Phenotypic Differences Among Familial Partial Lipodystrophy Due to LMNA or PPARG Variants

Abstract

Context: Despite several reports of familial partial lipodystrophy (FPLD) type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear.

Objective: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2.

Methods: A retrospective, cross-sectional comparison of patients from 2 tertiary referral centers-UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. A total of 196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years) were included. The main outcome measures were skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia.

Results: Compared with subjects with FPLD2, subjects with FPLD3 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 mean hemoglobin A1c (6.4% vs 7.5%). Compared with subjects with FPLD2, subjects with FPLD3 also had significantly higher mean upper limb fat (21% 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).

Conclusion: Compared with subjects with FPLD2, subjects with FPLD3 have milder lipodystrophy but develop more severe metabolic complications, suggesting that the remaining adipose tissue in subjects with FPLD3 may be dysfunctional or those with mild metabolic disease are underrecognized.

Keywords: LMNA; PPARG; diabetes mellitus; dual-energy X-ray absorptiometry; familial partial lipodystrophy; triglycerides.

Figure 1.

Fasting serum glucose, triglycerides, HDL cholesterol, and HbA1c levels in subjects with FPLD3 and FPLD2. (A) Fasting serum glucose, (B) fasting serum triglycerides, (C) HDL-cholesterol, and (D) blood hemoglobin A1c. Numbers of subjects for whom the value of the variable was available are shown below the x-axis. The gray box shows 25th and 75th percentile values with median shown as a horizontal line. The whiskers denote 5th and 95th percentiles. Individual values below the 5th and above the 95th percentile are shown. The 95th percentile of serum triglycerides (5577 mg/dL) for subjects with FPLD3 is not shown. Serum triglycerides exceeding 2000 mg/dL were seen in 5 subjects with FPLD3 (2104, 3115, 4127, 5577, and 7919 mg/dL) and 5 subjects with FPLD2 (2160, 2285, 7740, 9040, and 11 528 mg/dL), which are not shown in the figure. P values are shown above the box plots.

Figure 2.

Skinfold thickness measurements in subjects with FPLD3 and subjects with FPLD2. (A) Subscapular skinfold thickness (mm) measurements, (B) triceps skinfold thickness (mm) measurements, and (C) thigh skinfold thickness (mm) measurements. Numbers of subjects for whom the value of the variable was available are shown below the x-axis. The gray box shows 25th and 75th percentiles with median shown as a horizontal line. The whiskers denote 5th and 95th percentiles. Individual values below the 5th and above the 95th percentile are shown. P values are shown above the box plots.

Figure 3.

Regional body fat (% of fat mass/total regional mass) measurements by DXA scan in subjects with FPLD3 and FPLD2. (A) Upper limb fat (%) measurements, (B) lower limb fat (%) measurements, (C) truncal fat (%) measurements, and (D) ratio of lower limb fat/truncal fat. Numbers of subjects for whom the value of the variable was available are shown below the x-axis. The gray box shows 25th and 75th percentiles with median shown as a horizontal line. The whiskers denote 5th and 95th percentiles. Individual values below the 5th and above the 95th percentile are shown. P values are shown above the box plots.