The Janus-faced manifestations of homozygous familial hypobetalipoproteinemia due to apolipoprotein B truncations.

Familial hypobetalipoproteinemia is a codominant disorder characterized by low plasma levels of low-density lipoprotein cholesterol and apolipoprotein B (apoB), which in ∼50% of the cases is due to mutations in APOB gene. In most cases, these mutations cause the formation of truncated apoBs of various sizes, which have a reduced capacity to bind lipids and form lipoprotein particles. Here, we describe 2 children with severe hypobetalipoproteinemia found to be homozygous for novel APOB gene mutations. The first case (HBL-201) was an asymptomatic 13-year-old boy incidentally found to have slightly elevated serum transaminases associated with hepatic steatosis. He was homozygous for a truncated apoB (2211 amino acids, apoB-48.74) whose size is similar to that of wild-type apoB-48 (2152 amino acids) produced by the intestine. ApoB-48.74 is expected to be incorporated into chylomicrons in the intestine but might have a reduced capacity to form secretion-competent very low-density lipoprotein in the liver. The second patient (HBL-96) was a 6-month-old girl suspected to have abetalipoproteinemia, for the presence of chronic diarrhea, failure to thrive, extremely severe hypobetalipoproteinemia, and low plasma levels of vitamin E and vitamin A. She was homozygous for a nonsense mutation (Gln513*) resulting in a short truncated apoB (apoB-11.30), which is not secreted into the plasma. In this patient, the impaired chylomicron formation is responsible for the severe clinical manifestations and growth retardation. In homozygous familial hypobetalipoproteinemia, the capacity of truncated apoBs to form chylomicrons is the major factor, which affects the severity of the clinical manifestations.

Non-alcoholic steatohepatitis-related cirrhosis in a patient with APOB L343V familial hypobetalipoproteinaemia.

Familial hypobetalipoproteinaemia (FHBL) is a rare monogenic cause of hypocholesterolaemia. Increased liver transaminase concentrations and hepatic steatosis are a common occurrence in FHBL. Although FHBL subjects are protected against atherosclerotic cardiovascular disease, consequences of fatty liver in FHBL over the longer term are not known. We describe a case in which an obese woman with APOB L343V FHBL developed non-alcoholic steatohepatitis-related cirrhosis of the liver. Given the potential for progression to cirrhosis, it would seem prudent to serially monitor the livers of these individuals using biochemical and imaging techniques, particularly in the presence of known risk factors that lead to further liver injury, such as alcohol and caloric excess.

Variable phenotypic expression of homozygous familial hypobetalipoproteinaemia due to novel APOB gene mutations.

Homozygous familial hypobetalipoproteinaemia (Ho-FHBL) is a rare co-dominant disorder characterized by extremely low levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Most patients with Ho-FHBL have mutations in APOB gene resulting in truncated apoBs. Some patients are asymptomatic, while others have fatty liver, intestinal fat malabsorption and neurological dysfunctions. We investigated three adult subjects with severe hypobetalipoproteinaemia and a family history of FHBL. Proband FHBL-47 had liver cirrhosis with hepatocarcinoma and a renal carcinoma but no clinical manifestations related to FHBL. He was a compound heterozygote for a 7-bp deletion in exon 21 and a base insertion in exon 26 resulting in truncated apoBs (apoB-22.46/apoB-66.51). Proband FHBL-53, with severe hepatic steatosis and fibrosis, had a nonsense mutation in exon 19 resulting in a truncated apoB (apoB-20.61) and a rare nucleotide substitution in intron 14 (c.2068-4T>A). The latter was also present in her daughter, found to have low plasma LDL-C and apoB. Proband FHBL-82 had chronic diarrhoea and steatorrhoea. She was found to be homozygous for a nonsense mutation in exon 24 resulting in a truncated apoB (apoB-26.65). In adult subjects, the presence of chronic liver disease and chronic diarrhoea, when associated with severe hypobetalipoproteinaemia, may lead to the diagnosis of Ho-FHBL.