Endocrine Abstracts

Introduction: Familial Partial Lipodystrophy (FPLD) is a rare genetic disorder characterized by marked loss of subcutaneous adipose tissue from the extremities and is associated with a variety of metabolic abnormalities. While phenotypic elements of the disorder can vary across genotypes, symptomatic presentation, disease severity, and onset can also vary among individuals with the same disease-causing variant, or even among family members. Due to this variability, and the rarity of the disease, an encompassing patient profile has been challenging to determine. Therefore, we present a detailed phenotypic/genotypic description of the FPLD patients who participated in a Phase 2/3 clinical trial.

Methods: Baseline data from patients with FPLD (n = 40) participating in a phase 2/3 study of volanesorsen (apo C-III antisense oligonucleotide) were analyzed to provide greater insight into the clinical, genotypic and phenotypic profile of patients with FPLD. Patients were required to have FPLD by genetic, familial or phenotypic criteria, fasting triglycerides ≥ 2.3 mg/dl and confirmed diabetes mellitus by an elevated HgbA1c.

Results: Participants had a median age of 49 years (range 28–68 y), were predominately female (n = 29, 72.5%), with a 78.4 kg (range 57.8–126.1 kg) median body weight and BMI of 29.8 kg/m² (range 21.0–44.2). Sixteen patients had genetically confirmed FPLD, with 12 harboring pathogenic missense variants in LMNA and 4 in PPARG. Additionally, three patients had variants of uncertain significance in FPLD related genes. No patient had a pathogenic variant in PLIN1, AKT2 or CIDEC. Median fasting triglycerides were 8.6 mmol/l (range 2.4–60.4). Seven patients reported using triglyceride lowering medications (statins, fibrates, omega 3/fish oil). All patients had clinical diabetes mellitus with mean HgbA1C of 8.0% (s.d. 1.4%). Twenty-six patients reported use of insulin or other hypoglycemic medications. Medical history of fatty liver disease was reported by 26 patients and mean baseline hepatic fat fraction was 17.6% (s.d. 7.9%).

Conclusion: We conclude that the majority of the eligible participants for this trial lacked variants in the known FPLD genes. FPLD, type 2, due to LMNA variants was the most prevalent subtype of FPLD in our cohort followed by FPLD, type 3 due to PPARG variants. Both variant positive and negative patient groups had the hallmark traits of abnormal fat distribution, severely elevated triglycerides, diabetes and elevated HgbA1C, and significant hepatic steatosis. The complex characteristics of this disorder support the need for careful clinical phenotyping of the cases and investigation of the variability in the presentations.