RESUMO
Congenital myasthenic syndromes (CMS) associated with pathogenic variants in the DOK7 gene (DOK7-CMS) have phenotypic overlap with other neuromuscular disorders associated with limb-girdle muscular weakness (LGMW). Genetic analysis of the most common mutation (c.1124_1127dupTGCC) in DOK7 was performed in 34 patients with "unexplained" LGMW associated with non-specific changes in muscle biopsy. Of the 34 patients, one patient showed the DOK7 c.1124_1127dupTGCC variant in homozygousity. Our study estimates the minimum prevalence of undiagnosed DOK7-CMS to be 2.9% in southern Brazilian patients from our centre. Our data confirm that clinicians should look for DOK7-CMS patients when the clinical manifestation is an 'unexplained' LGMW, mainly if associated with non-specific changes in muscle biopsy.
Assuntos
Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação/genética , Síndromes Miastênicas Congênitas/diagnóstico , Síndromes Miastênicas Congênitas/genética , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Estudos de Coortes , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico , Debilidade Muscular/epidemiologia , Debilidade Muscular/genética , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Síndromes Miastênicas Congênitas/epidemiologia , Estudos Retrospectivos , Adulto JovemRESUMO
Mutations in the FKRP gene encoding the fukutin-related protein (FKRP) cause a wide spectrum of myopathies, ranging from severe forms of congenital muscular dystrophies associated with structural abnormalities of the central nervous system, to exertional myalgia or asymptomatic hyperCKemia, and to a form of limb girdle muscular dystrophy, LGMD-R9, (ex-LGMD-2I). LGMD-R9 is characterized by a proximal girdle deficit predominantly in the lower limbs to start with, with respiratory and cardiac damage that may affect the vital prognosis. Serum CK levels are markedly elevated and, on muscle biopsy, is detected a dystrophic formula associated with a reduction in the glycosylation of α-dystroglycan by immunostains and immunoblotting. Muscle MRI typically shows damage to proximal muscles (iliopsoas, adductors, gluteus maximus, quadriceps) with relative preservation of the muscles of the anterior compartment of the thighs (gracilis and sartorius). Genetic analysis, by specific sequencing of the FKRP gene or of a panel grouping together all the genes involved in the glycosylation of α-dystroglycan, or a larger panel of genes, generally confirms the diagnosis, the most frequent mutation being the missense p.(Leu276Ile). Currently, treatment of LGMD-R9 is symptomatic, requiring a multidisciplinary approach. A prospective study of the natural history of the disease is currently underway in Europe (GNT-015-FKRP). New therapeutic approaches are envisaged, such as gene therapy mediated by vectors derived from the adeno-associated virus (AAV). This is effective in animal models, allowing correction of defects in the glycosylation of alpha-dystroglycan and an increase in its binding capacity to the extracellular matrix. At the same time, preclinical studies have shown, in an animal model, the efficacy of ribitol, an alcohol pentose found in natural compounds, which has led to a phase I trial whose clinical development is underway.
TITLE: La dystrophie musculaire des ceintures de type R9 liée au gène FKRP - État des lieux et perspectives thérapeutiques. ABSTRACT: Les mutations du gène FKRP codant la fukutin-related protein (FKRP) sont à l'origine d'un large éventail de myopathies allant de formes sévères de dystrophies musculaires congénitales associées à des anomalies structurales du système nerveux central, jusqu'à des tableaux de myalgies à l'effort ou d'hyperCKémie asymptomatique, en passant par une forme de dystrophie musculaire des ceintures, la LGMD-R9 (ex-LGMD-2I), pour limb girdle muscular dystrophy récessive de type R9. La LGMD-R9 se caractérise par un déficit proximal des ceintures prédominant initialement aux membres inférieurs, avec une atteinte respiratoire et cardiaque pouvant conditionner le pronostic vital. Le taux sérique de CPK est nettement élevé et s'accompagne, sur la biopsie musculaire, d'une formule dystrophique associée à une réduction de la glycosylation de l'α-dystroglycane visible en immunomarquage et par immunoblot. L'IRM musculaire montre typiquement une atteinte des muscles proximaux (iliopsoas, adducteurs, grands fessiers, quadriceps) avec une relative préservation des muscles de la loge antérieure des cuisses (gracilis et sartorius). L'analyse génétique, par séquençage spécifique du gène FKRP ou d'un panel regroupant l'ensemble des gènes impliqués dans la glycosylation de l'α-dystroglycane, ou bien d'un panel plus large de gènes, confirme généralement le diagnostic, la mutation la plus fréquente étant le faux-sens p.(Leu276Ile). Actuellement, le traitement de la LGMD-R9 est symptomatique, requérant une approche pluridisciplinaire. Une étude prospective d'histoire naturelle de la maladie est en cours en Europe (GNT-015-FKRP). Des approches thérapeutiques inédites sont envisagées, telles que la thérapie génique médiée par des vecteurs dérivés du virus adéno-associé (AAV). Celle-ci est efficace dans les modèles animaux, permettant une correction des défauts de glycosylation de l'a-dystroglycane et une augmentation de sa capacité de liaison à la matrice extracellulaire. En parallèle, des études précliniques ont montré, dans un modèle animal, l'efficacité du ribitol, un pentose alcool retrouvé dans des composés naturels, ce qui a conduit à un essai de phase I dont le développement clinique est en cours.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/terapia , Pentosiltransferases/genética , Animais , Diagnóstico Diferencial , Humanos , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Mutação de Sentido Incorreto , Ribitol/uso terapêutico , Terapias em Estudo/métodos , Terapias em Estudo/tendênciasRESUMO
Limb-girdle muscular dystrophy (LGMD) type 2A (calpainopathy) is an autosomal recessive disease caused by mutation in the CAPN3 gene. The aim of this study was to examine genetic and phenotypic features of Serbian patients with calpainopathy. The study comprised 19 patients with genetically confirmed calpainopathy diagnosed at the Neurology Clinic, Clinical Center of Serbia and the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia during a ten-year period. Eighteen patients in this cohort had c.550delA mutation, with nine of them being homozygous. In majority of the patients, disease started in childhood or early adulthood. The disease affected shoulder girdle - upper arm and pelvic girdle - thigh muscles with similar frequency, with muscles of lower extremities being more severely impaired. Facial and bulbar muscles were spared. All patients in this cohort, except two, remained ambulant. None of the patients had cardiomyopathy, while 21% showed mild conduction defects. Respiratory function was mildly impaired in 21% of patients. Standard muscle histopathology showed myopathic and dystrophic pattern. In conclusion, the majority of Serbian LGMD2A patients have the same mutation and similar phenotype.
Assuntos
Calpaína/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idade de Início , Alelos , Biópsia , Criança , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mutação , Fenótipo , Sérvia/epidemiologiaRESUMO
In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10-6 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.
Assuntos
Predisposição Genética para Doença , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Alelos , Biomarcadores , Biópsia , Feminino , Estudos de Associação Genética , Humanos , Masculino , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Países Baixos/epidemiologia , Fenótipo , Vigilância da População , Estudos RetrospectivosRESUMO
Objective: To determine the prevalence and clinical features of anti-HMGCR myopathy among patients with presumed limb-girdle muscular dystrophy (LGMD) in whom genetic testing has failed to elucidate causative mutations. Methods: Patients with presumed LGMD and unrevealing genetic testing were selected based on a few clinico-pathologic features and tested for anti-HMGCR autoantibodies (n = 11). These clinico-pathologic features are peak creatine kinase (CK) greater than 1,000 IU/L and at least 3 of the following features: (1) limb-girdle pattern of weakness, (2) selective involvement of posterior thigh on clinical examination or muscle imaging, (3) dystrophic changes on muscle biopsy, and (4) no family history of muscular dystrophy. Results: Six patients tested positive for anti-HMGCR autoantibodies. In 4, there was a presymptomatic phase, lasting as long as 10 years, characterized by elevated CK levels without weakness. Muscle biopsies revealed variable degrees of a dystrophic pathology without prominent inflammation. In an independent cohort of patients with anti-HMGCR myopathy, 17 of 51 (â¼33%) patients were initially presumed to have a form of LGMD based on clinico-pathologic features but were ultimately found to have anti-HMGCR myopathy. Most of these patients responded favorably to immunomodulatory therapies, evidenced by reduction of CK levels and improved strength. Conclusions: Anti-HMGCR myopathy can resemble LGMD. Diagnosis of patients with a LGMD-like presentation of anti-HMGCR myopathy is critical because these patients may respond favorably to immunotherapy, especially those with shorter disease duration.
Assuntos
Hidroximetilglutaril-CoA Redutases/imunologia , Doenças Musculares/diagnóstico , Doenças Musculares/imunologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/epidemiologiaRESUMO
Limb-girdle muscular dystrophies (LGMDs) are a highly heterogeneous group of neuromuscular disorders that are associated with weakness and wasting of muscles in legs and arms. Signs and symptoms may begin at any age and usually worsen by time. LGMDs are autosomal disorders with different types and their prevalence is not the same in different areas. New technologies such as next-generation sequencing can accelerate their diagnosis. Several important pathological mechanisms that are involved in the pathology of the LGMD include abnormalities in dystrophin-glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions. Here, we provide a comprehensive review that integrates LGMD clinical manifestations, prevalence, and some pathological mechanisms involved in LGMDs.
Assuntos
Caquexia/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Doenças Neuromusculares/genética , Sarcômeros/genética , Caquexia/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Sarcômeros/metabolismoRESUMO
The aim of this study is to analyze the epidemiology of the clinical and genetic features of childhood-onset limb-girdle muscular dystrophies (LGMD) in the Aegean part of Turkey. In total fifty-six pediatric cases with LGMD followed in four different pediatric neurology departments in the Aegean region of Turkey were evaluated. Among them, LGMD2C was the most common followed by LGMD2A, LGMD2D, and LGMD2F with equal frequencies. In twenty-eight patients (50%) the diagnosis could be confirmed by genetic analysis, where SGCG proved to be disease-causing in most of the cases. About half of the patients were diagnosed with whole exome or targeted gene sequencing. A positive correlation between muscle biopsy and genetic findings were observed in 11% of the patients. We report one novel frameshifting mutation in TTN. Knowledge on frequencies of childhood-onset limb-girdle muscular dystrophies and related genes in Turkey will lead to a prompt diagnosis of these neuromuscular disorders.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Idade de Início , Biópsia , Calpaína/genética , Criança , Pré-Escolar , Conectina/genética , Feminino , Testes Genéticos , Humanos , Lactente , Lamina Tipo A/genética , Masculino , Manosiltransferases/genética , Proteínas dos Microfilamentos , Proteínas Musculares/genética , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/complicações , Distrofia Muscular do Cíngulo dos Membros/patologia , Sarcoglicanopatias/epidemiologia , Sarcoglicanopatias/genética , Sarcoglicanas/genética , Turquia/epidemiologiaRESUMO
Limb-Girdle Muscular Dystrophy type 2 (LGMD2) is a group of autosomally recessive inherited disorders defined by weakness and wasting of the shoulder and pelvic girdle muscles. In the past, several population isolates with high incidence of LGMD2 arising from founder mutation effects have been identified. The aim of this work is to describe the results of clinical, epidemiologic, and molecular studies performed in a Mexican village segregating numerous cases of LGMD2. A population census was conducted in the village to identify all LGMD affected patients. Molecular analysis included genome wide homozygosity mapping using a 250K SNP Affymetrix microarray followed by PCR amplification and direct nucleotide sequencing of the candidate gene. In addition, DNA from 401 randomly selected unaffected villagers was analyzed to establish the carrier frequency of the LGMD2 causal mutation. A total of 32 LGMD2 patients were identified in the village, rendering a disease prevalence of 4.3 (CI: 2.9-5.9) cases per 1,000 habitants (1 in 232). Genome wide homozygosity mapping revealed that affected individuals shared a 6.6 Mb region of homozygosity at chromosome 15q15. The identified homozygous interval contained CAPN3, the gene responsible for LGMD2 type A (LGMD2A). Direct sequencing of this gene revealed homozygosity for a novel c.348C>A mutation (p.Ala116Asp) in DNA from all 20 affected subjects available for genetic screening, except one which was heterozygous for the mutation. In such patient, a heterozygous c.2362AG>TCATCT deletion/insertion was recognized as the second CAPN3 mutation. Western blot and autocatalytic activity analyses in protein lysates from skeletal muscle biopsy obtained from a p.Ala116Asp homozygous patient suggested that this particular mutation increased the autocatalytic activity of CAPN3. Thirty eigth heterozygotes of the p.Ala116Asp mutation were identified among 401 genotyped unaffected villagers, yielding a population carrier frequency of 1 in 11. This study demonstrates that a cluster of patients with LGMD2A in a small Mexican village arises from a novel CAPN3 founder mutation. Evidence of allelic heterogeneity is demonstrated by the recognition of an additional CAPN3 mutation in a single affected. Our study provides an additional example of genetic isolation causing a high prevalence of LGMD and of successful molecular characterization of the disease by means of homozygosity mapping. The identification of a very high carrier frequency of the LGMD2-causing mutation has implications for more rational genetic counseling in this community.
Assuntos
Calpaína/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Efeito Fundador , Heterozigoto , Homozigoto , Humanos , Mutação INDEL , Lactente , Recém-Nascido , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Epidemiologia Molecular , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Polimorfismo de Nucleotídeo Único , Prevalência , Adulto JovemRESUMO
Peripheral and tissue eosinophilia can be a prominent feature of several unique rheumatologic and vascular diseases. These diseases span a wide range of clinical features, histologic findings, therapeutic approaches, and outcomes. Despite the rare nature of these entities--which makes large-scale studies challenging--knowledge has continued to grow regarding their epidemiology, pathophysiology, and management. This review compares and contrasts 5 rheumatologic and vascular conditions in which eosinophilia can be seen: eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin G4-related disease, diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, and eosinophilic myositis.
Assuntos
Síndrome de Churg-Strauss/patologia , Síndrome de Eosinofilia-Mialgia/patologia , Eosinofilia/patologia , Eosinófilos/patologia , Fasciite/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Artrite Reumatoide/patologia , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/epidemiologia , Síndrome de Churg-Strauss/terapia , Eosinofilia/diagnóstico , Eosinofilia/epidemiologia , Eosinofilia/terapia , Síndrome de Eosinofilia-Mialgia/diagnóstico , Síndrome de Eosinofilia-Mialgia/epidemiologia , Síndrome de Eosinofilia-Mialgia/terapia , Fasciite/diagnóstico , Fasciite/epidemiologia , Fasciite/terapia , Humanos , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/terapia , Triptofano/metabolismoAssuntos
Erros de Diagnóstico , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Polimiosite/diagnóstico , Adulto , Idade de Início , Biópsia , Disferlina , Eletromiografia , Feminino , Genes Recessivos , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação de Sentido Incorreto , Fenótipo , Mutação PuntualRESUMO
OBJECTIVE: We describe the characteristic features of 11 patients (6 men and 5 women) with dysferlinopathies confirmed by muscle biopsies. In addition, we aimed to provide a realistic comprehensive picture of the severe muscle diseases in the Aegean Region of Turkey. MATERIAL AND METHOD: We retrospectively reviewed 90 patients who underwent muscle biopsy examinations between 2008 and 2011 in the pathology laboratory of Izmir Dr.Behcet Uz Children's Hospital. Biopsy specimens of all patients clinically diagnosed as muscular dystrophy referred from 4 different centers of neurological disorders were collected. RESULTS: Dystrophinopathy was the most (n=45) and gammasarcoglycanopathy was the second common (n=13) muscular dystrophy in this series. The mean age of all 90 patients was 8.8 years (3 months- 64 years). Only 14 cases (15.5%) were older than 14, and 23 cases were younger than two years. Dysferlinopathy was the most common dystrophy in the older age group. There were statistical significant differences between the types of dystrophy and inflammation (0.021), creatine kinase levels (p= 0.001), age (p=0.001), and gender (p < 0.001) of the patients. CONCLUSION: The present study revealed that dysferlinopathies is not an uncommon form of muscular dystrophies in western Turkey. We have concluded that if avoidance from unnecessary therapeutic interventions is desired, we must be aware of the relative frequencies of dysferlinopathies.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Prevalência , Estudos Retrospectivos , Fatores Sexuais , Turquia/epidemiologia , Adulto JovemRESUMO
Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene. Seventeen mutations were novel; the majority of mutations were small deletions/insertions, and no mutational hotspots were identified. Sixty-one per cent of patients (22 patients) initially presented with limb girdle muscular dystrophy 2B, 31% (11 patients) with a Miyoshi phenotype, one patient with proximodistal mode of onset, one patient with muscle stiffness after exercise and one patient as a symptomatic carrier. A wider range of age of onset was noted than previously reported, with 25% of patients having first symptoms before the age of 13 years. Independent of the initial mode of presentation, in our cohort of patients the gastrocnemius muscle was the most severely affected muscle leading to an inability to stand on tiptoes, and lower limbs were affected more severely than upper limbs. As previous anecdotal evidence on patients affected by dysferlinopathy suggests good muscle prowess before onset of symptoms, we also investigated pre-symptomatic fitness levels of the patients. Fifty-three per cent of the patients were very active and sporty before the onset of symptoms which makes the clinical course of dysferlinopathy unusual within the different forms of muscular dystrophy and provides a challenge to understanding the underlying pathomechanisms in this disease.
Assuntos
Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas Musculares/deficiência , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Adolescente , Adulto , Idade de Início , Idoso , Criança , Creatina Quinase/metabolismo , Análise Mutacional de DNA , Disferlina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Mutação , Fenótipo , Aptidão FísicaRESUMO
OBJECTIVE: To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD). DESIGN: Prospective screening. SETTING: Neuromuscular Clinic and Department of Cardiology at Rigshospitalet. Patients One hundred one patients with LGMD2A-I and BMD and 29 patients with LGMD2 and no molecular diagnosis. MAIN OUTCOME MEASURES: Clinical investigation, echocardiography, and electrocardiographic findings. RESULTS: Cardiac involvement was present in 24 of 100 patients (24%) with LGMD2A-I and in 14 of 30 patients (47%) with BMD. Only a few patients with LGMD2A and unclassified LGMD2 had mild cardiac involvement, whereas 29% and 67% of patients with LGMD2I and LGMD2E, respectively, had cardiac involvement. Cardiac involvement was not correlated with age, muscle strength, or the level of dystrophic changes on muscle biopsy. CONCLUSIONS: This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement.
Assuntos
Doenças Cardiovasculares/complicações , Distrofia Muscular do Cíngulo dos Membros/complicações , Distrofia Muscular de Duchenne/complicações , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/patologia , Estudos ProspectivosRESUMO
BACKGROUND: There are few reports describing the coexistence of dystrophic features with those typical of mitochondrial myopathies in muscle biopsy. A recent study suggested that dystrophic features are frequent in patients with chronic progressive external ophthalmoplegia (CPEO) with a high mutation load, but the actual frequency of these abnormalities in CPEO remains undetermined. OBJECTIVE: To review the occurrence of dystrophic abnormalities in a large series of patients with CPEO to assess the frequency of such abnormalities and to verify whether they are correlated with specific mitochondrial DNA (mtDNA) mutations. METHODS: Retrospective survey of case series (86 patients with CPEO). RESULTS: Only three cases with dystrophic abnormalities were found: two with a large scale mtDNA deletion and one with the A3251G mutation. All three patients showed predominantly proximal muscular weakness resembling limb girdle muscular dystrophy. CONCLUSIONS: Dystrophic abnormalities are rare in CPEO and are not correlated with a specific molecular defect.
Assuntos
Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Oftalmoplegia Externa Progressiva Crônica/epidemiologia , Adulto , Biópsia , Creatina Quinase/sangue , DNA Mitocondrial/genética , Feminino , Expressão Gênica/genética , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Mutação Puntual/genética , Polimorfismo de Fragmento de Restrição , Estudos RetrospectivosRESUMO
Limb girdle muscular dystrophies (LGMDs) are a genetically heterogeneous group of primary myopathies involving progressive weakness and wasting of the muscles in the hip and shoulder girdles, with distal spread to the bulbar or respiratory musculature in rare cases. Depending on the mode of genetic transmission, six autosomal dominant forms (LGMD1A-F, 10-25%) and ten autosomal recessive forms (LGMD2A-J, 75-90%) are currently known. The prevalence of LGMDs is 0.8/100,000. These conditions are caused by mutations in genes encoding for myotilin (5q31, LGMD1A), lamin A/C (1q11-q21.2, LGMD1B), caveolin-3 (3p25, LGMD1C), unknown proteins (7q, LGMD1D, 6q23, LGMD1E, 7q32.1-32.2., LGMD1F), calpain-3 (15q15.1-21.1, LGMD2A), dysferlin (2p13.3-13.1, LGMD2B), gamma-sarcoglycan (13q12, LGMD2C), alpha-sarcoglycan, also known as adhalin (17q12-q21.3, LGMD2D), beta-sarcoglycan (4q12, LGMD2E), delta-sarcoglycan (5q33-q34, LGMD2F), telethonin (17q11-q12, LGMD2G), E3-ubiquitin ligase (9q31-q34.1, LGMD2H), fukutin-related protein (19q13.3, LGMD2I), and titin (2q31, LGMD2J). Cardiac involvement has been described for LGMD1B-E, LGMD2C-G, and LGMD2I. The time of onset varies between early childhood and middle age. There is no male or female preponderance. Disease progression and life expectancy vary widely, even among different members of the same family. The diagnosis is based primarily on DNA analysis. The history, clinical neurological examinations, blood chemistry investigations, electromyography, and muscle biopsy also provide information that is helpful for the diagnosis. No causal therapy is currently available.