Search

Objectifs : Les mutations du g&egrave ; ne EMD, codant l’ émerine, sont responsables de la forme liée &agrave ; l’ X de la Dystrophie musculaire d’ Emery-Dreifuss (X-EDMD), caractérisée par une faiblesse et amyotrophie huméro-péroni&egrave ; res, des rétractions tendineuses et une cardiopathie dominée par des troubles de la conduction auriculo-ventriculaire avec risque accru de mort subite. Les femmes transmettrices sont le plus souvent asymptomatiques. Nous rapportons ici 4 femmes porteuses d'une mutation du g&egrave ; ne EMD et présentant soit une atteinte cardiaque ou musculaire pures, soit un phénotype EDMD complet. Méthodes et résultats : Quatre femmes, m&egrave ; res de patients EDMD, ont été cliniquement analysées sur les plans neurologique et cardiologique. L’ émerine a été quantifiée sur lymphoblastes par Western Blot et le g&egrave ; ne EMD analysé par Southern blot/PCR-Séquençage. L’ inactivation du chromosome X a été testée par l’ analyse de la méthylation au locus du récepteur aux androg&egrave ; nes. Deux patientes avaient une cardiopathie pure, la troisi&egrave ; me une myopathie des ceintures isolée et la derni&egrave ; re un EDMD complet associé &agrave ; une hémiplégie gauche probablement d'origine thromboembolique. Chez cette patiente, l'émerine est tr&egrave ; s diminuée et l’ inactivation du chromosome X déséquilibrée. L'analyse du g&egrave ; ne EMD a identifié quatre mutations nulles &agrave ; l'état hétérozygote (un stop, une insertion et deux délétions). Conclusion : La transmettrices de mutations EMD expriment une symptomatologie variable non corrélée &agrave ; la génétique, mais elle les expose au m&ecirc ; me risque cardiologique que les sujets masculins hémizygotes. Leur suivi cardiologique semble nécessaire pour détecter et prévenir les complications cardiaques.

Emery-Dreifuss muscular dystrophies are characterized by early contractures, late humero-peroneal dystrophy and dilated cardiopathy with severe conduction defects leading to sudden death. They are caused by mutations affecting either the STA gene, in the X-linked form (XL-EDMD ; OMIM 310300), or the LMNA gene, in the autosomal dominant form (AD- EDMD ; OMIM 181350). Both genes code for nuclear membrane proteins, respectively, emerin and lamin A/C. Laminopathies are known to have a large clinical spectrum going from limb girdle muscular dystrophy (LGMD) to isolated cardiomyopathy. We report a large four- generation Croatian family in which clinical and pedigree data have oriented us primarily to AD-EDMD because of atypical clinical symptoms and confusing pedigree data. The proband presented as a slowly progressive LGMD (onset at teens) with moderate rigid spine and cardiomyopathy demanding pacemaker implantation in the age of 31. His mother when first seen at 61 years had moderate LGMD with slightly elevated CPK, EMG within normal limites, as were ECG and echocardiography. Proband's two sons aged 11 and 12 years respectively experienced mild weakness of the legs and arms since 10 years and CPK was scarcely elevated in younger son. An autosomal dominant inheritance was suspected, but the diagnosis of FSH and AD-EDMD were excluded by molecular analysis. Futher investigations showed that X-linked inheritance could not be rejected. Therefore, we carried out a western blot analysis of cultured lymphoblastoid cells from the proband which showed total absence of emerin. A large deletion in the exon 1 of the STA gene was characterized by sequencing, confirming the diagnosis of XL-EDMD. This deletion was also found in two other family's very differently affected males (one of them , now 69 years old is ambulant, with classical but moderate symptoms of LGMD, and pacemaker implantation since the age of 41) , in the probond's affected mother and in the asymptomatic mother of the third severely affected patient with early and prominent rigid spine and contractures. This observation emphasizes the phenotypic heterogeneity of XL-EDMD, especially when female carriers are symptomatic, and the diagnostic value of western blot analysis in perplexing situation. In conclusion, in such difficult cases an extensive clinical and genetic investigations with emerin screening by western blot are needed.

Questo è un lavoro del gruppo denominato EUROMEN (European muscle envelope nucleopathies) che è parte del progetto Myo-Cluster finanziato dalla comunità Europea (QLG1-CT-1999-00870) e di cui lo IOR è il centro di coordinamento e il Dr. Luciano MERLINI dello IOR è il responsabile scientifico dell'intero progetto al quale afferiscono complessivamente 16 centri europei. Nella authorship vi sono 3 ricercatori: due dello IOR e 1 del CNR: L. Merlini,B. Talim e S. Squarzoni. Al workshop aveva partecipato anche N. M. Maraldi, che però non figura nella authorship. Il suo nome figura però nella lista dei partecipanti al workshop (pag. 187). Vengono riportati risultati originali che sono stati comunicati e discussi ad un workshop che si è tenuto in Olanda (15-16 Settembre 2000) sotto l'egida dell'European Neuromuscular Centre (ENMC). In particolare è dettagliato lo spettro clinico, molecolare e genetico dei disordini da mutazioni del gene della lamina A/C. Il quadro clinico principale è quello di una distrofia muscolare con cardiomiopatia e retrazioni muscolo- scheletriche precoci, talora scoliosi. Sono poi riportati i criteri per ottimizzare la diagnosi dal punto di vista dell'indagine cardiologia, dell'imaging dei muscolo scheletrici, e dell'esame della biopsia muscolare. Infine vengono riassunti gli aspetti di base delle membrane nucleari con l'obiettivo di identificare filoni di ricerca per una possibile individuazione della fisiopatologia di tali disordini.

Emery-Dreifuss muscular dystrophy(EMD) is an uncommon but distinctive type of muscular dystrophy with striking inter and intrafamilial clinical variability. Therefore systematic clinico-genetic correlation studies are needed to better define the X-linked phenotype, to determine the major clinical features at different ages and to precise the diagnosis in sporadic cases. We report a three-generation X-linked EMD family. The propositus,initially seen at 24 years of age had severe,very early onset clinical course. Three affected maternal uncles died suddenly at 32, 34 and 62 respectively. His obligate carrier grand-mother died suddenly at 39 years of age. His sister was asymptomatic except ECG abnormalities. She had three children :a girl and DZ twin boys with normal early motor milestones. At 9 years,both twins had minimal clinical symptoms,moderately elevated CK and cardiac conduction defects. As no samples of the proband was available,the mutation was identified by direct sequencing of the whole EMDgene on genomic DNA of affected twins. It is a T insertion in exon 2(417 ins T) which results in a frameshift with a stop codon at position 62. The western blot, performed on lymphoblastoid cell lines, showed a total absence of emerin in both affected boys ,and normal labelled band in their sister.

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. The resulting sarcolemmal instability is presumed to render muscle fibers susceptible to necrosis. In the present study, we investigated the status of the dystrophin-associated proteins in the skeletal muscle from patients with Becker muscular dystrophy (BMD), a milder allelic form of DMD. BMD patients having in-frame deletions in the rod domain of dystrophin showed a mild to moderate reduction in all of the dystrophin-associated proteins in the sarcolemma, but this reduction was not as severe as that in DMD patients. The reduction of the immunostaining for the dystrophin-associated proteins showed a good correlation with that for dystrophin in both intensity and distribution. Our results indicate that (1) the abnormality of the sarcolemmal glycoprotein complex, which is similar to but milder than that in DMD patients, also exists in these BMD patients and (2) the rod domain of dystrophin is not crucial for the interaction with the dystrophin-associated proteins.