Phenotypic differences among Familial Partial Lipodystrophy due to LMNA or PPARG variants

CONTEXT: Despite several reports of familial partial lipodystrophy, type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. OBJECTIVES: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. DESIGN: A retrospective, cross-sectional comparison. SETTINGS: Patients from two tertiary referral centers - UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. PATIENTS: A total of196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years). MAIN OUTCOME MEASURES: Skinfold thickness, regional body fat measurements by dual energy X-ray absorptiometry (DXA), metabolic variables and prevalence of diabetes mellitus and hypertriglyceridemia. RESULTS: Compared to FPLD2 subjects, FPLD3 subjects had significantly increased prevalence of hypertriglyceridemia (66% vs. 84%) and diabetes (44% vs. 72%); and had higher median fasting serum triglycerides (208 vs. 255 mg/dL), and hemoglobin A1c (5.7% vs. 7.0%). Compared to FPLD2 subjects, FPLD3 subjects also had significantly higher median upper limb fat (20% vs. 27%) and lower limb fat (16% vs. 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs.11.3 mm); calf (4 vs. 6 mm); triceps (5.5 vs. 7.5 mm); and biceps (4.3 vs. 6.8 mm). CONCLUSIONS: Compared to FPLD2, FPLD3 subjects have milder lipodystrophy but develop more severe metabolic complications, suggesting that remaining adipose tissue in FPLD3 subjects may be dysfunctional or those with mild metabolic disease are under-recognized.