Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome

Bruno Donadille,Pascal Laforêt,Corinne Vigouroux,Sophie Christin-Maitre,Romulus Grigorescu,Sophie Ouzounian,Marc Sorel,Bruno Carbonne,Martine Auclair,Yves-Jean Bignon,Pierre Boulot,Nancy Uhrhammer,Pascal D’Anella,Gilles Cambonie

doi:10.1186/1750-1172-8-106

Abstract

BackgroundLaminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.MethodsWe analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied.ResultsTwo normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both 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 fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence.ConclusionsWe show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.

Highlights

Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships
Case reports Patient 1 A 32-year-old woman was referred to our Endocrinology Department for partial lipodystrophy
Among the five siblings of the patient, a brother died at 44 years old from myocardial infarction; he was reported with dysmorphic features, premature cataracts, insulin-treated diabetes since age 26, and severe atherosclerosis leading to foot amputation at age 38

Summary

Introduction

Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. The studies of clinical and cellular consequences of LMNA mutations in humans have provided several indications of a close physiopathological relationship between premature aging and lipodystrophic syndromes. Human naturally-occuring LMNA mutations, among other phenotypes of laminopathies, have been shown to be responsible for premature ageing syndromes (HutchinsonGilford progeria, HGPS, and mandibuloacral dysplasia, MAD) [1,2,3,4], lipodystrophic syndromes (familial partial lipodystrophy of the Dunnigan type, FPLD2) [5,6], and mixed phenotypes [7,8,9,10]. An initial clinical presentation as a lipodystrophic syndrome has not been previously described

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