RESUMO
BACKGROUND AND OBJECTIVES: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases. METHODS: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network. RESULTS: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course. DISCUSSION: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.
Assuntos
Miopatias Distais , Miopatias Congênitas Estruturais , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Itália , Adulto , Miopatias Distais/genética , Miopatias Distais/patologia , Miopatias Distais/epidemiologia , Estudos Retrospectivos , Idoso , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologiaRESUMO
Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG ⢠CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG ⢠CCG repeat motif and a specific pattern of muscle weakness.
Assuntos
Músculo Esquelético , Expansão das Repetições de Trinucleotídeos , População Branca , Humanos , Masculino , Feminino , Adulto , Expansão das Repetições de Trinucleotídeos/genética , Pessoa de Meia-Idade , População Branca/genética , Músculo Esquelético/patologia , Transportadores de Cassetes de Ligação de ATP/genética , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Linhagem , Idoso , Adulto Jovem , Fibroblastos/metabolismo , Fibroblastos/patologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Adolescente , Distrofias MuscularesRESUMO
BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system. METHODS: Data from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old. RESULTS: Of 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM. CONCLUSION: In this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support.
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Miopatias Congênitas Estruturais , Humanos , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/patologia , Masculino , Brasil , Criança , Adolescente , Pré-Escolar , Lactente , Atenção à Saúde , Feminino , Adulto Jovem , AdultoRESUMO
BACKGROUND: Congenital myopathies are a clinical, histopathological and genetic heterogeneous group of inherited muscle disorders that are defined on peculiar architectural abnormalities in the muscle fibres. Although there have been at least 33 different genetic causes of the disease, a significant percentage of congenital myopathies remain genetically unresolved. The present study aimed to report a novel TUBA4A variant in two unrelated Chinese patients with sporadic congenital myopathy. METHODS: A comprehensive strategy combining laser capture microdissection, proteomics and whole-exome sequencing was performed to identify the candidate genes. In addition, the available clinical data, myopathological changes, the findings of electrophysiological examinations and thigh muscle MRIs were also reviewed. A cellular model was established to assess the pathogenicity of the TUBA4A variant. RESULTS: We identified a recurrent novel heterozygous de novo c.679C>T (p.L227F) variant in the TUBA4A (NM_006000), encoding tubulin alpha-4A, in two unrelated patients with clinicopathologically diagnosed sporadic congenital myopathy. The prominent myopathological changes in both patients were muscle fibres with focal myofibrillar disorganisation and rimmed vacuoles. Immunofluorescence showed ubiquitin-positive TUBA4A protein aggregates in the muscle fibres with rimmed vacuoles. Overexpression of the L227F mutant TUBA4A resulted in cytoplasmic aggregates which colocalised with ubiquitin in cellular model. CONCLUSION: Our findings expanded the phenotypic and genetic manifestations of TUBA4A as well as tubulinopathies, and added a new type of congenital myopathy to be taken into consideration in the differential diagnosis.
Assuntos
Miopatias Congênitas Estruturais , Tubulina (Proteína) , Adulto , Feminino , Humanos , Masculino , Sequenciamento do Exoma , Músculo Esquelético/patologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Mutação , Miofibrilas/patologia , Miofibrilas/genética , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Miotonia Congênita/genética , Miotonia Congênita/patologia , Linhagem , Tubulina (Proteína)/genéticaRESUMO
Tubular aggregate myopathies comprise a rare group of disorders with characteristic pathological findings and heterogeneous phenotypes, including myasthenic syndrome. We describe a patient with tubular aggregate myopathy who presented with fatiguable weakness improving with pyridostigmine, respiratory involvement and possible cardiac manifestations. We highlight the utility of muscle biopsy in atypical myasthenic syndrome.
Assuntos
Doenças Autoimunes , Miopatias Congênitas Estruturais , Humanos , Músculo Esquelético/patologia , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , FenótipoRESUMO
BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).
Assuntos
Músculo Esquelético , Miopatias Congênitas Estruturais , Masculino , Lactente , Humanos , Músculo Esquelético/patologia , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Debilidade Muscular , Força Muscular , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/terapia , Miopatias Congênitas Estruturais/patologiaRESUMO
Autosomal dominant centronuclear myopathy (AD-CNM) is a rare congenital myopathy characterized by muscle weakness and centrally located nuclei in muscle fibers in the absence of any regeneration. AD-CNM is due to mutations in the DNM2 gene encoding dynamin 2 (DNM2), a large GTPase involved in intracellular membrane trafficking and a regulator of actin and microtubule cytoskeletons. DNM2 mutations are associated with a broad clinical spectrum ranging from severe neonatal to less severe late-onset forms. The histopathological signature includes nuclear centralization, predominance and atrophy of type 1 myofibers and radiating sarcoplasmic strands. To explain the muscle dysfunction, several pathophysiological mechanisms affecting key mechanisms of muscle homeostasis have been identified. They include defects in excitation-contraction coupling, muscle regeneration, mitochondria or autophagy. Several therapeutic approaches are under development by modulating the expression of DNM2 in a pan-allelic manner or by allele-specific silencing targeting only the mutated allele, which open the era of clinical trials for this pathology.
Title: La myopathie centronucléaire liée au gène de la dynamine 2. Abstract: La myopathie centronucléaire autosomique dominante (AD-CNM) est une myopathie congénitale rare caractérisée par une faiblesse musculaire et par la présence de noyaux centraux dans les fibres musculaires en absence de tout processus de régénération. L'AD-CNM est due à des mutations du gène DNM2 codant la dynamine 2 (DNM2), une volumineuse GTPase impliquée dans le trafic membranaire intracellulaire et un régulateur des cytosquelettes d'actine et de microtubules. Les mutations de la DNM2 sont associées à un large éventail clinique allant de formes sévères néonatales à des formes moins graves à début plus tardif. La signature histopathologique inclut une centralisation nucléaire, une prédominance et une atrophie des fibres lentes, ainsi que des travées sarcoplasmiques en rayons de roue. Pour expliquer la dysfonction musculaire, plusieurs mécanismes physiopathologiques affectant des étapes clés de l'homéostasie musculaire ont été identifiés. Ils incluent des défauts du couplage excitation-contraction, de la régénération musculaire, des mitochondries ou de l'autophagie. Plusieurs approches thérapeutiques sont en développement, en particulier la modulation de l'expression de la DNM2 pan-allélique ou ne ciblant que l'allèle muté, ouvrant ainsi la porte à des essais cliniques dans cette pathologie.
Assuntos
Músculo Esquelético , Miopatias Congênitas Estruturais , Humanos , Recém-Nascido , Dinamina II/genética , Dinamina II/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Mutação , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologiaRESUMO
Striated skeletal muscles are made of post-mitotic and multinucleated cells: muscle fibers, in which nuclei are regularly spaced and positioned at their periphery. The specific positioning of nuclei, necessary for the proper functioning of the muscle, is mainly regulated by the microtubule network and partner proteins. Many muscular pathologies present alterations in both the organization of the microtubule network and nuclear positioning, as observed in Duchenne Muscular Dystrophy, centronuclear myopathies or various neuromuscular diseases. The importance of the microtubule interactome and its influence in the maintenance of skeletal muscle homeostasis is a key issue in understanding muscle diseases.
Title: Réseau microtubulaire et fonctionnalité du muscle strié squelettique. Abstract: Les muscles striés squelettiques sont constitués de cellules post-mitotiques et multinucléées : les fibres musculaires, dans lesquelles les noyaux sont régulièrement espacés et positionnés à leur périphérie. Ce positionnement spécifique des noyaux, nécessaire au bon fonctionnement du muscle, est essentiellement régulé par le réseau microtubulaire et ses partenaires protéiques. De nombreuses pathologies musculaires présentent une altération à la fois de l'organisation du réseau microtubulaire et du positionnement nucléaire, comme observé dans la Dystrophie Musculaire de Duchenne, les myopathies centronucléaires ou certaines maladies neuromusculaires. L'importance de l'interactome microtubulaire et son influence dans le maintien de l'homéostasie du muscle strié squelettique est un enjeu capital dans la compréhension des pathologies musculaires.
Assuntos
Distrofia Muscular de Duchenne , Miopatias Congênitas Estruturais , Humanos , Músculo Esquelético/fisiologia , Fibras Musculares Esqueléticas/fisiologia , Distrofia Muscular de Duchenne/patologia , Núcleo Celular/metabolismo , Miopatias Congênitas Estruturais/patologiaRESUMO
Congenital myopathies are defined by early clinical onset, slow progression, hereditary nature and disease-specific myopathological lesions - however, with exceptions - demanding special techniques in regard to morphological diagnostic and research work-up. To identify an index disease in a family requires a muscle biopsy - and no congenital myopathy has ever been first described at autopsy. The nosographic history commenced when - in addition to special histopathological techniques in the earliest classical triad of central core disease, 1956, nemaline myopathy, 1963, and centronuclear myopathy, 1966/67, within a decade - electron microscopy and enzyme histochemistry were applied to unfixed frozen muscle tissue and, thus, revolutionized diagnostic and research myopathology. During the following years, the list of structure-defined congenital myopathies grew to some 40 conditions. Then, the introduction of immunohistochemistry allowed myopathological documentation of proteins and their abnormalities in individual congenital myopathies. Together with the diagnostic evolution of molecular genetics, many more congenital myopathies were described, without new disease-specific lesions or only already known ones. These were nosographically defined by individual mutations in hitherto congenital myopathies-unrelated genes. This latter development may also affect the nomenclature of congenital myopathies in that the mutant gene needs to be attached to the individually identified congenital myopathies with or without the disease-specific lesion, such as CCD-RYR1 or CM-RYR1. This principle is similar to that of the nomenclature of Congenital Disorders of Glycosylation. Retroactive molecular characterization of originally and first described congenital myopathies has only rarely been achieved.
Assuntos
Miopatias da Nemalina , Miopatias Congênitas Estruturais , Miopatia da Parte Central , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Miopatias Congênitas Estruturais/patologia , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Músculos/patologia , Miopatia da Parte Central/patologia , Mutação , Músculo Esquelético/patologiaRESUMO
Polyhydramnios can be caused by genetic defects at times. However, to establish an accurate diagnosis and provide a precise prenatal consultation in a given case is still a great challenge toward obstetricians. To uncover the genetic cause of polyhydramnios in the two consecutive pregnancies, we performed whole-exome sequencing of DNA for the second suffering fetuses, their parents, and targeted sanger sequencing of other members of this family. We discovered a hemizygous truncating variant in MTM1 gene, c.438_439 del (p. H146Q fs*10) in this Chinese family. In the light of the molecular discoveries, the fetus's clinical phenotype was considered to be a good fit for X-linked myotubular myopathy (XLMTM). There is no related research to the prenatal manifestations of MTM1-related XLMTM among Chinese population, and this is the first one to present. Though the etiology of polyhydramnios is complicated, WES may provide us with a creative avenue in prenatal diagnosis.
Assuntos
Miopatias Congênitas Estruturais , Poli-Hidrâmnios , Gravidez , Feminino , Humanos , Sequenciamento do Exoma , Poli-Hidrâmnios/diagnóstico por imagem , Poli-Hidrâmnios/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologiaRESUMO
Myo-inositol belongs to one of the sugar alcohol groups known as cyclitols. Phosphatidylinositols are one of the derivatives of Myo-inositol, and constitute important mediators in many intracellular processes such as cell growth, cell differentiation, receptor recycling, cytoskeletal organization, and membrane fusion. They also have even more functions that are essential for cell survival. Mutations in genes encoding phosphatidylinositols and their derivatives can lead to many disorders. This review aims to perform an in-depth analysis of these connections. Many authors emphasize the significant influence of phosphatidylinositols and phosphatidylinositols' phosphates in the pathogenesis of myotubular myopathies, neurodegenerative disorders, carcinogenesis, and other less frequently observed diseases. In our review, we have focused on three of the most often mentioned groups of disorders. Inositols are the topic of many studies, and yet, there are no clear results of successful clinical trials. Analysis of the available literature gives promising results and shows that further research is still needed.
Assuntos
Miopatias Congênitas Estruturais , Doenças Neurodegenerativas , Humanos , Fosfatidilinositóis/metabolismo , Inositol/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Carcinogênese/genética , Patrimônio Genético , Redes e Vias Metabólicas , Doenças Neurodegenerativas/genéticaRESUMO
X-linked myotubular myopathy (XLMTM) is a severe congenital disease characterized by profound muscle weakness, respiratory failure, and early death. No approved therapy for XLMTM is currently available. Adeno-associated virus (AAV)-mediated gene replacement therapy has shown promise as an investigational therapeutic strategy. We aimed to characterize the transcriptomic changes in muscle biopsies of individuals with XLMTM who received resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) in the ASPIRO clinical trial and to identify potential biomarkers that correlate with therapeutic outcome. We leveraged RNA-sequencing data from the muscle biopsies of 15 study participants and applied differential expression analysis, gene co-expression analysis, and machine learning to characterize the transcriptomic changes at baseline (pre-dose) and at 24 and 48 weeks after resamirigene bilparvovec dosing. As expected, MTM1 expression levels were significantly increased after dosing (p < 0.0001). Differential expression analysis identified upregulated genes after dosing that were enriched in several pathways, including lipid metabolism and inflammatory response pathways, and downregulated genes were enriched in cell-cell adhesion and muscle development pathways. Genes involved in inflammatory and immune pathways were differentially expressed between participants exhibiting ventilator support reduction of either greater or less than 6 h/day after gene therapy compared to pre-dosing. Co-expression analysis identified similarly regulated genes, which were grouped into modules. Finally, the machine learning model identified five genes, including MTM1, as potential RNA biomarkers to monitor the progress of AAV gene replacement therapy. These findings further extend our understanding of AAV-mediated gene therapy in individuals with XLMTM at the transcriptomic level.
Assuntos
Miopatias Congênitas Estruturais , Transcriptoma , Humanos , Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Terapia Genética , Músculo Esquelético/metabolismo , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/terapia , Miopatias Congênitas Estruturais/patologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , RNA/metabolismo , Transcriptoma/genéticaRESUMO
INTRODUCTION: Myotubular myopathy is a congenital muscle disease caused by a mutation in the myotubularin (MTM1) gene. The X-linked myotubular myopathy (XLMTM) affects males with early-onset symptoms such as muscle weakness, hypotonia, and respiratory distress. To our knowledge, cardiac involvement has not been previously described in this condition, in contrast to other types of congenital myopathies such as nemaline myopathy or core myopathy. CASE REPORTS: We report two clinical cases of XLMTM that started with severe sinus bradycardia or auriculoventricular block from the first days of life, with pathologic 24-hours Holter monitoring in both cases. A primary cardiac affection was excluded by electrophysiological studies and normal heart rate was recovered with proper respiratory support. DISCUSSION: These cases with sever bradyarrhythmia in a well know pathology such the XLMTM represents a nuance on the usual differential diagnostics of congenital myopathies.
TITLE: Arritmias en pacientes con miopatía miotubular ligada al cromosoma X.Introducción. La miopatía miotubular es una enfermedad muscular congénita causada por una mutación en el gen de la miotubularina (MTM1). La miopatía miotubular ligada al cromosoma X (XLMTM) afecta a los hombres con síntomas de aparición temprana como debilidad muscular, hipotonía y dificultad respiratoria. Hasta donde sabemos, la afectación cardíaca en estos pacientes no se ha descrito previamente, a diferencia de otros tipos de miopatías congénitas, como la miopatía nemalínica o la miopatía con cores. Casos clínicos. Presentamos dos casos clínicos de XLMTM que comenzaron con bradicardia sinusal grave o bloqueo auriculoventricular desde los primeros días de vida, con Holter patológico en ambos casos. Se descartó una afectación cardíaca primaria por estudios electrofisiológicos y se recuperó la frecuencia cardíaca normal con soporte respiratorio adecuado. Conclusión. Estos casos con bradicardia grave en una patología bien conocida, como la XLMTM, suponen un matiz en el diagnóstico diferencial habitual de las miopatías congénitas.
Assuntos
Miopatias da Nemalina , Miopatias Congênitas Estruturais , Masculino , Humanos , Mutação , Hipotonia Muscular , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Arritmias Cardíacas , Músculo Esquelético/patologiaRESUMO
X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and preliminarily in patients. However, 4 patients with XLMTM treated with gene therapy have died from progressive liver failure, and hepatobiliary disease has now been recognized more broadly in association with XLMTM. In an attempt to understand whether loss of MTM1 itself is associated with liver pathology, we have characterized what we believe to be a novel liver phenotype in a zebrafish model of this disease. Specifically, we found that loss-of-function mutations in mtm1 led to severe liver abnormalities including impaired bile flux, structural abnormalities of the bile canaliculus, and improper endosome-mediated trafficking of canalicular transporters. Using a reporter-tagged Mtm1 zebrafish line, we established localization of Mtm1 in the liver in association with Rab11, a marker of recycling endosomes, and canalicular transport proteins and demonstrated that hepatocyte-specific reexpression of Mtm1 could rescue the cholestatic phenotype. Last, we completed a targeted chemical screen and found that Dynasore, a dynamin-2 inhibitor, was able to partially restore bile flow and transporter localization to the canalicular membrane. In summary, we demonstrate, for the first time to our knowledge, liver abnormalities that were directly caused by MTM1 mutation in a preclinical model, thus establishing the critical framework for better understanding and comprehensive treatment of the human disease.
Assuntos
Miopatias Congênitas Estruturais , Peixe-Zebra , Animais , Humanos , Modelos Animais de Doenças , Proteínas de Membrana Transportadoras/metabolismo , Músculo Esquelético/metabolismo , Mutação , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/terapia , Miopatias Congênitas Estruturais/patologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
Congenital myopathies (CMs) are a group of diseases that primarily affect the muscle fiber, especially the contractile apparatus and the different components that condition its normal functioning. They present as muscle weakness and hypotonia at birth or during the first year of life. Centronuclear CM is characterized by a high incidence of nuclei located centrally and internally in muscle fibers. Clinical case: a 22-year-old male patient with symptoms of muscle weakness since early childhood, with difficulty in performing physical activity according to his age, with the presence of a long face, a waddling gait, and a global decrease in muscle mass. Electromyography was performed, showing a neurogenic pattern and not the expected myopathic one, neuroconduction with reduced amplitude of the motor potential of the peroneal nerve and axonal and myelin damage of the posterior tibial nerves. The microscopic study of the studied striated muscle fragments stained with hematoxylin-eosin and Masson's trichrome showed the presence of fibers with central nuclei, diagnosing CM. The patient meets most of the description for CM, with involvement of all striated muscles, although it is important to note the neurogenic pattern present in this case, due to the denervation of damaged muscle fibers, which contain terminal axonal segments. Neuroconduction shows the involvement of motor nerves, but with normal sensory studies, axonal polyneuropathy is unlikely, due to normal sensory potentials. Different pathological findings have been described depending on the mutated gene in this disease, but all coincide with the presence of fibers with central nuclei for diagnosis by this means, which is so important in institutions where it is not possible to carry out genetic studies, and allowing early specific treatment, according to the stage through which the patient passes.
Assuntos
Miopatias Congênitas Estruturais , Masculino , Recém-Nascido , Humanos , Pré-Escolar , Adulto Jovem , Adulto , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/patologia , Músculo Esquelético/patologia , Debilidade Muscular , EletromiografiaRESUMO
Pathogenic variants in the skeletal muscle α-actin 1 gene (ACTA1) cause a spectrum of myopathies with clinical and myopathological diversity. Clinical presentations occur from the prenatal period to adulthood, commonly with proximal-predominant weakness and rarely preferential distal weakness. Myopathological findings are wide-ranging, with nemaline rods being most frequent. Associated cardiomyopathy is rare and conduction defects are not reported. We describe a family with congenital myopathy with prominent finger flexor weakness and cardiomyopathy with cardiac conduction defects. The proband, a 48-year-old Caucasian male, his 73-year-old mother, 41-year-old sister, and 19-year-old nephew presented with prominent finger flexor weakness on a background of neonatal hypotonia and delayed motor milestones. All had progressive cardiomyopathy with systolic dysfunction and/or left ventricular dilation. The proband and sister had intraventricular conduction delay and left anterior fascicular block, respectively. The mother had atrial fibrillation. Muscle biopsy in the proband and sister demonstrated congenital fiber-type disproportion and rare nemaline rods in the proband. A novel dominant variant in ACTA1 (c.81C>A, p.Asp27Glu) segregated within the family. This family expands the genotypic and phenotypic spectrum of ACTA1-related myopathy, highlighting preferential finger flexor involvement with cardiomyopathy and conduction disease. We emphasize early and ongoing cardiac surveillance in ACTA1-related myopathy.
Assuntos
Cardiomiopatias , Miopatias da Nemalina , Miopatias Congênitas Estruturais , Adulto , Idoso , Feminino , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Actinas/genética , Doença do Sistema de Condução Cardíaco/complicações , Doença do Sistema de Condução Cardíaco/patologia , Cardiomiopatias/patologia , Mães , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Mutação , Miopatias da Nemalina/patologia , Miopatias Congênitas Estruturais/patologiaRESUMO
X-linked centronuclear myopathy is caused by pathogenic variants in the MTM1 gene, which encodes myotubularin, a phosphatidylinositol 3-phosphate (PI3P) phosphatase. This form of congenital myopathy predominantly affects males. This study presents a case of X-linked myotubular myopathy in a female carrier of a pathogenic c.1261-10A>G variant in the MTM1 gene.
Assuntos
Miopatias Congênitas Estruturais , Proteínas Tirosina Fosfatases não Receptoras , Feminino , Humanos , Masculino , Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Proteínas Tirosina Fosfatases não Receptoras/genéticaRESUMO
Myofibrillar myopathies (MFM) are a group of chronic muscle diseases pathophysiologically characterized by accumulation of protein aggregates and structural failure of muscle fibers. A subtype of MFM is caused by heterozygous mutations in the filamin C (FLNC) gene, exhibiting progressive muscle weakness, muscle structural alterations and intracellular protein accumulations. Here, we characterize in depth the pathogenicity of two novel truncating FLNc variants (p.Q1662X and p.Y2704X) and assess their distinct effect on FLNc stability and distribution as well as their impact on protein quality system (PQS) pathways. Both variants cause a slowly progressive myopathy with disease onset in adulthood, chronic myopathic alterations in muscle biopsy including the presence of intracellular protein aggregates. Our analyses revealed that p.Q1662X results in FLNc haploinsufficiency and p.Y2704X in a dominant-negative FLNc accumulation. Moreover, both protein-truncating variants cause different PQS alterations: p.Q1662X leads to an increase in expression of several genes involved in the ubiquitin-proteasome system (UPS) and the chaperone-assisted selective autophagy (CASA) system, whereas p.Y2704X results in increased abundance of proteins involved in UPS activation and autophagic buildup. We conclude that truncating FLNC variants might have different pathogenetic consequences and impair PQS function by diverse mechanisms and to varying extents. Further studies on a larger number of patients are necessary to confirm our observations.
Assuntos
Miopatias Congênitas Estruturais , Agregados Proteicos , Humanos , Filaminas/genética , Filaminas/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/metabolismo , Miopatias Congênitas Estruturais/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismoRESUMO
Phosphoinositides (PIs) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the MTM1 gene, which encodes the myotubularin phosphatidylinositol 3-phosphate (PtdIns3P) lipid phosphatase. No therapy for this disease is currently available. Previous studies showed that loss of expression of the class II phosphoinositide 3-kinase (PI3K) PI3KC2ß (PI3KC2B) protein improved the phenotypes of an XLCNM mouse model. PI3Ks are well known to have extensive scaffolding functions and the importance of the catalytic activity of this PI3K for rescue remains unclear. Here, using PI3KC2ß kinase-dead mice, we show that the selective inactivation of PI3KC2ß kinase activity is sufficient to fully prevent muscle atrophy and weakness, histopathology, and sarcomere and triad disorganization in Mtm1-knockout mice. This rescue correlates with normalization of PtdIns3P level and mTORC1 activity, a key regulator of protein synthesis and autophagy. Conversely, lack of PI3KC2ß kinase activity did not rescue the histopathology of the BIN1 autosomal CNM mouse model. Overall, these findings support the development of specific PI3KC2ß kinase inhibitors to cure myotubular myopathy.
Assuntos
Miopatias Congênitas Estruturais , Fosfatidilinositol 3-Quinases , Animais , Camundongos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositóis , Mutação , Camundongos Knockout , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologiaRESUMO
INTRODUCTION: X-linked myotubular myopathy is a rare centronuclear myopathy that affects approximately 1 in 50,000 male newborns caused by pathogenic variants in the myotubularin 1 gene (MTM1). The clinical severity varies, however the need for ventilatory support occurs almost invariably. CASE REPORT: We report the case of a 4-year-old boy presenting mild muscle hypotonia at 12 months-old, expressive language disorder, global developmental delay, and a sensory processing disorder. Clinical exome sequencing identified the hemizygous variant c.722G>A p.(Arg241His) in exon 9 of the myotubularin 1 gene (NM_000252.2). The mother is a heterozygous carrier of the same variant. A diagnosis of a mild form of maternal inherited X-linked myotubular myopathy was established. The child presented significant improvement with speech, occupational, and physical therapies, with no respiratory intercurrences or ventilator dependency. CONCLUSION: The presentation of a mild form of this myotubular myopathy, being less commonly reported, added challenge to the diagnosis. The combination of mild hypotonia, feeding difficulties and expressive language disorder should raise suspicion of a neuromuscular disease. There is a lack of verified motor or developmental scores specific to this myopathy to further determine prognosis and need of other therapies. While currently the severity myotubular myopathy is classified according to ventilator dependency, this may be insufficient and unapplicable to milder cases. There is an evident need for a grading system for mild and moderate cases assessing muscle weakness and fatigue, daily life limitations, motor developmental delay, early phenotypical scores, or recurrent respiratory infections.
TITLE: Miopatía miotubular ligada al cromosoma X: informe clínico y revisión del fenotipo leve.Introducción. La miopatía miotubular ligada al X es una miopatía centronuclear rara que afecta aproximadamente a 1 de cada 50.000 recién nacidos varones causada por variantes patógenas en el gen de la miotubularina 1 (MTM1). La gravedad clínica varía; sin embargo, la necesidad de soporte ventilatorio ocurre casi invariablemente. Caso clínico. Presentamos el caso de un niño de 4 años que presentaba hipotonía muscular leve a los 12 meses, trastorno del lenguaje expresivo, retraso global del desarrollo y trastorno del procesamiento sensorial. La secuenciación clínica del exoma identificó la variante hemicigótica c.722G>A p.(Arg241His) en el exón 9 del gen de la miotubularina 1 (NM_000252.2). La madre es portadora heterocigota de la misma variante. Se estableció el diagnóstico de una forma leve de miopatía miotubular ligada al cromosoma X de herencia materna. El niño presentó una mejoría significativa con terapias del habla, ocupacional y física, sin intercurrencias respiratorias ni dependencia de ventilador. Conclusión. La presentación de una forma leve de esta miopatía miotubular, al notificarse más raramente, añadió desafío al diagnóstico. La combinación de hipotonía leve, dificultades de alimentación y trastorno del lenguaje expresivo debe hacer sospechar una enfermedad neuromuscular. Se carece de puntuaciones motoras o de desarrollo verificadas específicas de esta miopatía para determinar el pronóstico y la necesidad de otras terapias. Aunque actualmente la gravedad de la miopatía miotubular se clasifica según la dependencia del ventilador, esto puede ser insuficiente e inaplicable a los casos más leves. Es evidente la necesidad de un sistema de clasificación para los casos leves y moderados que evalúe la debilidad muscular y la fatiga, las limitaciones de la vida diaria, el retraso del desarrollo motor, las puntuaciones fenotípicas tempranas o las infecciones respiratorias recurrentes.