Familial Partial Lipodystrophy—Literature Review and Report of a Novel Variant in PPARG Expanding the Spectrum of Disease-Causing Alterations in FPLD3

Abstract

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by the selective loss of adipose tissue. Its estimated prevalence is as low as 1 in 1 million. The deficiency of metabolically active adipose tissue is closely linked with a wide range of metabolic complications, such as insulin resistance, lipoatrophic diabetes, dyslipidemia with severe hypertriglyceridemia, hypertension or hepatic steatosis. Moreover, female patients often develop hyperandrogenism, hirsutism, polycystic ovaries and infertility. The two most common types are FPLD type 2 and 3. Variants within LMNA and PPARG genes account for more than 50% of all reported FPLD cases. Because of its high heterogeneity and rarity, lipodystrophy can be easily unrecognized or misdiagnosed. To determine the genetic background of FPLD in a symptomatic woman and her close family, an NGS custom panel was used to sequence LMNA and PPARG genes. The affected patient presented fat deposits in the face, neck and trunk, with fat loss combined with muscular hypertrophy in the lower extremities and hirsutism, all features first manifesting at puberty. Her clinical presentation included metabolic disturbances, including hypercholesterolemia with severe hypertriglyceridemia, diabetes mellitus and hepatic steatosis. This together with her typical fat distribution and physical features raised a suspicion of FPLD. NGS analysis revealed the presence of missense heterozygous variant c.443G>A in exon 4 of PPARG gene, causing glycine to glutamic acid substitution at amino acid position 148, p.(Gly148Glu). The variant was also found in the patient’s mother and son. The variant was not previously reported in any public database. Based on computational analysis, crucial variant localization within DNA-binding domain of PPARγ, available literature data and the variant cosegregation in the patient’s family, novel c.443G>A variant was suspected to be causative. Functional testing is needed to confirm the pathogenicity of the novel variant. Inherited lipodystrophy syndromes represent a heterogenous group of metabolic disorders, whose background often remains unclear. A better understating of the genetic basis would allow earlier diagnosis and targeted treatment implementation.

Lipodystrophies in non-insulin-dependent children: Treatment options and results from recombinant human leptin therapy

“…Affected patients, especially females, in which phenotypic features are more evident, exhibit a typical fat tissue. Specifically, absence of fat tissue is mainly seen in the upper and lower extremities, while fat accumulation can be observed in certain areas (as the face, neck, perineal and intra-abdominal depots) [1][2][3][11][12][13]. The typical facial fat accumulation, together with increased fat in the dorsocervical region and thin limbs, resemble a Cushingoid-phenotype.…”

“…Common denominator of all forms of lipodystrophy is IR, which in turn induces the development of a metabolic derangement [3,13,17,[43][44][45]. Usually, complications' onset is before adulthood and tends to be more severe and have an earlier onset in CL [2].…”

“…Under physiological conditions, it performs numerous roles, including excess calorie storage, buffering postprandial circulating lipid fluxes, synthesizing and secreting hormones and adipokines, such as leptin and adiponectin, which are crucial in regulating critical processes, such as food intake and insulin sensitivity [49,50]. In lipodystrophy, secondary to adipokine deficiency, there are excessive postprandial levels of circulating triglycerides and non-esterified fatty acids, which, unable to be stored in adipose tissue, are deposited in ectopic sites [1,13,14], such as the liver, skeletal muscles, and pancreas, causing local damage of these organs and metabolic sequelae [51,52]. Insulin resistance is probably secondary to the lipotoxicity of this mechanism and is proportional to the extent of the alteration in adipose tissue [13,45].…”

“…In lipodystrophy, secondary to adipokine deficiency, there are excessive postprandial levels of circulating triglycerides and non-esterified fatty acids, which, unable to be stored in adipose tissue, are deposited in ectopic sites [1,13,14], such as the liver, skeletal muscles, and pancreas, causing local damage of these organs and metabolic sequelae [51,52]. Insulin resistance is probably secondary to the lipotoxicity of this mechanism and is proportional to the extent of the alteration in adipose tissue [13,45]. Indeed, leptin is crucial in modulating energy homeostasis, neuroendocrine and immune functions, and glucose, lipid and bone metabolism [52][53][54], Table 4.…”

“…• Control of food intake, energy expenditure, and, therefore, body weight Adipose tissue Hyperinsulinemia and severe IR result from dysmetabolic complications due to partial or near-total deficiency of adipose tissue and leptin [43]. Patients with lipodystrophy have some of the classic clinical markers of IR, such as acanthosis nigricans, which is typically characterized by hyperkeratosis, sometimes with hyperpigmentation, typically most evident in body flexures and is most frequently seen after puberty [8,13,16,43,63]. A high serum insulin level stimulates keratinocytes and fibroblasts to grow and proliferate more powerfully, which underlies the process of AN formation [13,64].…”