Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 758-785-Diabetes Case Reports: Type 1, Type 2, MODY & Complications
Clinical
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-780
Bruno Donadille*1, Pascal D'anella2, Martine Auclair3, Nancy Uhrhammer4, Marc Sorel5, Romulus Grigorescu6, Sophie Ouzounian7, Gilles Cambonie8, Pierre Boulot8, Pascal Laforêt9, Bruno Carbonne10, Yves-Jean Bignon11, Sophie Christin-Maitre12 and Corinne Vigouroux13
1Hôpital St Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Cedex 12, France, 2Hôpital Henri Duffaut, Avigon, France, 3INSERM UMR_S938, Paris, France, 4Centre Jean Perrin, Clermont-Ferrand, France, 5Centre Hospitalier de Nemours, Nemours, France, 6Hôpital Armand-Trousseau (AP-HP), PARIS, France, 7Hôpital St Antoine (AP-HP), PARIS Cedex 12, France, 8Hôpital A. de Villeneuve, Montpellier, France, 9Groupe Hospitalier Pitié-Salpêtrière (AP-HP), PARIS Cedex 13, France, 10Hôpital Armand-Trousseau, PARIS, France, 11Centre Jean Perrin, Clermont-Ferrand, 12Hôpital St Antoine (AP-HP) and UMPC Univ Paris 6, Paris Cedex 12, France, 13Hôpital Tenon (AP-HP) and INSERM UMR_S938, Paris Cedex 12, France
Mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome (WS) linked to mutations in WRN, encoding a RecQ DNA helicase.

Two women, referred for lipodystrophy, were studied. Cultured skin fibroblasts were used for western blot analysis, immunofluorescence microscopy, oxidative stress and senescence studies.

Two women aged 32 and 36 presented with subcutaneous peripheral lipoatrophy, truncal fat accumulation, hypertriglyceridemia, and liver steatosis. Major insulin resistance was evidenced by dramatic hyperinsulinemia following OGTT, with diabetes in one patient.  Both patients had early bilateral cataracts, greying hair, distal skin atrophy and infertility, which was related to diminished follicular ovarian reserve and insulin resistance-linked ovarian hyperandrogenism. We observed biallelic WRN null mutations in both women (p.Q748X and p.Q1257X/p.M1329fs). The two patients became pregnant after metformin treatment. Pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester abortion in the other. WRN-mutated cultured fibroblasts showed premature senescence, oxidative stress, nuclear dysmorphies and lamin abnormalities.

We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes. Cellular lamin alterations could be secondary to premature senescence and/or oxidative stress.

Nothing to Disclose: BD, PD, MA, NU, MS, RG, SO, GC, PB, PL, BC, YJB, SC, CV

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm