P-08

XL-EDMD genotypic spectrum among portuguese patients

Emília Vieira^I; Ana Gonçalves^I; Elsa Bronze-da-Rocha^II,III; Rosário Santos^I,II

^IUnidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal
^IIDepartamento de Bioquímica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
^IIIInstituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of joint  contractures that begin in early childhood, slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later  extends to the scapular and pelvic girdle muscles, and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure, that can result in sudden death. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both interand intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade. The three genes in which mutations are known to cause EDMD are EMD (encoding emerin) and FHL1 (encoding FHL1), which cause X-linked EDMD (XLEDMD) and LMNA (encoding lamin A and C), which causes autosomal dominant and autosomal recessive EDMD (ADEDMD and AR-EDMD). For all forms of EDMD the diagnosis is based on clinical findings and family history. The diagnosis of X-linked EDMD also relies on failure to detect emerin or FHL1 protein in various tissues and molecular genetic testing of EMD or FHL1 whereas ADand AR-EDMD diagnosis relies on molecular genetic testing of LMNA. We describe the molecular results for EMD gene screening, in a group of twenty-one Portuguese families, with clinical diagnosis of EDMD and presenting different clinical phenotypes, with or without cardiac involvement. Differential diagnosis of XL-EDMD was achieved in five families (eight patients). Four different mutations were identified, two of which have not been documented in the literature. In a female patient, a skewed X inactivation pattern was observed, explaining disease manifestation. In the remaining families, the LMNA gene was studied leading to confirmation of laminopathy in a four families. Molecular diagnosis is therefore very important for an early diagnosis, to prevent sudden deaths, and to distinguish X-linked EDMD from the autosomal forms, which is essential for a correct genetic counseling and subsequent prenatal diagnosis.