Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.

Hypobetalipoproteinemias (HBL) represent a heterogeneous group of disorders characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in the population. HBL are defined as primary or secondary according to the underlying causes. Primary monogenic HBL are caused by mutations in several known genes (APOB, PCSK9, MTP, SARA2) or mutations in genes not yet identified. Familial hypobetalipoproteinemia (FHBL) is the most frequent monogenic form of HBL with a dominant mode of inheritance. It may be due to loss-of-function mutations in APOB or, less frequently, in PCSK9 genes. The rare recessive forms of primary monogenic HBL are represented by abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD) due to mutations in MTP and SARA2 genes, respectively. The clinical phenotype of heterozygous FHBL is usually mild, being frequently characterized by fatty liver. The clinical phenotype of homozygous FHBL, ABL, and CMRD is usually severe being characterized by intestinal lipid malabsorption and fat-soluble vitamin deficiency. Secondary HBL are due to several nongenetic factors such as diet, drugs, and disease-related conditions. The aim of this review is to discuss the biochemistry, genetics, and clinical spectrum of HBL and to provide a clinical and laboratory diagnostic algorithm.