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Submitted on March 22, 2007
Accepted on August 13, 2007
INSERM U680, Paris, F-75012, France (A. D., M. A., B. D., V. B., J. C., O. L., C. V.), Université Pierre et Marie Curie-Paris6, UMR S680 Paris, F-75012 France (A. D., M. A., B. D., V. B., J. C., O. L., C. V.), AP-HP, Hôpital Tenon, Service de Biochimie et d'Hormonologie, Paris, F-75020 France, (J. C., C. V.), Service d'Endocrinologie et Maladies métaboliques, CHU de Lille, France (MC. V.), Hôpital Jeanne d'Arc, Service de Diabétologie, Endocrinologie et Nutrition, CHU Nancy, France (B. G.), Service d'Endocrinologie, Maladies métaboliques et Médecine interne, CHU de Reims, France (AC. H.), Service d'Endocrinologie et Maladies métaboliques, CHU Côte de Nacre, France (Y. R.), Hôpital Sainte Marguerite, AP-HM, Service de Nutrition, Maladies Métaboliques, Endocrinologie, Marseille, France (H. N.), Centre de recherche en Nutrition Humaine, Hospices Civils, Lyon, France (PH. D.), AP-HP, Hôpital Saint-Louis, Service de Dermatologie, Paris, France (C. L.), AP-HP, Hôpital Saint-Antoine, Département de Biologie Moléculaire, Paris, France (O. L.)
* To whom correspondence should be addressed. E-mail: vigouroux{at}st-antoine.inserm.fr.
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 (FPLD2) and ten patients with other mutations. We report here the phenotypes of the patients with non-codon 482 mutations, and compare them with those of eleven 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 ten patients with non-codon 482-associated mutations fullfilled the International Diabetes Federation diagnosis criteria for metabolic syndrome. Most of them lacked the typical lipoatrophy observed in FPLD2. However, the severity of insulin resistance, altered glucose tolerance and hypertriglyceridemia, and the alterations of cells' 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). DEXA 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 further studied.
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