Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

Abstract

Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase β (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144 *) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.

Congenital generalized lipodystrophy in two siblings from Saudi Arabia: A case report

“…Adipocytes secrete several bioactive substances including leptin, adiponectin, and tumor necrosis factor‐α, which play an important role in the pathophysiology of insulin resistance and dyslipidemia 17 . The very low level of leptin and adiponectin in our patients is consistent with previous reports 7,15 . Serum leptin levels reflect the amount of adipose tissue in the body and correlate positively with adiposity.…”

“…3,12 Most of the AGPAT2 mutations include frameshifts or altered mRNA splicing producing nonfunctional enzyme. 15 Our two cases have pathogenic homozygous variants recognized at AGPAT2 gene, c.158del/p.(Gly53Alafs*8). This genetic variant was reported in one Emirati female presented with diabetes firstly diagnosed at 14 years of age with hypertriglyceridemia and acanthosis.…”

“…Hepatic involvement in these two siblings manifested with mild elevations of liver enzymes and hepatomegaly attributed to the accumulation of triglycerides in the livers. Another mechanism of steatohepatitis hypothesized that functional insufficiency of AGPAT2 could induce upregulation of liver activity of AGPAT1 enzyme isoform leading to overproduction of triglycerides with subsequent steatosis and hepatomegaly 15 …”

Severe insulin resistance syndromes

“…AGPAT2 deficiency associates with impaired signaling of critical elements such as PI3K/AKT and PPARγ, affecting adipogenesis and reducing the levels of stored triglycerides inside the adipose (84). At least 150 cases and 42 AGPAT2 mutations have been published, and the number of related variants has increased over time (85,86).…”

Molecular and Cellular Bases of Lipodystrophy Syndromes

“…Congenital generalized lipodystrophy syndromes (CGL or Berardinelli-Seip Congenital Lipodystrophy) are autosomal recessive diseases, mainly observed in patients from consanguineous families. They are mainly due to null variants in AGPAT2 encoding 1-acylglycerol-3-phosphate-O-acyltransferase 2, involved in triglyceride and phospholipid synthesis, or in BSCL2 encoding seipin, an endoplasmic reticulum membrane protein which contributes to lipid droplet biogenesis (11)(12)(13)(14)(15)(16). CGL3 and CGL4 are due to genetic defects in caveolin-1 or cavin-1 respectively, involved in the formation of cell plasma membrane microdomains called caveolae, that initiate several signaling pathways.…”