Targeted Therapeutic Approach in Patients With Familial Partial Lipodystrophy Type 3

Introduction: Familial partial lipodystrophy (FPLD) syndromes are genetic disorders characterized by selective lipoatrophy affecting the upper and lower extremities leading to severe insulin resistance and metabolic complications. We describe a patient diagnosed with a pathogenic variant in the peroxisome proliferator-activated receptor γ (PPARγ) gene that causes FPLD type 3 (FPLD3) subsequently treated with pioglitazone with excellent response. Clinical Case: A 52-year-old Hispanic woman with type 2 diabetes mellitus and hypertension presented with epigastric pain and vomiting. Workup revealed elevated lipase to 1889 U/L and triglycerides to 4117 mg/dL, consistent with hypertriglyceridemia-induced pancreatitis. CT abdomen showed acute pancreatitis with hepatic steatosis. Family history was significant for hypertension, diabetes, and hyperlipidemia in her father, mother, and five siblings. Examination revealed facial and truncal obesity, lipoatrophy of her limbs and buttocks, acanthosis nigricans, and hepatomegaly. The patient was treated with an insulin drip with decline in triglyceride levels (450 mg/dL) and discharged on atorvastatin, fenofibrate, metformin, and pioglitazone. Laboratory evaluation revealed an HbA1c of 9%, normal thyroid and liver function tests, and a serum leptin of 1.2 ng/ ml (N females: 4.7–23.7 ng/ml). Lipoprotein electrophoresis showed type 4 lipoproteinemia. A liver fibroscan showed hepatic steatosis with portal fibrosis. Genetic testing was notable for an autosomal dominant pathogenic heterozygous loss-of-function mutation in the ligand binding domain AF-2 region of PPARγ (c.452 A>G) confirming FPLD3. Pioglitazone was increased to 30mg/day with improvement in HbA1c to 8.3% and dyslipidemia at three-month follow up. Conclusion: FPLD3 is caused by loss-of-function mutations in PPARγ, a transcription factor involved in adipogenesis(1). FPLD is estimated to affect 1 per 1 million, with FPLD3 reported in approximately 30 individuals worldwide per National Organization for Rare Disorders. Treatment is currently directed at reducing insulin resistance, dyslipidemia, and their sequelae of pancreatitis and cardiovascular disease. Thiazolidinediones (TZDs), PPARγ agonists targeting insulin sensitivity and adipocyte differentiation, have been used in FPLD with variable results. Different mutations in the ligand-binding domains of PPARγ may affect the binding capacity to synthetic agonists, affecting clinical response. Use of TZDs in individuals with PPARγ mutations (R308P, A261E) have been shown to improve hyperglycemia and dyslipidemia(2). Our patient was treated with pioglitazone with excellent response to therapy in three months. TZDs may offer a targeted approach to treat FPLD3 based on PPARγ ligand-dependent responsiveness. References: (1) Garg A. JCEM 2011;96:3313–3325(2) Agostini M. Diabetes. 2018;67(6):1086–1092