Hypobetalipoproteinaemia

• Reduced Apo B, LDL-C and VLDL
• Fatty liver disease (hepatic steatosis)
• Fat malabsorption in some carriers
• Weakened tendon reflexes
• Neurological symptoms in severe cases
• Panhypolipidaemia in ANGPTL3-related FHBL2

• FHBL1 prevalence: 1:1,000–1:3,000
• PCSK9-associated FHBL: <1:100,000
• Homozygous hypobetalipoproteinaemia (HHBL): <1:1,000,000

FHBL1 (APOB-associated)

FHBL1 is often caused by heterozygous truncating variants in APOB. The hepatic secretion rate of Apo B–containing lipoproteins correlates with the length of the shortened Apo B polypeptides. Truncated Apo B molecules are generally non-functional and degrade rapidly, resulting in markedly reduced plasma Apo B levels (below the 5th percentile) and LDL-C concentrations, typically between 20 and 50 mg/dl. Despite the presence of one wild-type allele, plasma Apo B levels average only 24%. Clinically, this results in a risk factor for hepatic steatosis.

Homozygous hypobetalipoproteinaemia (HHBL)

HHBL is very rare. Affected individuals carry homozygous or combined heterozygous variants in APOB. The clinical phenotype is indistinguishable from abetalipoproteinaemia.

PCSK9-associated FHBL

PCSK9-associated FHBL is caused by heterozygous pathogenic loss-of-function variants in PCSK9. The PCSK9 protein regulates LDL receptor availability on hepatocytes. Loss of PCSK9 function results in reduced LDL receptor degradation, increased receptor recycling, and consequently lower LDL-C levels. In contrast, pathogenic gain-of-function variants in PCSK9 cause PCSK9-associated hypercholesterolaemia.

FHBL2 / Familial combined hypolipidaemia (ANGPTL3-associated)

FHBL2 is caused by homozygous or combined heterozygous loss-of-function variants in ANGPTL3. The ANGPTL3 protein normally inhibits lipases such as lipoprotein lipase and endothelial lipase. Loss-of-function variants remove this inhibition, leading to more efficient VLDL and HDL metabolism. Clinically, this manifests as panhypolipidaemia with reductions in all plasma lipoproteins and apolipoproteins, including HDL-C.

• FHBL is inherited in a codominant manner.
• FHBL1 is typically caused by heterozygous truncating variants in APOB.
• PCSK9-associated FHBL results from heterozygous loss-of-function variants in PCSK9.
• FHBL2 results from homozygous or combined heterozygous loss-of-function variants in ANGPTL3.

Diagnosis is based on lipid profiling demonstrating markedly reduced Apo B and LDL-C levels, clinical findings such as fatty liver disease, and molecular genetic analysis of APOB, PCSK9 and ANGPTL3.

• Abetalipoproteinaemia
• Secondary hypolipidaemias, including those caused by malnutrition, strict vegan diet, malignancies, and chronic liver disease

Most heterozygous carriers do not require treatment. In the presence of neurological symptoms, dietary measures and supplementation with vitamins A and E may be required, following treatment protocols established for abetalipoproteinaemia.

Carriers generally have a reduced coronary risk due to low LDL and VLDL levels.

• Rimbert et al. 2015, Atherosclerosis 250:52
• Burnett et al. 2012, Eur J Hum Genet 20
• Martin-Campos et. al. 2012, Clin Chim Acta. 413:552
• Tarugi et Averna 2011, Adv Clin Chem 54:81
• Kane et Havel, in Scriver CR et al. 2001 (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th Ed. Chapter 115
• Fasano et al. 2007, Arterioscler Thromb Vasc Biol. 27:677