Context: Mutations in the LMNA gene are responsible for several laminopathies, including lipodystrophies, with complex genotype/phenotype relationships. OBJECTIVE, DESIGN, SETTING, AND PATIENTS: Sequencing of the LMNA coding regions in 277 unrelated adults investigated for lipodystrophy and/or insulin resistance revealed 17 patients with substitutions at codon 482 observed in typical Dunnigan's familial partial lipodystrophy and 10 patients with other mutations. We report here the phenotypes of the patients with non-codon 482 mutations and compare them with those of 11 patients with codon 482 mutations. We also studied skin fibroblasts or lymphocytes from seven patients.
Results: LMNA mutations found in nine patients studied here affected the three protein domains. Eight of them were novel. The 10 patients with non-codon 482-associated mutations fulfilled the International Diabetes Federation diagnosis criteria for metabolic syndrome. Most of them lacked the typical lipoatrophy observed in Dunnigan's familial partial lipodystrophy. However, the severity of insulin resistance, altered glucose tolerance, and hypertriglyceridemia and the alterations of cell nuclei were similar in patients with codon 482- and non-codon 482-associated mutations. Calf hypertrophy, myalgia, and muscle cramps or weakness were present in nine patients and cardiac conduction disturbances in two patients with non-codon 482 LMNA mutations.
Conclusions: We describe here new phenotypes of metabolic laminopathy associated with non-codon 482 LMNA mutations and characterized, in the absence of obvious clinical lipoatrophy, by severe metabolic alterations and frequent muscle signs (muscular hypertrophy, myalgias, or weakness). Dual-energy x-ray absorptiometry and/or cross-sectional abdominal and thigh imaging can help diagnosis by revealing subclinical lipodystrophy. The prevalence and pathophysiology of metabolic laminopathies need to be studied further.