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MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue.
- Source :
- Journal of Clinical Lipidology; Nov2018, Vol. 12 Issue 6, p1420-1435, 16p
- Publication Year :
- 2018
-
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 <superscript>18</superscript>F-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 <superscript>18</superscript>F-FDG body fat uptake may be disease markers. Highlights • Mitofusin-2 (MFN2)-related multiple symmetric lipomatosis (MSL) is associated with neuropathy. • MFN2 -related MSL also includes lipoatrophy, insulin resistance, and liver steatosis. • The p.Arg707Trp variant is involved in all reported forms of MFN2 -associated MSL. • Lipomatous tissue shows mitochondrial alterations and expresses thermogenic markers. • Low leptin/high serum fibroblast growth factor 21 and increased <superscript>18</superscript>F-FDG fat uptake may be disease markers. [ABSTRACT FROM AUTHOR]
- Subjects :
- MITOCHONDRIAL pathology
ADIPOSE tissues
BIOMARKERS
BIOCHEMISTRY
CHARCOT-Marie-Tooth disease
DEOXY sugars
DIABETES
ENZYMES
FAT cells
GENE expression
GROWTH factors
HEALTH care teams
HYPERLIPIDEMIA
INSULIN resistance
PHENOMENOLOGY
MESSENGER RNA
RADIOPHARMACEUTICALS
POSITRON emission tomography
PHENOTYPES
GENETIC testing
LEPTIN
SEVERITY of illness index
ADIPONECTIN
LIPOMA
LIPODYSTROPHY
SEQUENCE analysis
LIPOMATOSIS
Subjects
Details
- Language :
- English
- ISSN :
- 19332874
- Volume :
- 12
- Issue :
- 6
- Database :
- Supplemental Index
- Journal :
- Journal of Clinical Lipidology
- Publication Type :
- Academic Journal
- Accession number :
- 133438735
- Full Text :
- https://doi.org/10.1016/j.jacl.2018.07.009