Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor-[gamma] mutation, H449L

Tevfik Demir; Huseyin Onay; David B Savage; Ayse Kubat Kuruuzum; Senay Savas Erdeve; Canan Altay; Samim Ozen; Leyla Demir; Umit Cavdar; Baris Akinci

doi:10.1530/endoabs.37.EP342

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Endocrine Abstracts (2015) 37 EP342 | DOI: 10.1530/endoabs.37.EP342

ECE2015 Eposter Presentations Diabetes (pathiophysiology & epitemiology) (80 abstracts)

Familial partial lipodystrophy linked to a novel peroxisome proliferator activator receptor-γ mutation, H449L

Tevfik Demir ¹ , Hüseyin Onay ² , David B Savage ³ , Ayse Kubat Kuruuzum ⁴ , Senay Savas Erdeve ⁵ , Canan Altay ⁶ , Samim Ozen ² , Leyla Demir ⁷ , Umit Cavdar ¹ & Baris Akinci ¹

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¹Division of Endocrinology, Dokuz Eylul University, Izmir, Turkey; ²Department of Medical Genetics, Ege University, Izmir, Turkey; ³Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, London, UK; ⁴Division of Endocrinology, Istanbul University, Istanbul, Turkey; ⁵Division of Pediatric Endocrinology, Dr Sami Ulus Women and Children’s Hospital, Ankara, Turkey; ⁶Department of Radiology, Dokuz Eylul University, Izmir, Turkey; ⁷Department of Biochemistry, Ataturk Training Hospital, Izmir, Turkey.

Introduction: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterised by a selective lack of subcutaneous fat that is associated with insulin resistance and diabetes. FPL has been reported to be caused by mutations in the peroxisome proliferator activator receptor-γ (PPARG) gene, which encodes a key transcription factor that regulates adipocyte differentiation and insulin sensitivity.

Material and methods: The objective of this study was i) to describe the phenotype associated with a novel heterozygous missense PPARG mutation, H449L, discovered in a Turkish family; and ii) to compare the fat distribution and metabolic characteristics of subjects with the PPARG H449L mutation (n=4) to that of a cluster of FPL patients with various LMNA mutations (n=5; R482W, R582H, L306V and T528M).

Results: Compared to patients with LMNA mutations, fat loss was generally less prominent in subjects with PPARG H449L mutation. Partial fat loss was limited to the extremities whilst truncal fat mass was preserved. The PPARG H449L mutation was associated with insulin resistance, hypertriglyceridemia and non-alcoholic fatty liver disease in all affected subjects but the severity was variable. Three of four mutation carriers were overtly diabetic or had impaired glucose tolerance. Pioglitazone therapy in these three individuals resulted in a modest improvement in their metabolic control, and regular menstrual cycles in both females.

Conclusion: We suggest that relatively modest fat loss in patients with PPARG mutations may render the recognition of the syndrome more difficult in routine clinical practice. The PPARG H449L mutation is associated with insulin resistance and metabolic complications; however the severity is variable among the affected subjects, suggesting that additional factors such as variations in other predisposing genes, gender, age and lifestyle factors might affect the clinical features in patients with PPARG mutations.