Efficacy of Metreleptin Treatment in Familial Partial Lipodystrophy Due to PPARG vs LMNA Pathogenic Variants.

Familial partial lipodystrophy (FPLD) is most commonly caused by pathogenic variants in LMNA and PPARG. Leptin replacement with metreleptin has largely been studied in the LMNA group. To understand the efficacy of metreleptin in PPARG vs LMNA pathogenic variants and investigate predictors of metreleptin responsiveness. Subgroup analysis of a prospective open-label study of metreleptin in lipodystrophy. National Institutes of Health, Bethesda, Maryland. Patients with LMNA (n = 22) or PPARG pathogenic variants (n = 7), leptin <12 ng/mL, and diabetes, insulin resistance, or high triglycerides. Metreleptin (0.08 to 0.16 mg/kg) for 12 months. Hemoglobin A1c (HbA1c), lipids, and medication use at baseline and after 12 months. Baseline characteristics were comparable in patients with PPARG and LMNA: HbA1c, 9.2 ± 2.3 vs 7.8 ± 2.1%; median [25th, 75th percentile] triglycerides, 1377 [278, 5577] vs 332 [198, 562] mg/dL; leptin, 6.3 ± 3.8 vs 5.5 ± 2.5 ng/mL (P > 0.05). After 12 months of metreleptin, HbA1c declined to 7.7 ± 2.4 in PPARG and 7.3 ± 1.7% in LMNA; insulin requirement decreased from 3.8 [2.7, 4.3] to 2.1 [1.6, 3.0] U/kg/d in PPARG and from 1.7 [1.3, 4.4] to 1.2 [1.0, 2.3] U/kg/d in LMNA (P < 0.05). Triglycerides decreased to 293 [148, 406] mg/dL in LMNA (P < 0.05), but changes were not significant in PPARG: 680 [296, 783] mg/dL at 12 months (P = 0.2). Both groups were more likely to experience clinically relevant triglyceride (≥30%) or HbA1c (≥1%) reduction with metreleptin if they had baseline triglycerides ≥500 mg/dL or HbA1c >8%. Metreleptin resulted in similar metabolic improvements in patients with LMNA and PPARG pathogenic variants. Our findings support the efficacy of metreleptin in patients with the two most common genetic causes of FPLD.

Sekizkardes H ，Cochran E ，Malandrino N ，Garg A ，Brown RJ ... -  《-》

Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin.

Diker-Cohen T ，Cochran E ，Gorden P ，Brown RJ ... -  《-》

Clinical presentations, metabolic abnormalities and end-organ complications in patients with familial partial lipodystrophy.

Familial partial lipodystrophy (FPLD) is a rare genetic disorder characterized by partial lack of subcutaneous fat. This multicenter prospective observational study included data from 56 subjects with FPLD (18 independent Turkish families). Thirty healthy controls were enrolled for comparison. Pathogenic variants of the LMNA gene were determined in nine families. Of those, typical exon 8 codon 482 pathogenic variants were identified in four families. Analysis of the LMNA gene also revealed exon 1 codon 47, exon 5 codon 306, exon 6 codon 349, exon 9 codon 528, and exon 11 codon 582 pathogenic variants. Analysis of the PPARG gene revealed exon 3 p.Y151C pathogenic variant in two families and exon 7 p.H477L pathogenic variant in one family. A non-pathogenic exon 5 p.R215Q variant of the LMNB2 gene was detected in another family. Five other families harbored no mutation in any of the genes sequenced. MRI studies showed slightly different fat distribution patterns among subjects with different point mutations, though it was strikingly different in subjects with LMNA p.R349W pathogenic variant. Subjects with pathogenic variants of the PPARG gene were associated with less prominent fat loss and relatively higher levels of leptin compared to those with pathogenic variants in the LMNA gene. Various metabolic abnormalities associated with insulin resistance were detected in all subjects. End-organ complications were observed. We have identified various pathogenic variants scattered throughout the LMNA and PPARG genes in Turkish patients with FPLD. Phenotypic heterogeneity is remarkable in patients with LMNA pathogenic variants related to the site of missense mutations. FPLD, caused by pathogenic variants either in LMNA or PPARG is associated with metabolic abnormalities associated with insulin resistance that lead to increased morbidity.

Akinci B ，Onay H ，Demir T ，Savas-Erdeve Ş ，Gen R ，Simsir IY ，Keskin FE ，Erturk MS ，Uzum AK ，Yaylali GF ，Ozdemir NK ，Atik T ，Ozen S ，Yurekli BS ，Apaydin T ，Altay C ，Akinci G ，Demir L ，Comlekci A ，Secil M ，Oral EA ... -  《-》

Effects of Metreleptin in Pediatric Patients With Lipodystrophy.

Lipodystrophy syndromes are rare disorders of deficient adipose tissue. Metreleptin, a human analog of leptin, improved metabolic abnormalities in mixed cohorts of children and adults with lipodystrophy and low leptin. Determine effects of metreleptin on diabetes, hyperlipidemia, nonalcoholic fatty liver disease (NAFLD), growth, and puberty in pediatric patients with lipodystrophy and low leptin. Prospective, single-arm, open-label studies with continuous enrollment since 2000. National Institutes of Health, Bethesda, Maryland. Fifty-three patients aged 6 months to <18 years with lipodystrophy, leptin level <8 ng/mL (male patients) or <12 ng/mL (female patients), and ≥1 metabolic abnormality (diabetes, insulin resistance, or hypertriglyceridemia). Subcutaneous metreleptin injections (0.04 to 0.19 mg/kg/d). Change in A1c, lipid, and transaminase levels after a mean ± standard deviation (SD) of 12 ± 0.2 months and 61 ± 39 months. Changes in liver histology, growth, and pubertal development throughout treatment. After 12 months, the A1c level (mean ± SD) decreased from 8.3% ± 2.4% to 6.5% ± 1.8%, and median triglyceride level decreased from 374 mg/dL [geometric mean (25th,75th percentile), 190, 1065] to 189 mg/dL (112, 334; P < 0.0001), despite decreased glucose- and lipid-lowering medications. The median [geometric mean (25th,75th percentile)] alanine aminotransferase level decreased from 73 U/L (45, 126) to 41 U/L (25, 59; P = 0.001), and that of aspartate aminotransferase decreased from 51 U/L (29, 90) to 26 U/L (18, 42; P = 0.0002). These improvements were maintained over long-term treatment. In 17 patients who underwent paired biopsies, the NAFLD activity score (mean ± SD) decreased from 4.5 ± 2.0 to 3.4 ± 2.0 after 3.3 ± 3.2 years of metreleptin therapy (P = 0.03). There were no clinically significant changes in growth or puberty. Metreleptin lowered A1c and triglyceride levels, and improved biomarkers of NAFLD in pediatric patients with lipodystrophy. These improvements are likely to reduce the lifetime burden of disease.

Brown RJ ，Meehan CA ，Cochran E ，Rother KI ，Kleiner DE ，Walter M ，Gorden P ... -  《-》

Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety.

Simha V ，Subramanyam L ，Szczepaniak L ，Quittner C ，Adams-Huet B ，Snell P ，Garg A ... -  《-》