Endocrine Abstracts

Introduction: Familial Chylomicronemia-FC syndrome is characterized by severely elevated triglyceride levels, i.e., levels of TG above 1000 mg/dl. Monogenic etiology is associated with a small but a significant fraction of Familial Chylomicronemia (FC) Syndrome cases, which is mainly attributed to a few genes, that are involved in Lipoprotein Lipase activity (LPL / LMF1 / APOC2 / GPIHBP1 / APOA5). Bi-allelic variants in these genes cause this rare Autosomal Recessive disorder with a prevalence of ~1 to a million. We herein report a case of a 51year old male, diagnosed with FC syndrome due to a homozygous pathogenic variant in the LMF1 gene, and the clinical implications of this diagnosis.

Case description: A 51 years old male of consanguineous Jewish Yemenite ancestry, has been investigated in the Endocrinology Clinic due to recurrent pancreatitis. He was diagnosed with severe hypertriglyceridemia (TG levels up to 2300 mg/dl). His past medical history includes type 2 diabetes mellitus and complex PTSD. No family history could be retrieved. Initial treatment included a combination of fibrates, statin, ezetimibe and omega3 fatty acids. The patient was instructed to avoid alcohol, and a strict dietary-fat restriction. Despite good adherence to this treatment, triglyceride levels remained high, around 700mg/dl, and he continues to suffer from mild episodes of pancreatitis that reduce his quality of life.

Molecular investigation: Homozygous LMF1 c.1391G>A p.Trp464* (RefSeq NM_022773), classified as “Pathogenic” according to the ACMG guidelines.

Discussion: Involvement of LMF1 gene by loss-of-function mechanism has been initially reported in 2007 [Péterfy et al]. LMF1 gene encodes a transmembrane protein, which is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in the endoplasmic reticulum. The LMF1 variant diagnosed in our patient, was previously described (doi: 10.1210/jc.2009-0594). Functional analysis of this variant revealed significantly reduced expression and activity of LMF1 protein. The clinical presentation of our patient is consistent with the molecular diagnosis of Lipase Deficiency (OMIM #246650). Due to lack of improvement on current available treatments, he is a candidate for treatment with Volanesorsen-, a second-generation 2’-O-methoxyethyl (2’-MOE) chimeric antisense therapeutic oligonucleotide, that decreases plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. We suspect that the rarity of this syndrome is partly due to underdiagnosis, and the availability of Next generation sequencing will improve our diagnosis and treatment options for our patients. Our hope is to offer personalized treatment based on the specific molecular diagnosis.