Key Points
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Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by near total absence of body fat and extreme muscularity present at birth or soon thereafter
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Patients with CGL are extremely hypoleptinaemic and are predisposed to develop metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis
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Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutation; and type 4 is associated with PTRF mutations
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Therapeutic options for patients with CGL include conventional lipid-lowering and antihyperglycaemic drugs, as well as metreleptin replacement therapy
Abstract
Congenital generalized lipodystrophy (CGL) is a heterogeneous autosomal recessive disorder characterized by a near complete lack of adipose tissue from birth and, later in life, the development of metabolic complications, such as diabetes mellitus, hypertriglyceridaemia and hepatic steatosis. Four distinct subtypes of CGL exist: type 1 is associated with AGPAT2 mutations; type 2 is associated with BSCL2 mutations; type 3 is associated with CAV1 mutations; and type 4 is associated with PTRF mutations. The products of these genes have crucial roles in phospholipid and triglyceride synthesis, as well as in the formation of lipid droplets and caveolae within adipocytes. The predominant cause of metabolic complications in CGL is excess triglyceride accumulation in the liver and skeletal muscle owing to the inability to store triglycerides in adipose tissue. Profound hypoleptinaemia further exacerbates metabolic derangements by inducing a voracious appetite. Patients require psychological support, a low-fat diet, increased physical activity and cosmetic surgery. Aside from conventional therapy for hyperlipidaemia and diabetes mellitus, metreleptin replacement therapy can dramatically improve metabolic complications in patients with CGL. In this Review, we discuss the molecular genetic basis of CGL, the pathogenesis of the disease's metabolic complications and therapeutic options for patients with CGL.
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Acknowledgements
A.G. acknowledges grant support from the NIH RO1 DK105448, CTSA Grant UL1 RR024982 and Southwest Medical Foundation. We thank P.-Y. Tseng for help with illustrations and mutational screening.
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A.G. co-holds a patent regarding the use of leptin for treating human lipoatrophy and the method of determining predisposition to this treatment but receives no financial compensation. A.G. has received research grants from Aegerion, Astra-Zeneca, Bristol-Myers-Squibb and Pfizer and is a consultant for Amgen, Back Bay Life Sciences, Biomarin Pharmaceuticals, BioMedical Insights, Clearview Healthcare, Eli Lilly, Engage Health, Gerson Lehrman Group, Health Advances, Ipsen Pharmaceuticals, Intellisphere, Medscape and Tekmira. A.G. is also an advisory board member for AstraZeneca. N.P. declares no competing interests.
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Patni, N., Garg, A. Congenital generalized lipodystrophies—new insights into metabolic dysfunction. Nat Rev Endocrinol 11, 522–534 (2015). https://doi.org/10.1038/nrendo.2015.123
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DOI: https://doi.org/10.1038/nrendo.2015.123
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