Update of Emerinopathies’ clinical-genetic spectrum: the French network experience

Abstract

Emerinopathies include diseases caused by EMD gene mutations localized on chromosome X and encoding emerin, an integral protein of the nuclear envelope. The most frequent emerinopathy is the X-linked EmeryDreifuss muscular dystrophy (X-EDMD) that was first reported in the 60ths by Emery and Dreifuss [1]. The disease is characterized by muscle weakness and wasting usually with a humeroperoneal distribution in the first stages, early joint contractures involving Achilles tendons, elbows, neck and the whole spine, and cardiac involvement featuring conduction defects, arrhythmias, subsequent cardiomyopathy (usually dilated) and frequently responsible of sudden death. Bione et al. [2] identified the first mutations of EMD gene encoding emerin to be responsible of X-EDMD. These mutations usually lead to absence or reduced level of emerin in different tissues of affected males including skeletal muscle, skin, oral mucosa cells and lymphocytes as it is demonstrated by immunocytochemical and histochemical methods [3,4]. Female carriers exhibit mosaic expression patterns with usually normal emerin amounts [3]. These methods may thus be used in the diagnostic strategy of X-EDMD prior to EMD gene analysis. In a recent study (unpublished work from the French network and LBGM) aiming to assess the diagnostic utility of emerin study by western blot on lymphoblastoid cell lines, we looked at EMD mutation rate observed in a cohort of 269 male and female patients with variable emerin amounts. In male patients, absence or severe reduction of emerin (<5%) lead to EMD mutation identification in all cases, while moderate emerin amount reduction revealed EMD mutation in 75% of the patients. Interestingly, in all cases where emerin amounts were considered as normal, no EMD mutations were found. In female cases, all cases with emerin moderate or severe reduction harbored EMD mutation. When emerin is normal, EMD mutation was found in 58% of female cases. These results suggest that a diagnostic rate of 100% may be reached if emerin study by western blot is performed prior to EMD gene screening in male patients. Moreover, emerin gene mutations have been rarely observed in rare cases of isolated cardiac disease [5,6] and limb girdle muscular dystrophies with cardiac disease and without joint contractures [7,8].