- Heterozygous LMNA variants (p.T528R, p.R527P, p.R541P, p.R453W) produce overlapping FPLD2 and AD-EDMD phenotypes in five families.
- Affected individuals showed proximal muscle weakness, joint contractures, and cardiac arrhythmias often requiring pacemaker-defibrillator implantation.
- Female patients uniformly exhibited limb and trunk fat loss with frequent diabetes and hypertriglyceridaemia; male manifestations were less consistent.
J Endocr Soc. 2026 Jun 5;10(7):bvag128. doi: 10.1210/jendso/bvag128. eCollection 2026 Jul.
ABSTRACT
CONTEXT: Specific heterozygous pathogenic variants in LMNA have been reported in patients with Dunnigan-type familial partial lipodystrophy (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 2 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 5 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, ages 18-57 years; 3 males, ages 25-41 years) harbored heterozygous p.T528R, p.R527P, p.R541P, or p.R453W LMNA variants. Five females and 2 males had joint contractures and proximal muscle weakness, and 4 females and 1 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 1 male had hypertriglyceridemia. Two females, 50 and 58 years 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 the future, all patients with AD-EDMD should be carefully evaluated for clinical signs of lipodystrophy and metabolic complications.
PMID:42555405 | PMC:PMC13338774 | DOI:10.1210/jendso/bvag128
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