Last Updated: January 10, 2024
Introduction to Abetalipoproteinemia
Abetalipoproteinemia is a dyslipidemic disorder resulting from mutations in the gene (MTTP) encoding microsomal triglyceride transfer protein, MTP. There are three essential functions associated with MTP including lipid transfer, apoB binding, and membrane association. Functional MTP is composed of a large subunit encoded by the MTTP gene and a small subunit which is a member of the protein disulfide isomerase (PDI) family of proteins involved in the processes of protein folding in the endoplasmic reticulum (ER).
Microsomal triglyceride transfer protein functions in the assembly and secretion of primordial apoB-containing lipoproteins in a process that includes two major steps. In the first step, the so-called primordial lipoprotein particle is synthesized while in the second step there is core expansion of the primordial lipoproteins and the synthesis of what is referred to as nascent lipoproteins. The first step of primordial lipoprotein assembly involves both a nucleation and a desorption. When the newly synthesized apoB protein is translocated into the endoplasmic reticulum, the N-terminus of the protein associates with the inner membrane and acquires neutral lipids forming nucleation sites. These nucleation sites most likely arise from endoplasmic reticulum microdomains harboring triglyceride-synthesizing enzymes. The formation of these nucleation sites is enhanced in the presence of MTP due to its neutral lipid transfer activity.
Molecular Biology of Abetalipoproteinemia: MTTP Gene
The MTTP gene is located on chromosome 4q23 and is composed of 19 exons that generate three alternatively spliced mRNAs that collectively encode two precursor proteins of 894 amino acids (isoform 1) and 921 amino acids (isoform 2). Expression of the MTTP gene is essentially exclusive to the liver and the small intestines with very low level of expression seen in the kidney and testes. Over 30 different mutations in the MTTP gene have been identified in ABL patients.
Clinical Features of Abetalipoproteinemia
ABL is a rare autosomal recessive disease that is characterized by very low plasma concentrations of triglyceride and total cholesterol (<30 mg/dl) and is also associated with undetectable levels of LDL and apoB. In addition to the low serum lipid profiles, ABL patients have low serum levels of all four fat soluble vitamins (A, D, E, and K). Because hepatic production and secretion of VLDL is required for normal lipid homeostasis, the loss of MTP activity is associated with hepatic steatosis resulting from triglyceride accumulation.
Major clinical findings in abetalipoproteinemia patients include failure to thrive, fat malabsorption, steatorrhea, hepatomegaly, and spinocerebellar ataxia.
Hematologic findings in patients with ABL include acanthocytosis, anemia, reticulocytosis, hyperbilirubinemia, and prolonged bleeding (as measured by INR: international normalized ratio) due to deficiency in vitamin K.
Patients with abetalipoproteinemia experience ophthalmological problems that are most often associated with abnormal pigmentation of the retina. In the absence of treatment this condition may eventually lead to total loss of vision.
Treatment of Abetalipoproteinemia
The characterization of the dramatically reduced plasma levels of LDL cholesterol in patients with ABL prompted investigations aimed at targeting MTP inhibition in the treatment of various hypercholesterolemias. Indeed, lomitapide, a small molecule inhibitor of microsomal triglyceride transfer protein, was approved for use in the treatment of familial hypercholesterolemia by the US FDA in 2012.