MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

Emilie Capel, Camille Vatier, Pascale Cervera, Tanya Stojkovic, Emmanuel Disse, Anne Ségolène Cottereau, Martine Auclair, Marie Christine Verpont, Héléna Mosbah, Pierre Gourdy, Sara Barraud, Anne Miquel, Stephan Züchner, Amélie Bonnefond, Philippe Froguel, Sophie Christin-Maitre, Brigitte Delemer, Bruno Fève, Martine Laville, Juliette RobertFlorence Tenenbaum, Olivier Lascols, Corinne Vigouroux, Isabelle Jéru

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Background: Multiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy. Objective: To investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL. Methods: We sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients. Results: Six patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity. Conclusion: MFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

Original languageEnglish (US)
Pages (from-to)1420-1435
Number of pages16
JournalJournal of Clinical Lipidology
Issue number6
StatePublished - Nov 1 2018


  • Dyslipidemia
  • Genetics
  • Insulin resistance
  • Leptin
  • Lipodystrophy
  • Lipomatosis
  • Mitochondria
  • Mitofusin 2
  • Neuropathy
  • Thermogenic markers

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics
  • Cardiology and Cardiovascular Medicine


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