Clinical Information

Monogenic causes of hypobetalipoproteinemia include familial hypobetalipoproteinemia (FHBL), abetalipoproteinemia (ABL), chylomicron retention disease (CMRD), loss of function variants in PCSK9, and familial combined hypolipidemia (FCH).

FHBL is the most common form of hypobetalipoproteinemia and is characterized by apolipoprotein B (ApoB) levels below the 5th percentile and low-density lipoprotein cholesterol (LDL-C) concentrations in the range of 20 mg/dL to 50 mg/dL. FHBL displays codominant inheritance, whereby heterozygous individuals may be asymptomatic or have mild disease, and (rare) compound heterozygous and homozygous individuals develop more severe, early-onset disease. In cases of mild to moderate FHBL with little or no liver involvement, prognosis is good and, in fact, may be associated with increased longevity. In severe disease, symptoms include fatty liver, which may progress to cirrhosis over time, symptoms of fat malabsorption, failure to thrive, and neurological and ocular dysfunction. FHBL is most commonly due to disease-causing truncating variants in the APOB gene resulting in reduced or nonfunctional protein.

ABL is a rare (<1:1,000,000) condition characterized by triglyceride concentrations of less than 30 mg/dL, cholesterol concentrations of less than 30 mg/dL, and undetectable LDL and ApoB levels. Clinical presentation is similar to that described above for compound heterozygous and homozygous FHBL. ABL displays autosomal recessive inheritance and is caused by compound heterozygous or homozygous disease-causing variants in the MTTP gene.

CMRD is a rare lipid malabsorption syndrome that typically presents in young infants with diarrhea, steatorrhea, abdominal distention, and failure to thrive. Laboratory findings include LDL-C and high-density lipoprotein cholesterol-C reduction of approximately 50% with normal triglyceride concentrations. CMRD displays autosomal recessive inheritance and is caused by compound heterozygous or homozygous disease-causing variants in the SAR1B gene.

Heterozygous loss-of-function variants in the PCSK9 gene are associated with mild to moderate reduction in LDL-C and normal health with significantly lower prevalence of atherosclerotic heart disease. Rare individuals with biallelic loss-of-function variants in PCSK9 have been reported with extremely low levels of LDL-C (approximately 15 mg/dL), normal health and reproductive capacity, and no evidence of neurologic or cognitive dysfunction. Notably, heterozygous gain-of-function variants in PCSK9 are associated with familial hypercholesterolemia.

Finally, FCH is a very rare condition of panhypolipidemia associated with normal health and significantly lower prevalence of atherosclerotic heart disease. This condition is caused by loss-of-function variants in the ANGPTL3 gene. Similar to FHBL and PCSK9, FCH displays codominant inheritance, with heterozygotes having normal HDL-C and LDL-C concentrations that are below the 25th percentile, while compound heterozygous and homozygous individuals display significant reductions in HDL-C levels as well.