engleski

Diagnostic dilemma in an atypical X-linked Emery-Dreifuss family

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.

muscular dystrophy; Emery-Dreifuss; phenotype; emerin; mutational analysis DNA; carrier state

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