Familial hypobetaliproteinemia E78.6

Familial hypobetalipoproteinemia" is a group of genetically different, phenotypically identical, hereditary diseases of the lipoprotein metabolism, which are associated with permanently low levels of

• apolipoprotein B
• and
• LDL cholesterol.

Familial HBL can be either severe with early onset (abetalipoproteinemia / homozygous familial hypobetalipoproteinemia) or benign (benign familial hypobetalipoproteinemia), with a milder course or clinically inapparent.

This is caused by autosomal-dominantly inherited mutations that impair the synthesis, secretion and catabolism of apolipoprotein B-containing proteins (LDL, VLDL and chylomicrons).

• Abetalipoproteinaemia is an autosomal recessive inherited disease caused by mutations in the MTTP gene (4q22-q24).
• Severe early familial hyperlipoproteinemia is inherited codominantly and is caused by mutations in the APOB gene (2p24.1).
• Benign familial HBL is inherited codominantly. It is caused by heterozygous mutations in the APOB gene and the PCSK9 gene (1p34.1-p32). The PCSK9 gene (proprotein convertase subtilisin-like kexin type 9) encodes a serine protease.
• CMRD is inherited autosomal recessively and is caused by mutations in the gene for the GTPase SARA2 (SAR1B; 5q31.1).

The prevalence of FHBL for the heterozygous form of familial hypobetalipoproteinemia ranges from 1:1,000 to 1:3,000 individuals. The homozygous form is extremely rare.

There are different mutations in the following genes:

• MTTP gene (Microsomal triglyceride transfer protein) Abetalipoproteinemia
• APOB gene (Apolipoprotein B gene) - Familial hypobetalipoproteinemia
• PCSK9 gene (protein convertase subtilisin-like kexin type 9)
• ANGPTL3 gene (angiopoietin-related protein 3)
• GTPase SARA1B (Secretion Associated Ras Related GTPase 1B)
• chylomicron retention disease
• Other mutations whose genloci have not yet been identified are known.

Mutations in the MTP gene (microsomal triglyceride transfer protein), which codes for the microsomal triglyceride transfer protein, cause abetalipoproteinaemia (OMIM 200100; Wetterau JR et al.1992). MTP catalyses the transport and incorporation of triglycerides, cholesterol esters, phospholipids and retinyl palmitate (vitamin A) into the plasma lipoproteins associated with apolipoprotein B (Apo B) (VLDL, IDL, LDL, chylomicrons).

Mutations in the apolipoprotein B gene can lead to shortened functionally altered apolipoprotein B molecules. These are then catabolized more quickly. The apolipoprotein B concentration in blood plasma is reduced by about 25-30% of the normal value.

Mutations in the ANGPTL3 gene (Angiopoietin-Related Protein 3) (OMIM: 604774) result in apolipoprotein B levels about 50% below normal. The ANGPTL3 protein encoded by the ANGPTL3 gene is produced by the liver and inhibits on the one hand the endogenous lipase which breaks down fats and on the other hand the lipoprotein lipase which removes triglyceride rich lipoproteins from the bloodstream. Versch. mutations associated with a loss of ANGPTL3 function lead to a phenotype with greater fat breakdown and faster removal of lipoproteins from the blood. Laboratory chemistry shows that people with complete loss of ANGPTL3 function have very low serum levels of the triglycerides LDL and HDL.

Missense mutations in the PCSK9 gene (Proprotein Convertase Subtilisin/Kexin Type 9) lead to a functional change of the PCSK9 serine protease (Berge KE et al. 2006). The serine protease regulates the breakdown of LDL receptors (LDLRs) in the liver and thus indirectly the amount of LDL in the blood plasma. The consequence of this missense mutation is a disturbed degradation rate of the LDRLs and thus an extension of their duration of action. Thus, the LDL concentration in the blood plasma decreases.

Autosomal recessive mutations in the GTPase SARA1B gene (Secretion Associated Ras Related GTPase 1B) are the cause of chylomicron retention disease (CMRD; Andersen's disease; OMIM: 246700). The SARA1B mutation leads to accumulation of prechylomicron transport silica in the cytoplasm of intestinal cells. One of the consequences is a lack of absorption of fat-soluble vitamins (e.g. vitamin A, E and K). Treatment includes supplementation with fat-soluble vitamins and large amounts of vitamin E. Vitamin A in combination with vitamin E can help prevent ophthalmological complications. Early treatment with vitamin D can prevent osteopenia.

Patients often only stand out due to a non-alcoholic fatty liver (NAFLD) and an increase in transaminases in the blood plasma. In laboratory findings, the LDL value is lowered and the HDL value is normal. Hypocholesterolemia and hypotriglyceridemia are possible. The diagnosis of CMRD is based on the absence of intestinal apolipoprotein B (ApoB-48) after oral lipid load and the endoscopic detection of a 'white bowel'.

Metabolic diseases with hepatic overload, with steatosis and/or hepatomegaly, atypical courses of diseases of the central and peripheral nervous system and secondary causes of hypercholesterolemia.

1. Berge KE et al (2006) Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy. Arterioscler Thromb Vasc Biol 26:1094-1100.
2. Jones B et al (2003) Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nat Genet 34:29-31.
3. Wetterau J R et al (1992) Absence of microsomal triglyceride transfer protein in individuals with a betalipoproteinemia. Science 258: 999-1001