Hypobetalipoproteinaemia

FHBL is characterised by a wide clinical spectrum. The mild form predominates and is typically detected incidentally on routine lipid testing in adulthood. Affected individuals show moderate reductions in plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B. The severe form is extremely rare and manifests in infancy or early childhood. It is characterised by failure to thrive, fat and fat-soluble vitamin malabsorption, acanthocytosis, retinitis pigmentosa and peripheral neuropathy, and is clinically indistinguishable from abetalipoproteinaemia. Hepatic steatosis is a recognised feature of the milder spectrum and is associated with the heterozygous state. Chronic liver disease incidence is elevated across follow-up in adults, with the strongest association in those with concomitant diabetes or obesity.

Whole-entity prevalence is not well established. A UK Biobank cohort identified 241 APOB loss-of-function carriers among 410,962 participants, a carrier frequency of roughly 1/1,705. This is a derived APOB-only carrier frequency and excludes the PCSK9 and ANGPTL3 subtypes. Reported estimates accordingly range from about 1/1,700, as a derived APOB loss-of-function carrier frequency, to about 1/3,000 as a clinical FHBL prevalence; the difference reflects methodology rather than a genuine discrepancy.

FHBL is caused by germline pathogenic variants in genes encoding components of the apoB-containing lipoprotein assembly and clearance pathway. APOB (located on chromosome 2p24.1) is the most common cause for FHBL (FHBL1). Loss-of-function or truncating APOB variants disable hepatic very low-density lipoprotein and intestinal chylomicron assembly and secretion. This leads to intrahepatic triglyceride accumulation and markedly reduced plasma apoB-containing lipoproteins. Loss-of-function variants in PCSK9 (located on chromosome 1p32.3) cause PCSK9-related hypocholesterolaemia, and biallelic loss-of-function variants in ANGPTL3 (located on chromosome 1p31.3) cause familial combined hypolipidaemia (FHBL2).¹ Biallelic loss-of-function variants in MTTP (located on chromosome 4q23) cause abetalipoproteinaemia, a recessive disorder that is clinically indistinguishable from severe FHBL1 and is covered by the panel.

FHBL1 follows an autosomal codominant mode of inheritance. Heterozygous carriers of a single APOB loss-of-function variant are relatively common and generally show the mild, often asymptomatic phenotype. Homozygous or compound-heterozygous individuals are extremely rare and develop the severe multisystem form. Each child of a heterozygous carrier has a 50 % probability of inheriting that variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established primarily by molecular genetic testing. Biochemically, affected individuals show markedly reduced plasma LDL cholesterol and apolipoprotein B levels; in a UK Biobank cohort, APOB loss-of-function carriers showed approximately 35% lower LDL-C and apoB than non-carriers. Hepatic imaging assesses steatosis. Ophthalmological and neurological assessment supports detection of retinitis pigmentosa and peripheral neuropathy in the severe form.

Main differential diagnosis:

• Abetalipoproteinaemia: biallelic disease clinically indistinguishable from severe FHBL1; MTTP

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

• Wakabayashi T, Takahashi M, Okazaki H, Okazaki S, Yokote K, Tada H, et al. Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1. J Atheroscler Thromb. 2024;31(7):1005-1023. doi: 10.5551/jat.RV22018. PMID: .
• Di Costanzo A, Pirona I, Buonaiuto S, Covino S, Maiorca C, Bini S, et al. Low Cholesterol due to APOB Variants: Exploring the Balance Between Liver and Cardiovascular Risk. Liver Int. 2026;46(2):e70515. doi: 10.1111/liv.70515. PMID: .