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 language | English (US) |
|---|---|
| Journal | Journal of Clinical Lipidology |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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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 journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85054196633&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054196633&partnerID=8YFLogxK
U2 - 10.1016/j.jacl.2018.07.009
DO - 10.1016/j.jacl.2018.07.009
M3 - Article
C2 - 30158064
AN - SCOPUS:85054196633
JO - Journal of Clinical Lipidology
JF - Journal of Clinical Lipidology
SN - 1933-2874
ER -