Brain Advance Access originally published online on April 3, 2006
Brain 2006 129(5):1260-1268; doi:10.1093/brain/awl062
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Disease severity in dominant Emery Dreifuss is increased by mutations in both emerin and desmin proteins
1 Dubowitz Neuromuscular Centre, Imperial College, Hammersmith Hospital, London, 2 Comparative Neuromuscular Diseases Laboratory, Royal Veterinary College, Hertfordshire, 3 Department of Histopathology, Harefield Hospital, Harefield, 4 Centre for Inherited Neuromuscular Disorders, Oswestry, UK, 5 Inserm, U582, Institut de Myologie and Inserm IFR14, Université Paris VI, GH Pitié-Salpétrière, 6 AP-HP-UF de Myogénétique et Cardiogénétique, GH Pitié-Salpêtrière, 7 AP-HP-Laboratoire de Biochimie et Génétique Moléculaire, Hôpital Cochin, Paris, France and 8 National Institute of Neurological Disorders and Stroke, NIH, Bethesda, USA
Correspondence to: Francesco Muntoni, Department of Paediatrics, Imperial College, Hammersmith Hospital, Du Cane Road, London W12ONN, UK E-mail: f.muntoni{at}ic.ac.uk
Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.
Key Words: muscular dystrophy; dilated cardiomyopathy; lamin; desmin; emerin
Abbreviations: CSD = conduction system disease; EDMD = Emery Dreifuss muscular dystrophy; PCR = polymerase chain reaction
Received October 24, 2005. Revised February 4, 2006. Accepted February 20, 2006.
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