Case Report: Metreleptin Treatment in a Patient With a Novel Mutation for Familial Partial Lipodystrophy Type 3, Presenting With Uncontrolled Diabetes and Insulin Resistance

Abstract

BackgroundFamilial partial lipodystrophy type 3 (FPLD3) is a very rare autosomal dominant genetic disorder which is caused by mutations in the peroxisome proliferator activated receptor gamma (PPARG) gene. It is characterized by a partial loss of adipose tissue leading to subnormal leptin secretion and metabolic complications. Metreleptin, a synthetic analogue of human leptin, is an effective treatment for generalized lipodystrophies, but the evidence for efficacy in patients with FPLD3 is scarce.Case PresentationWe present a 61-year-old woman, initially misdiagnosed as type 1 diabetes since the age of 29, with severe insulin resistance, who gradually displayed a more generalized form of lipoatrophy and extreme hypertriglyceridemia, hypertension and multiple manifestations of cardiovascular disease. She was found to carry a novel mutation leading to PPARGGlu157Gly variant. After six months of metreleptin treatment, HbA1c decreased from 10 to 7.9% and fasting plasma triglycerides were dramatically reduced from 2.919 mg/dl to 198 mg/dl.ConclusionsThis case highlights the importance of early recognition of FPLD syndromes otherwise frequently observed as difficult-to-classify and manages diabetes cases, in order to prevent cardiovascular complications. Metreleptin may be an effective treatment for FPLD3.

Therapeutic indications and metabolic effects of metreleptin in patients with lipodystrophy syndromes: Real‐life experience from a national reference network

“…10,35 Interestingly, PLD patients with inadequate metabolic control (diabetes and/or triglycerides) were mostly responders to metreleptin treatment, as previously reported. 17,36,37 In our study, insulin treatment at baseline was predictive of a poorer response to metreleptin therapy on HbA1c in patients with PLD. Similarly, in clinical trials including patients with PLD, insulin therapy at baseline was associated with a smaller decrease in HbA1c after 1 year of metreleptin therapy, although HbA1c was higher at metreleptin initiation.…”

“…Moreover, in patients with chronic metabolic complications, treatments are generally less effective in real‐life studies than in clinical trials 10,35 . Interestingly, PLD patients with inadequate metabolic control (diabetes and/or triglycerides) were mostly responders to metreleptin treatment, as previously reported 17,36,37 …”

Familial Partial Lipodystrophy: Clinical Features, Genetics and Treatment in a Greek Referral Center

“…A reduction in appetite and weight loss following metreleptin treatment were reported. This case report has been described in detail previously in the literature [11].…”

“…In four patients (P36-P39), the genetic analysis included the following genes: AGPAT2, BSCL2, CAV1, CAVIN1, PLIN1, PPARG, LIPE, LMNA, AKT2, exon and exon-intron junctions. The LMNA exons, including the splice site regions, were amplified in 11 segments (10) and PPARG exons in seven segments (11) from 50 ng of genomic DNA using the PCR and exon-specific primers pairs (available on request). The resulting PCR products were analyzed in an agarose gel and purified using a PCR purification kit (Qiagen, Hilden, Germany).…”

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…High blood pressure is frequent, and can be very severe, in particular in partial lipodystrophies associated with pathogenic variants of PPARG encoding the adipogenic factor PPARg (peroxisome proliferator-activated receptor gamma) (59)(60)(61). The risk of atherosclerosis is strongly increased, which could result from insulin resistance, diabetes, and hypertension (62), but also from genetic variants that directly target the vascular wall, as observed in LMNA-related lipodystrophies (40,63,64).…”