Jovem , Cadeia B de alfa-Cristalina/metabolismo
16.
Handb Clin Neurol ; 113: 1291-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23622354

RESUMO

Clinical symptoms of neuromuscular diseases vary according to age and type of primary involvement (spinal motor neuron, nerve, neuromuscular junction or muscle). Tools at our disposal for diagnostic purposes are graduated based on the age of the patient and diagnostic suspicions generated by the clinical workup. Seven clinical presentations can be identified that all require technical facilities specifically dedicated to pediatric neuromuscular diseases: congenital hypomobility and arthrogryposis, paralytic hypotonia in infancy, motor delay and chronic walking difficulties after the age of 18 months, progressive walking difficulties after the age of 3 years, effort intolerance and acute rhabdomyolysis, acute motor symptoms or fatigability, and variability of symptoms. Electrophysiological investigation, particularly electromyography, is a valuable tool where neurogenic involvement or neuromuscular block is suspected. However, the technique is difficult to perform in children. Muscle biopsy is generally the key investigation and can be performed at any age. Molecular biology helps to improve diagnostic strategy. Muscle MRI, in combination with clinical evaluation, assists the selection of appropriate genetic tests and more generally the identification of genetically distinct forms of neuromuscular disorder. None of these are by any means routine investigations, and only a specialized multidisciplinary clinical approach can permit correct diagnosis and proper follow-up.


Assuntos
Neurônios Motores/patologia , Músculo Esquelético/patologia , Doenças Neuromusculares/diagnóstico , Biópsia , Criança , Humanos , Doenças Neuromusculares/patologia , Exame Físico
17.
Am J Hum Genet ; 92(2): 271-8, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23332920

RESUMO

Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca(2+) sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca(2+)-binding EF hands. Ca(2+) stores are refilled through a process called store-operated Ca(2+) entry (SOCE). Upon Ca(2+)-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca(2+) entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca(2+) sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca(2+) level in TAM cells and a dysregulation of intracellular Ca(2+) homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function.


Assuntos
Cálcio/metabolismo , Proteínas de Membrana/metabolismo , Miopatias Congênitas Estruturais/patologia , Proteínas de Neoplasias/metabolismo , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Criança , Feminino , Homeostase , Humanos , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Músculos/patologia , Músculos/ultraestrutura , Mutação/genética , Mioblastos/metabolismo , Mioblastos/patologia , Miopatias Congênitas Estruturais/genética , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Linhagem , Fenótipo , Molécula 1 de Interação Estromal , Adulto Jovem
18.
Acta Neuropathol ; 125(3): 439-57, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23315026

RESUMO

X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.


Assuntos
Adenosina Trifosfatases/metabolismo , Autofagia/genética , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/prevenção & controle , Doenças Musculares/genética , Doenças Musculares/prevenção & controle , ATPases Vacuolares Próton-Translocadoras/deficiência , ATPases Vacuolares Próton-Translocadoras/genética , Animais , Células Cultivadas , Humanos , Concentração de Íons de Hidrogênio , Leucina/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Lisossomos/genética , Lisossomos/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/patologia , Mutação/genética , Interferência de RNA/fisiologia , RNA Mensageiro/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Frações Subcelulares/metabolismo , Frações Subcelulares/patologia , Fatores de Tempo , Vacúolos/metabolismo
19.
PLoS One ; 8(1): e53826, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23326516

RESUMO

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient's biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation.


Assuntos
Debilidade Muscular , Músculo Esquelético , Síndromes Miastênicas Congênitas , Junção Neuromuscular , Receptores Proteína Tirosina Quinases/genética , Receptores Colinérgicos/genética , Agrina/metabolismo , Animais , Criança , Células HEK293 , Humanos , Masculino , Camundongos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiopatologia , Mutação de Sentido Incorreto , Síndromes Miastênicas Congênitas/genética , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/fisiopatologia , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Junção Neuromuscular/fisiopatologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Colinérgicos/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Transmissão Sináptica/genética
20.
Brain Behav ; 3(4): 476-86, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24381816

RESUMO

The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM 1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM 1-mutations according to the "adjusted-age" at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM 1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.

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