RESUMO
BACKGROUND AND PURPOSE: To describe a large series of patients with α, ß, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. METHODS: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. RESULTS: One hundred patients (54 γ-SG; 41 α-SG; 5 ß-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and ß-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% ß-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. CONCLUSIONS: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.
Assuntos
Sarcoglicanopatias , Adolescente , Seguimentos , Homozigoto , Humanos , Músculo Esquelético , Estudos Retrospectivos , Sarcoglicanopatias/epidemiologia , Sarcoglicanopatias/genética , Sarcoglicanas/genéticaRESUMO
AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.
Assuntos
Calpaína/genética , Aberrações Cromossômicas , Proteínas Musculares/genética , Doenças Neuromusculares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Genes Dominantes/genética , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Adulto JovemRESUMO
AIMS: Previously, detection of ANO5 protein has been complicated by unspecific antibodies, most of which have not identified the correct protein. The aims of the study were to specify ANO5 protein expression in human skeletal muscle, and to investigate if the ANO5 protein levels are affected by different ANO5 mutations in anoctaminopathy patients. METHODS: Four different antibodies were tested for ANO5 specificity. A sample preparation method compatible with membrane proteins, combined with tissue fractionation was used to determine ANO5 expression in cell cultures expressing ANO5, in normal muscles and eight patient biopsies with six different ANO5 mutations in homozygous or compound heterozygous states, and in other dystrophies. RESULTS: Only one specific monoclonal N-terminal ANO5 antibody was efficient in detecting the protein, showing that ANO5 is expressed as a single 107 kD polypeptide in human skeletal muscle. The truncating mutations c.191dupA and c.1261C>T were found to abolish ANO5 expression, whereas the studied point mutations had variable effects; however, all the ANO5 mutations resulted in clearly reduced ANO5 expression in the patient muscle membrane fraction. Attempts to detect ANO5 using immunohistochemistry were not yet successful. CONCLUSIONS: The data presented here indicate that the ANO5 protein expression is decreased in ANO5-mutated muscular dystrophy and that most of the non-truncating pathogenic ANO5 mutations likely destabilize the protein and cause its degradation. The method described here allows direct analysis of human ANO5 protein, which can be used in diagnostics, for evaluating the pathogenicity of the potentially harmful ANO5 variants of uncertain significance.
Assuntos
Anoctaminas/análise , Anoctaminas/genética , Anoctaminas/metabolismo , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Anticorpos Monoclonais , Especificidade de Anticorpos , Western Blotting/métodos , Feminino , Humanos , Masculino , MutaçãoRESUMO
Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD). This is a Duchenne-like disease affecting both males and females first described in Tunisian families. Adhalin deficiency has been found in SCARMD patients from North Africa Europe, Brazil, Japan and North America (SLR & KPC, unpublished data). The disease was initially linked to an unidentified gene on chromosome 13 in families from North Africa, and to the adhalin gene itself on chromosome 17q in one French family in which missense mutations were identified. Thus there are two kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin (primary adhalinopathies), and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13. We have examined the importance of primary adhalinopathies among myopathies with adhalin deficiency, and describe several additional mutations (null and missense) in the adhalin gene in 10 new families from Europe and North Africa. Disease severity varies in age of onset and rate of progression, and patients with null mutations are the most severely affected.
Assuntos
Proteínas do Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Adolescente , Sequência de Bases , Criança , Pré-Escolar , Proteínas do Citoesqueleto/análise , Proteínas do Citoesqueleto/deficiência , Distrofina/análise , Distrofina/genética , Feminino , Genes Recessivos , Humanos , Masculino , Glicoproteínas de Membrana/análise , Glicoproteínas de Membrana/deficiência , Modelos Moleculares , Dados de Sequência Molecular , Mutação Puntual , Conformação Proteica , Sarcoglicanas , Índice de Gravidade de DoençaRESUMO
Miyoshi myopathy is the most common form of recessive distal myopathy. Recessive mutations in the ANO5 gene have been recently identified in Northern Europe as a cause of non dysferlin-linked distal myopathy and limb girdle muscular dystrophy. We report here the first French cases of anoctamin 5 myopathy in 2 brothers presenting with a Miyoshi-like pattern. Comparing these patients with 12 other cases from the literature shows that all cases share a homogeneous clinical pattern, characterized by initial calf muscles involvement. Asymmetric muscle atrophy often precedes weakness. In this setting, high CK level and normal expression of dysferlin in muscle should lead to consider the diagnosis, which will be confirmed by ANO5 gene testing. The c.191dupA mutation, already reported as a founder mutation in Caucasian patients with anoctamin myopathies, was found in our family in a heterozygous state.
Assuntos
Canais de Cloreto/genética , Miopatias Distais/genética , Atrofia Muscular/genética , Mutação , Adulto , Anoctaminas , Miopatias Distais/diagnóstico , Heterozigoto , Humanos , Masculino , Atrofia Muscular/diagnóstico , Mutação/fisiologia , Linhagem , IrmãosRESUMO
It has been hypothesized that the tight localization of dystrophin at the muscle membrane is carried out by its cysteine-rich and/or carboxyl domains. We report the results of biochemical and immunocytochemical investigations of dystrophin in muscle from a 1-yr-old patient with a large deletion that removes the distal part of the dystrophin gene, thus spanning the exons coding for the cysteine-rich and the carboxy-terminal domains, and extends beyond the glycerol kinase and congenital adrenal hypoplasia genes. Immunological analysis of muscle dystrophin shows that the deletion results in the production of a truncated, but stable, polypeptide correctly localized at the sarcolemma. These data indicate that neither the cysteine-rich domain, nor the carboxyl domain, are necessary for the appearance of normal dystrophin sarcolemmal localization.
Assuntos
Distrofina/análise , Distrofias Musculares/metabolismo , Sarcolema/química , Cisteína/análise , Distrofina/genética , Humanos , Lactente , Masculino , Modelos QuímicosRESUMO
The absence of dystrophin causes the drastic reduction of the dystrophin-associated proteins (DAPs) in the sarcolemma and the loss of the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in Duchenne muscular dystrophy (DMD) skeletal muscle. Here, we report a mild reduction of the DAPs in the unique Becker muscular dystrophy patients with huge deletions in the rod domain of dystrophin and a moderate reduction of the DAPs in patients with huge deletions that involve both the NH2-terminal and rod domains of dystrophin. The phenotype of the latter patients was more severe than that of the former. In both cases, however, the reduction in the DAPs was milder than in typical DMD patients or DMD patients lacking the COOH-terminal domains of dystrophin. Our results suggest that (a) the NH2-terminal and rod domains of dystrophin may not be essential for the interaction with the sarcolemmal glycoprotein complex; and (b) defects in the actin binding activity of dystrophin may cause disruption of the anchorage of the dystrophin-glycoprotein complex to the subsarcolemmal cytoskeleton, which may render muscle fibers susceptible to degeneration.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Distrofina/genética , Proteínas de Membrana , Músculos/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Deleção de Sequência , Adolescente , Adulto , Biópsia , Criança , Pré-Escolar , Proteínas do Citoesqueleto/análise , Distrofina/metabolismo , Éxons , Feminino , Ligação Genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Peso Molecular , Músculos/patologia , Distrofias Musculares/patologia , UtrofinaRESUMO
Becker's muscular dystrophy is an X-linked hereditary disorder characterised by progressive muscle weakness and possible cardiac disease. Cardiac involvement is assumed to be rare in young patients. Early diagnosis could lead to earlier treatment at an infra-clinical stage of the disease. The object of the study was to evaluate systolic and diastolic cardiac function of young patients with Becker's disease by echocardiography and using Doppler tissue imaging. Consecutive patients under 20 years of age with Becker's disease confirmed genetically were included and compared with paired normal subjects. Subendocardial and subepicardial myocardial velocities were obtained by Doppler tissue imaging and the corresponding velocity gradients were measured. Twelve patients were included (17.4 +/- 2.5 years). None of them had disabling muscle disease. No significant difference was observed from normal subjects with respect to: ventricular dimensions, wall thickness, fractional shortening, E/A ratio measured by transmitral Doppler. Nevertheless, patients with Becker's disease had lower systolic and diastolic intra-myocardial velocity gradients: 2.2 +/- 1.1 vs. 4.7 +/- 2.4 s(-1), p = 0.006, and 3.6 +/- 2.0 vs. 5.6 +/- 1.3 s(-1), p = 0.048, respectively, compared with the control group. These results show that myocardial disease is possible in patients with Becker's muscular dystrophy under the age of 20. Myocardial Doppler tissue imaging is a sensitive method for detecting these early abnormalities and should be recommended in the young patients.
Assuntos
Cardiomiopatias/diagnóstico , Ecocardiografia Doppler , Distrofia Muscular de Duchenne/complicações , Adolescente , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Cardiomiopatias/diagnóstico por imagem , Estudos de Casos e Controles , Diagnóstico Precoce , Ecocardiografia , Eletrocardiografia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Contração Miocárdica/fisiologia , Estudos Prospectivos , Ventriculografia com Radionuclídeos , Volume Sistólico/fisiologiaAssuntos
Calpaína/genética , Eosinofilia/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Miosite/genética , Adulto , Criança , Pré-Escolar , Eosinofilia/diagnóstico , Eosinófilos/patologia , Feminino , Humanos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Miosite/diagnósticoRESUMO
We present here the clinical, molecular and biochemical findings from 238 limb-girdle muscular dystrophy type 2A (LGMD2A) patients, representing approximately 50% (238 out of 484) of the suspected calpainopathy cases referred for the molecular study of the calpain 3 (CAPN3) gene. The mean age at onset of LGMD2A patients was approximately 14 years, and the first symptoms occurred between 6 and 18 years of age in 71% of patients. The mean age at which the patients became wheelchair bound was 32.2 years, with 84% requiring the use of a wheelchair between the age of 21 and 40 years. There was no correlation between the age at onset and the time at which the patient became wheelchair bound, nor between the sex of the patient and the risk of becoming wheelchair bound. Of the cases where the CAPN3 gene was not affected, approximately 20% were diagnosed as LGMD2I muscular dystrophy, while facioscapulohumeral muscular dystrophy (FSHD) was uncommon in this sample. We identified 105 different mutations in the CAPN3 gene of which 50 have not been described previously. These were distributed throughout the coding region of the gene, although some exons remained free of mutations. The most frequent mutation was 2362AG-->TCATCT (exon 22), which was present in 30.7% of the chromosomes analysed (146 chromosomes). Other recurrent mutations described were N50S, 550DeltaA, G222R, IVS6-1G-->A, A483D, IVS17+1G-->T, 2069-2070DeltaAC, R748Q and R748X, each of which was found in >5 chromosomes. The type of mutation in the CAPN3 gene does not appear to be a risk factor for becoming dependent on a wheelchair at a determined age. However, in the cases with two null mutations, there were significantly fewer patients that were able to walk than in the group of patients with at least one missense mutation. Despite the fact that the results of phenotyping and western blot might be biased due to multiple referral centres, producing a diagnosis on the basis of the classical phenotype is neither sufficiently sensitive (86.7%) nor specific (69.3%), although western blot proved to be even less sensitive (52.5%) yet more specific (87.8%). In this case LGMD2I was a relevant cause of false-positive diagnoses. Considering both the clinical phenotype and the biochemical information together, the probability of correctly diagnosing a calpainopathy is very high (90.8%). However, if one of the analyses is lacking, the probability varies from 78.3 to 73.7% depending on the information available. When both tests are negative, the probability that the sample comes from a patient with LGMD2A was 12.2%.
Assuntos
Calpaína/genética , Isoenzimas/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Idade de Início , Teorema de Bayes , Western Blotting , Criança , Análise Mutacional de DNA/métodos , Progressão da Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/epidemiologia , Mutação de Sentido Incorreto , Fenótipo , Estudos RetrospectivosRESUMO
OBJECTIVE: In this study, muscle involvement assessed by MRI and levels of GMPPB and glycosylation of α-dystroglycan expression in muscle were examined in patients with limb-girdle muscular dystrophy (LGMD) type 2T. METHODS: Six new patients with genetically verified mutations in GMPPB were studied. T1-weighted magnetic resonance images were obtained in 4 participants. Muscle strength and potential involvement of extramuscular organs were examined. Glycosylation of α-dystroglycan in muscle was studied, and GMPPB and α-dystroglycan expression was analyzed by Western blotting. Prevalence of LGMD2T was calculated from the total LGMD population in Denmark. GMPPB was sequenced in all unclassified cases. RESULTS: Two patients carried 3 new mutations in GMPPB. The other 4 patients carried previously described pathogenic mutations in GMPPB. MRI showed that the paraspinal muscles were the most affected, followed by involvement of hamstrings. Our results showed a loss of glycosylation of α-dystroglycan as well as secondary loss of merosin expression on Western blotting. The prevalence of LGMD2T in the Danish cohort of patients with LGMD is 1.5%. CONCLUSIONS: The new findings of this study are (1) the consistent finding of a preferential affection of paraspinal and hamstring muscles in LGMD2T, (2) 3 new mutations in GMPPB, (3) variable loss of glycosylation tested with IIH6 and VIA4 antibodies, and (4) a prevalence of LGMD2T of 1.5% in a well-characterized Danish LGMD cohort.
RESUMO
OBJECTIVE: To determine on a large scale the multiple medical and nonmedical factors that influence glycemic control in the general population of children with diabetes, we performed a nationwide French cross-sectional study. RESEARCH DESIGN AND METHODS: We enrolled 2,579 patients aged 1-19 years with type 1 diabetes of > 1 year's duration. The study was center based: 270 centers were identified, 206 agreed to participate, and 147 included at least 90% of their patients. Questionnaires were completed by physicians interviewing patients and family, and HbA1c measurements were centralized. To identify explanatory variables for HbA1c level and frequency of severe hypoglycemia, we performed multiple regression analysis using all the quantitative variables collected and stepwise logistic regression for the qualitative variables. RESULTS: Mean HbA1c value for the whole population was 8.97 +/- 1.98% (normal 4.7 +/- 0.7% [SD]). Only 19 children (0.7%) had ketoacidosis during the 6 months before the study, whereas 593 severe hypoglycemia events occurred in 338 children (13.8%). Control was better in university-affiliated hospitals and centers following > 50 patients, reflecting the importance of access to experienced diabetologists. Children had a mean of 2.3 injections, allegedly performed 2.8 glucose measurements per day, and were seen an average of 4.6 times per year at the center. In the multiple regression analysis, 94% of the variance of HbA1c was explained by our pool of selected variables, with the highest regression coefficient between HbA1c and age (Rc = 0.43, P < 0.0001), then with daily insulin dosage per kilogram (Rc = 0.28, P < 0.0001), mother's age (Rc = 0.26, P < 0.0001), frequency of glucose measurements (Rc = 0.21, P < 0.0001), and diabetes duration (Rc = 0.14, P < 0.0001). Logistic regression identified quality of family support and dietary compliance, two related qualitative and possibly subjective variables, as additional explanatory determinants of HbA1c. The frequency of severe hypoglycemia was 45 per 100 patient-years and correlated with diabetes duration, but not with HbA1c levels or other variables. CONCLUSIONS: Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.
Assuntos
Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Adolescente , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/epidemiologia , Cetoacidose Diabética/etiologia , Família , Feminino , França/epidemiologia , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/sangue , Hiperglicemia/etiologia , Hipoglicemia/sangue , Hipoglicemia/etiologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Prevalência , Qualidade de Vida , Análise de Regressão , Fatores de Risco , Apoio Social , Inquéritos e QuestionáriosRESUMO
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the DMD gene that encodes the cytoskeletal protein, dystrophin. Dystrophinopathies are inherited in an X-linked recessive manner. Due to the tremendous size of the gene (2.2 megabases), the DMD locus has a high spontaneous mutation rate, and one third of sporadic cases of DMD are due to a de novo mutation. There are seven tissue-specific promoters in the gene. The skeletal muscular transcript contains 79 exons and encode the full-length protein (427-kDa) located at the inner face of the sarcolemma of muscle fibers. DMD gene mutations are highly heterogeneous. Large rearrangements (deletions or duplications of one or more exons) are most frequently involved while point mutations account for 20 %-30 % of cases. A survey of current strategies of molecular diagnosis is presented here. In particular, the role of muscle biopsy (for dystrophin and RNA analyses) in the diagnosis of dystrophinopathies is discussed. In more than 90 % of cases, the clinical severity is correlated with the impact of the mutations on the reading frame and the expression of the dystrophin (absence or residual amount of mutated protein). Various mechanisms contribute to the exceptions. Besides the clinical interest for the patient, the identification of the mutation allows accurate genetic counseling in the familles, and is a necessary prerequisite for the inclusion of the patient in the genotype-based clinical trials.
Assuntos
Distrofia Muscular de Duchenne/genética , Criança , Distrofina/genética , Genótipo , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Mutação , Patologia Molecular , FenótipoRESUMO
We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a gamma-sarcoglycan peptide and used to examine the expression of gamma-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment.
Assuntos
Proteínas do Citoesqueleto , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Músculo Esquelético/metabolismo , Distrofias Musculares/genética , Animais , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 13 , Distrofina/genética , Ligação Genética , Humanos , Glicoproteínas de Membrana/análise , Especificidade de Órgãos , Coelhos , Valores de Referência , Sarcoglicanas , Sarcolema/química , Sarcolema/metabolismoRESUMO
Primary adhalin (or alpha-sarcoglycan) deficiency due to a defect of the adhalin gene localized on chromosome 17q21 causes an autosomal recessive myopathy. We evaluated 20 patients from 15 families (12 from Europe and three from North Africa) with a primary adhalin deficiency with two objectives: characterization of the clinical phenotype and analysis of the correlation with the level of adhalin expression and the type of gene mutation. Age at onset and severity of the myopathy were heterogeneous: six patients were wheel-chair bound before 15 years of age, whereas five other patients had mild disease with preserved ambulation in adulthood. The clinical pattern was similar in all the patients with symmetric characteristic involvement of trunk and limb muscles, calf hypertrophy, and absence of cardiac dysfunction. Immunofluorescence and immunoblot studies of muscle biopsy specimens showed a large variation in the expression of adhalin. The degree of adhalin deficiency was fairly correlated with the clinical severity. There were 15 different mutations (10 missense, five null). Double null mutations (three patients) were associated with severe myopathy, but in the other cases (null/missense and double missense) there was a large variation in the severity of the disease.
Assuntos
Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Genes Recessivos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Distrofias Musculares/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Proteínas do Citoesqueleto/metabolismo , Progressão da Doença , Feminino , Genes , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Glicoproteínas de Membrana/metabolismo , Músculos/patologia , Músculos/fisiopatologia , Distrofias Musculares/patologia , Mutação , SarcoglicanasRESUMO
OBJECTIVE: To characterize the clinical phenotype of LGMD2C in gypsies. BACKGROUND: Limb-girdle muscular dystrophy (LGMD) in gypsies of Western Europe is caused by a homozygous C283Y mutation on the same haplotype, suggesting a founder effect. METHODS: We performed clinical, laboratory, and muscle imaging studies of 40 patients. RESULTS: Mean age at onset was 5.3 years. One half of the patients had loss of ambulation by the age of 12; 13% still could walk after age 16. Calf hypertrophy, scapular winging, macroglossia, and lumbar hyperlordosis were common. Girdle, trunk, and proximal limb flexor muscles had earlier and more severe involvement. Cardiomyopathy was not observed. Five patients in the third decade of life required mechanical ventilation. Scoliosis was common in the nonambulatory stage. CONCLUSIONS: LGMD2C in gypsy patients with C283Y mutation presents a rather homogeneous phenotype, characterized by an initial Duchenne-like progressive course followed by a more prolonged survival rate possibly due to the absence of early respiratory impairment and cardiac failure.
Assuntos
Proteínas do Citoesqueleto/genética , Glicoproteínas de Membrana/genética , Distrofias Musculares/genética , Roma (Grupo Étnico) , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Músculos/patologia , Músculos/fisiopatologia , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Mutação/genética , FenótipoRESUMO
The dystrophin-glycoprotein complex spans the sarcolemma to provide a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix in skeletal muscle. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to a drastic reduction in all of the dystrophin-associated proteins in the sarcolemma, thus causing the disruption of the dystrophin-glycoprotein complex and the loss of the linkage to the extracellular matrix. This is presumed to lead to sarcolemmal instability which could render muscle fibers susceptible to necrosis. In DMD, a very small percentage of muscle fibers show dystrophin staining along the sarcolemma, presumably due to a second in-frame deletion in the dystrophin gene. However, the functional significance of these rare dystrophin-positive muscle fibers (revertants) in DMD has been unclear. Here we report the co-expression of the dystrophin-associated proteins with dystrophin in revertants of DMD skeletal muscle. Our results suggest that the entire dystrophin-glycoprotein complex is restored in revertants and, thus, the linkage between the subsarcolemmal cytoskeleton and the extracellular matrix is restored in these muscle fibers.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Distrofina/metabolismo , Glicoproteínas de Membrana/metabolismo , Músculos/metabolismo , Distrofias Musculares/metabolismo , Distroglicanas , Humanos , Imuno-Histoquímica/métodos , Coloração e RotulagemRESUMO
We report a 6-year-old female patient presenting with a sudden and severe single episode of rhabdomyolysis in which screening for a metabolic disorder was negative. Four months after the episode a muscle biopsy was performed and showed a mild pattern of necrosis/regeneration. Upon immunofluorescence, a mosaic pattern of dystrophin deficiency was found, and in the dystrophin deficient muscle fibres, the four proteins of the sarcoglycan complex were also lacking. Genetic analysis showed a duplication of exons 3 to 17 on one X-chromosome of the proband, but not on the mother's X-chromosome. A clearly skewed X-inactivation (85% of the defective X being active) was found and is consistent with the patient being symptomatic. To our knowledge, a spontaneous rhabdomyolysis in a female Duchenne muscular dystrophy carrier has never been reported.
Assuntos
Mecanismo Genético de Compensação de Dose , Distrofina/genética , Genes Duplicados , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Biópsia , Criança , Feminino , Heterozigoto , Humanos , Distrofia Muscular de Duchenne/metabolismo , Rabdomiólise/genética , Rabdomiólise/metabolismo , Rabdomiólise/patologia , Cromossomo XRESUMO
We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH2 domains of dystrophin were almost normal. The immunoreactions for alpha-sarcoglycan, gamma-sarcoglycan and beta-dystroglycan were normal. In the five male patients of this family with increased serum creatine kinase levels (from x8 to x50), mass spectrometry screening of the urine revealed a large increase in glycerol elimination which was quantified by enzymatic assay (from x14 to x39). An in-frame deletion of the dystrophin gene (exons 13-29) was found in the same five males and in three carrier females. All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278. These findings indicate that the two mutations cosegregate on the same chromosome in this family. This is the first reported case of two physically independent mutations, within the DMD and GK genes, which are contiguous but several hundred kilobases apart.
Assuntos
Distrofina/genética , Ligação Genética , Glicerol Quinase/genética , Distrofias Musculares/genética , Mutação Puntual , Cromossomo X , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Deleção de Genes , Humanos , Masculino , Linhagem , SíndromeRESUMO
Out of 10 autosomal recessive limb-girdle muscular dystrophies reported, 4 are caused by mutations in the genes encoding for sarcoglycans (alpha-, beta-, gamma- and delta-SG). Beta-sarcoglycanopathy (limb-girdle muscular dystrophy 2E) is a genetically heterogeneous disorder which usually presents a severe progressive clinical course. A complete immunohistochemical evaluation of the sarcoglycan complex should be carried out to direct the mutation analysis approach. The present report concerns a Spanish family with a genetically confirmed beta-sarcoglycanopathy. The patient, a 16-year-old female, offspring of a consanguineous marriage, developed a severe limb-girdle muscular dystrophy with a Duchenne-like phenotype. Muscle biopsy showed dystrophic changes and complete absence of the four sarcoglycans. Genetic analysis demonstrated homozygosis for the M100K missense mutation in exon 3, encoding for the proximal extracellular domain. The parents and one sister were found to be carriers. Missense mutations affecting this domain result in the instability of the entire sarcoglycan complex and lead to severe phenotypes as seen in non-sense mutations.