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

MFN2-Study Group

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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)
JournalJournal of Clinical Lipidology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Multiple Symmetrical Lipomatosis
Lipomatosis
Adipose Tissue
Lipoma
Fluorodeoxyglucose F18
Tooth
Fats
Mitochondrial Dynamics
Hypertriglyceridemia
Subcutaneous Fat
Mitochondrial Proteins
Adiponectin
Genetic Testing
Leptin
Serum
Adipocytes
Positron-Emission Tomography
Insulin Resistance
Phenotype
Messenger RNA

Keywords

  • 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

Cite this

MFN2-associated lipomatosis : Clinical spectrum and impact on adipose tissue. / MFN2-Study Group.

In: Journal of Clinical Lipidology, 01.01.2018.

Research output: Contribution to journalArticle

@article{8ba982b00ae946159d0fde0543b9a3e8,
title = "MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue",
abstract = "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.",
keywords = "Dyslipidemia, Genetics, Insulin resistance, Leptin, Lipodystrophy, Lipomatosis, Mitochondria, Mitofusin 2, Neuropathy, Thermogenic markers",
author = "{MFN2-Study Group} and Emilie Capel and Camille Vatier and Pascale Cervera and Tanya Stojkovic and Emmanuel Disse and Cottereau, {Anne S{\'e}gol{\`e}ne} and Martine Auclair and Verpont, {Marie Christine} and H{\'e}l{\'e}na Mosbah and Pierre Gourdy and Sara Barraud and Anne Miquel and Zuchner, {Stephan L} and Am{\'e}lie Bonnefond and Philippe Froguel and Sophie Christin-Maitre and Brigitte Delemer and Bruno F{\`e}ve and Martine Laville and Juliette Robert and Florence Tenenbaum and Olivier Lascols and Corinne Vigouroux and Isabelle J{\'e}ru",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.jacl.2018.07.009",
language = "English (US)",
journal = "Journal of Clinical Lipidology",
issn = "1933-2874",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - MFN2-associated lipomatosis

T2 - Clinical spectrum and impact on adipose tissue

AU - MFN2-Study Group

AU - Capel, Emilie

AU - Vatier, Camille

AU - Cervera, Pascale

AU - Stojkovic, Tanya

AU - Disse, Emmanuel

AU - Cottereau, Anne Ségolène

AU - Auclair, Martine

AU - Verpont, Marie Christine

AU - Mosbah, Héléna

AU - Gourdy, Pierre

AU - Barraud, Sara

AU - Miquel, Anne

AU - Zuchner, Stephan L

AU - Bonnefond, Amélie

AU - Froguel, Philippe

AU - Christin-Maitre, Sophie

AU - Delemer, Brigitte

AU - Fève, Bruno

AU - Laville, Martine

AU - Robert, Juliette

AU - Tenenbaum, Florence

AU - Lascols, Olivier

AU - Vigouroux, Corinne

AU - Jéru, Isabelle

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Dyslipidemia

KW - Genetics

KW - Insulin resistance

KW - Leptin

KW - Lipodystrophy

KW - Lipomatosis

KW - Mitochondria

KW - Mitofusin 2

KW - Neuropathy

KW - Thermogenic markers

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U2 - 10.1016/j.jacl.2018.07.009

DO - 10.1016/j.jacl.2018.07.009

M3 - Article

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AN - SCOPUS:85054196633

JO - Journal of Clinical Lipidology

JF - Journal of Clinical Lipidology

SN - 1933-2874

ER -