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

  • Author Footnotes
    1 Equally contributing to this paper.
    Emilie Capel
    Footnotes
    1 Equally contributing to this paper.
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France
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  • Author Footnotes
    1 Equally contributing to this paper.
    Camille Vatier
    Footnotes
    1 Equally contributing to this paper.
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Centre National de Référence des Pathologies Rares de l’Insulino–Sécrétion et de l’Insulino–Sensibilité (PRISIS), Service d’Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Paris, France
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  • Pascale Cervera
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Service d’Anatomie Pathologique, Paris, France
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  • Tanya Stojkovic
    Affiliations
    Assistance Publique–Hôpitaux de Paris, Hôpital Pitié–Salpêtriére, Centre National de Référence des maladies neuromusculaires, Paris, France
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  • Emmanuel Disse
    Affiliations
    Hospices Civils de Lyon, Université Lyon 1, Centre Hospitalier Lyon–Sud, Service d’Endocrinologie, Diabétologie et Nutrition, Lyon, France
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  • Anne-Ségolène Cottereau
    Affiliations
    Sorbonne Université, Assistance Publique–Hôpitaux de Paris, Hôpital Tenon, Service de Médecine Nucléaire, Sorbonne Université, Paris, France
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  • Martine Auclair
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France
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  • Marie-Christine Verpont
    Affiliations
    Sorbonne Université, Inserm UMR_S1155, LUMIC, Plate–forme d’Imagerie et de Cytométrie de Tenon, Paris, France
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  • Héléna Mosbah
    Affiliations
    Assistance Publique–Hôpitaux de Paris, Hôpital Pitié–Salpêtrière, Service de Diabétologie, Paris, France
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  • Pierre Gourdy
    Affiliations
    Centre Hospitalo–Universitaire de Toulouse, Service de Diabétologie, Maladies Métaboliques et Nutrition, Université de Toulouse Paul Sabatier, Toulouse, France
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  • Sara Barraud
    Affiliations
    Centre Hospitalo–Universitaire de Reims, Service d’Endocrinologie, Diabétologie et Nutrition, Reims, France
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  • Anne Miquel
    Affiliations
    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Service de Radiologie, Paris, France
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  • Stephan Züchner
    Affiliations
    University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Miami, FL, USA
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  • Amélie Bonnefond
    Affiliations
    Institut Pasteur de Lille, Université de Lille, CNRS UMR 8199, Lille, France
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  • Philippe Froguel
    Affiliations
    Institut Pasteur de Lille, Université de Lille, CNRS UMR 8199, Lille, France
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  • Sophie Christin-Maitre
    Affiliations
    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Centre National de Référence des Pathologies Rares de l’Insulino–Sécrétion et de l’Insulino–Sensibilité (PRISIS), Service d’Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Paris, France
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  • Brigitte Delemer
    Affiliations
    Centre Hospitalo–Universitaire de Reims, Service d’Endocrinologie, Diabétologie et Nutrition, Reims, France
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  • Bruno Fève
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Centre National de Référence des Pathologies Rares de l’Insulino–Sécrétion et de l’Insulino–Sensibilité (PRISIS), Service d’Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Paris, France
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  • Martine Laville
    Affiliations
    Hospices Civils de Lyon, Université Lyon 1, Centre Hospitalier Lyon–Sud, Service d’Endocrinologie, Diabétologie et Nutrition, Lyon, France
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  • Juliette Robert
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France
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  • Florence Tenenbaum
    Affiliations
    Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Département de Médecine Nucléaire, Paris, France
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  • Olivier Lascols
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France
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  • Author Footnotes
    2 Equally contributing to this paper and corresponding authors: [email protected], [email protected], Faculté de Médecine Sorbonne Université Site Saint-Antoine, Inserm UMR_S938, Equipe Lipodystrophies génétiques et acquises, 27 rue Chaligny, 75571 Paris Cédex 12, France.
    Corinne Vigouroux
    Correspondence
    Corresponding author. Prof. Corinne Vigouroux, Faculté de Médecine Sorbonne, Université Site Saint-Antoine, Faculté de médecine Paris 6, 27 rue Chaligny, Cédex 12, 75571 Paris, France.
    Footnotes
    2 Equally contributing to this paper and corresponding authors: [email protected], [email protected], Faculté de Médecine Sorbonne Université Site Saint-Antoine, Inserm UMR_S938, Equipe Lipodystrophies génétiques et acquises, 27 rue Chaligny, 75571 Paris Cédex 12, France.
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Centre National de Référence des Pathologies Rares de l’Insulino–Sécrétion et de l’Insulino–Sensibilité (PRISIS), Service d’Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France
    Search for articles by this author
  • Author Footnotes
    2 Equally contributing to this paper and corresponding authors: [email protected], [email protected], Faculté de Médecine Sorbonne Université Site Saint-Antoine, Inserm UMR_S938, Equipe Lipodystrophies génétiques et acquises, 27 rue Chaligny, 75571 Paris Cédex 12, France.
    Isabelle Jéru
    Footnotes
    2 Equally contributing to this paper and corresponding authors: [email protected], [email protected], Faculté de Médecine Sorbonne Université Site Saint-Antoine, Inserm UMR_S938, Equipe Lipodystrophies génétiques et acquises, 27 rue Chaligny, 75571 Paris Cédex 12, France.
    Affiliations
    Sorbonne Université, Inserm UMR_S 938, Centre de Recherche Saint–Antoine, Institut Hospitalo–Universitaire de Cardio–métabolisme et Nutrition (ICAN), Paris, France

    Assistance Publique–Hôpitaux de Paris, Hôpital Saint–Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, Paris, France
    Search for articles by this author
  • Author Footnotes
    1 Equally contributing to this paper.
    2 Equally contributing to this paper and corresponding authors: [email protected], [email protected], Faculté de Médecine Sorbonne Université Site Saint-Antoine, Inserm UMR_S938, Equipe Lipodystrophies génétiques et acquises, 27 rue Chaligny, 75571 Paris Cédex 12, France.

      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 18F-FDG fat uptake may be disease markers.

      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

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