Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contract ures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. W e recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we r eport on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 spora dic cases). Twelve of the 53 patients showed cardiac involvement exclusivel y, although the remaining 41 all showed muscle weakness and contractures. W e were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, sca pular winging, rigidity of the spine, and elbow and Achilles tendon contrac tures. The disease course was generally slow, but we observed either a mild er phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapid ly progressive course in a few cases. Mutation analysis identified 18 mutat ions in LMNA tie, 1 nonsense mutation, 2 deletions of a codon, and 15 misse nse mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clea r correlation between the phenotype and type or localization of the mutatio ns within the gene. Moreover, a marked inter- and intra-familial variabilit y in the clinical expression of LMNA mutations exists, racing from patients expressing the full clinical picture of EDMD to those characterized only b y cardiac involvement, which points toward a significant role of possible m odifier genes in the course of this disease. In conclusion, the high propor tion of de novo mutations together with the large spectrum of both LMNA mut ations and the expression of the disease should now prompt screening for LM NA in familial and sporadic cases of both EDMD and dilated cardiomyopathy a ssociated with conduction system disease.