Emery-Dreifuss Muscular Dystrophy and Familial partial Lipodystrophy, Dunnigan variety due to heterozygous LMNA variants

Context Specific heterozygous pathogenic variants in LMNA have been reported in patients with familial partial lipodystrophy type 2 (FPLD2), while other variants cause autosomal dominant Emery Dreifuss muscular dystrophy (AD-EDMD). FPLD2 is characterized by variable loss of subcutaneous fat from the extremities and trunk, and AD-EDMD is characterized by early joint contractures, proximal muscle weakness and cardiac conduction defects. Previously, only two families have been reported with combined features of FPLD2 and AD-EDMD. Objective To report the overlapping phenotype of both FPLD2 and AD-EDMD in five families with heterozygous LMNA variants. Methods Clinical, anthropometric, laboratory and genotyping data of affected subjects from 5 families with female probands presenting with FPLD2 and AD-EDMD phenotypes were collected. Results Affected individuals (8 females, age 18-57 years; and 3 males, age 25-41 years) harbored heterozygous p.T528R, p.R527P, p.R541P or p.R453W LMNA variants. Five females and two males had joint contractures and proximal muscle weakness, and four females and one male had pacemaker-defibrillator implantation for cardiac arrhythmias, confirming AD-EDMD. Subcutaneous fat loss from the extremities confirming FPLD2 was observed in all females but only in 2 males. Four females had diabetes mellitus and hypertriglyceridemia, and one male had hypertriglyceridemia. Two females, 50- and 58-year-old, died due to aspiration pneumonia and cerebrovascular accident, respectively; and one 40-year-old male died of alcoholic liver disease. Conclusion Our report brings attention to the frequent co-occurrence of FPLD2 and AD-EDMD. In future, all patients with AD-EDMD should be carefully evaluated for clinical signs of lipodystrophy and metabolic complications.