Hypobetalipoproteinemia, Familial, 2


A number sign (#) is used with this entry because of evidence that familial hypobetalipoproteinemia-2 (FHBL2) is caused by homozygous or compound heterozygous mutation in the ANGPTL3 gene (604774) on chromosome 1p31.


Hypobetalipoproteinemia (HBL) is defined as permanently low levels, below the 5th percentile of sex- and age-matched individuals in the population, of apolipoprotein B (apoB), total cholesterol, and low-density lipoprotein (LDL) cholesterol; the lipid profile in FHBL2 includes low HDL cholesterol as well. HBL can result from environmental factors such as a strict vegetarian diet, or can be secondary to certain diseases such as intestinal fat malabsorption, chronic pancreatitis, severe liver disease, malnutrition, or hyperthyroidism. Heritable primary causes of HBL include chylomicron retention disease (CMRD; 246700), abetalipoproteinemia (200100), and familial hypobetalipoproteinemia (FHBL) (summary by Martin-Campos et al., 2012).

For a discussion of genetic heterogeneity of familial hypobetalipoproteinemia, see FHBL1 (615558).

Clinical Features

Pisciotta et al. (2012) studied 3 kindreds from northern Italy in which affected members had absence of plasma ANGPTL3 and mutations in the ANGPTL3 gene (see MOLECULAR GENETICS). In the first kindred, the proband was a 65-year-old woman who presented with very low plasma lipid levels at 52 years of age, including low total, LDL, and HDL cholesterol, triglyceride, and apoA1 and apoB levels. Density gradient ultracentrifugation showed an almost complete absence of the VLDL peak and substantial reduction of the LDL and HDL peaks. She had no family history of cardiovascular disease and no clinical manifestations; ECG stress test was normal and carotid intima-media thickness was within the normal range, with a maximum of 0.8 mm. Over 13 years of follow-up, she remained in good health and the plasma lipid profile was unchanged. Reexamination of the carotid arteries by ultrasonography at age 65 showed a moderate increase in maximum intima-media thickness, to 1.0 to 1.2 mm; abdominal ultrasound showed no evidence of fatty liver. In the second kindred, the proband was a healthy 59-year-old man who presented with low total, LDL, and HDL cholesterol and triglyceride levels. The proband, a former smoker, was clinically healthy, although carotid ultrasonography showed fibrous plaques at the left carotid bifurcation with 25% stenosis. There was a family history of premature coronary artery disease; his father had died of a myocardial infarction at 40 years of age. The proband's healthy brother, a current smoker, had an identical lipid profile; his carotid ultrasound showed a moderate increase in intima-media thickness, with a maximum thickness of 0.9 mm. Abdominal ultrasound was normal in both brothers. In the third kindred, the proband presented at 85 years of age with an acute respiratory tract infection, at which time she was found to have marked hypolipidemia. She died suddenly at 91 years of age.

Martin-Campos et al. (2012) studied 2 unrelated Spanish families with hypobetalipoproteinemia, including a brother and sister from the first family and a male patient from the second, who showed the typical lipid profile of FHBL, with total, HDL, and LDL cholesterol and triglyceride levels below the 5th percentile of the age- and sex-matched Spanish population. Comparison of the lipid profile of the Spanish population to that of family members showed significant differences only between the general population and homozygotes, although a trend was observed toward lower HDL cholesterol in heterozygotes compared to the mean for the Spanish population. Liver ultrasound in the proband from the second family was normal, and liver function tests were normal in the proband and his mother.

Minicocci et al. (2012) studied 9 hypocholesterolemic families from a small town in Italy in which at least 1 family member had an LDL cholesterol level less than the age- and gender-matched 5th percentile for the general Italian population; 1 of the families had previously been reported by Fazio et al. (1991) and was known not to be linked to APOB. The 23 hypocholesterolemic family members tended to be older and also had significantly reduced plasma levels of HDL cholesterol and triglycerides compared to normocholesterolemic relatives. All family members studied were carriers of the common E3/E3 APOE genotype (107741.0015) except for 1 individual who was E2/E2 (107741.0001). Examination of 352 residents of the town revealed 46 more persons who had LDL cholesterol levels less than age- and gender-matched 5th percentile individuals, as well as significantly lower HDL cholesterol and triglyceridemia levels than normocholesterolemic individuals. There was no evidence of liver abnormalities among hypocholesterolemic individuals.


Pulai et al. (1998) reported a 4-generation family (family 'F') with FHBL in which linkage to the APOB gene could be excluded.

Yuan et al. (2000) performed genomewide linkage analysis in the 4-generation FHBL family originally studied by Pulai et al. (1998) and identified regions on chromosome 3p22-p21.1 with 2-point lod scores greater than 1.5. Genotyping of additional markers yielded 2-point lod scores in the region of D3S2407 of 3.3 (theta = 0.0), and a nonparametric multipoint lod score of 7.5 was obtained (p = 0.0004). Yuan et al. (2000) concluded that a locus for FHBL might reside on chromosome 3.

Using LDL and high-density lipoprotein (HDL) cholesterol levels as quantitative traits, Musunuru et al. (2010) performed genomewide linkage analysis in the 4-generation FHBL family originally studied by Pulai et al. (1998) and found the most significant linkage on chromosome 1p33-p31.1. No significant linkage was found on chromosomes 3 or 10, which had been previously reported to be associated with familial hypobetalipoproteinemia (Yuan et al., 2000 and Sherva et al., 2007, respectively).

Clinical Management

Graham et al. (2017) evaluated antisense oligonucleotides (ASOs) targeting Angptl3 mRNA for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants, with triglyceride levels of either 90 to 150 mg per deciliter or greater than 150 mg per deciliter, depending on the dose group, were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). Treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, p less than 0.01 for all doses vs placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very low density lipoprotein cholesterol (27.9 to 60.0%), non-high density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). There were no serious adverse events. Graham et al. (2017) concluded that oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans.

Dewey et al. (2017) tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%.

Molecular Genetics

Musunuru et al. (2010) performed whole-genome exome sequencing in 2 sibs with a clinical syndrome of combined hypolipidemia, consisting of extremely low plasma levels of LDL cholesterol, HDL cholesterol, and triglycerides, from the 4-generation FHBL family originally studied by Pulai et al. (1998). Only 1 gene, ANGPTL3 (604774) on chromosome 1p31, harbored novel variants in both alleles in both sibs, who were compound heterozygous for S17X (604774.0001) and E129X (604774.0002). Family members who were heterozygous for either mutation had plasma levels of LDL cholesterol and triglycerides that were intermediate between the levels in persons with neither mutation and those with both mutations, findings consistent with a codominant mode of inheritance for the LDL cholesterol and triglyceride phenotypes. In contrast, the level of HDL cholesterol appeared to segregate as a recessive trait: family members who carried both nonsense alleles had significantly lower plasma HDL cholesterol levels than members with 1 or no mutations. Musunuru et al. (2010) proposed the designation 'familial combined hypolipidemia' for the compound heterozygous phenotype of low plasma levels of LDL and HDL cholesterol and triglycerides.

Romeo et al. (2009) sequenced the ANGPTL3, ANGPTL5 (607666), and ANGPTL6 (609336) genes in a large multiethnic population and identified multiple rare nonsynonymous sequence variations that were associated with low plasma triglyceride (TG) levels but not other metabolic phenotypes. Functional studies showed that all mutant alleles of ANGPTL3 that were associated with low plasma TG levels (see, e.g., 604774.0003 and 604774.0005) interfered either with synthesis or secretion of the protein, or with the ability of the ANGPTL protein to inhibit lipoprotein lipase (LPL; 609708).

In 4 affected members of 3 kindreds originally ascertained for very low levels of LDL and HDL cholesterol, who were negative for mutation in 6 genes known to be associated with lipid disorders, Pisciotta et al. (2012) analyzed ANGPTL3 and in 1 family identified homozygosity for a splice site mutation (604774.0003), previously found to be associated with low plasma TG levels by Romeo et al. (2009) and designated chr1:62,842,495. In the other 2 families, Pisciotta et al. (2012) identified compound heterozygosity for a 1-bp and a 4-bp deletion (604774.0004 and 604774.0005); the 4-bp deletion had previously been found to be associated with low plasma TG levels by Romeo et al. (2009) and designated as being an in/del at chr1:62,836,264. Homozygotes or compound heterozygotes showed absence of ANGPTL3 in plasma and reduced plasma levels of TG-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-beta high density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through various pathways; however, these patients had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced LDL cholesterol but normal plasma HDL cholesterol.

In 4 unrelated Spanish patients with severe hypolipidemia who were negative for mutation in the APOB gene (107730), Martin-Campos et al. (2012) analyzed ANGPTL3 and identified homozygosity for a 5-bp deletion in 2 of the patients (604774.0006).

In a cohort of 78 patients with low total, LDL, and HDL cholesterol and TG levels, who were negative for mutation in the APOB, PCSK9 (607786), and MTP (157147) genes, Noto et al. (2012) sequenced the ANGPTL3 gene and identified homozygous or compound heterozygous mutations in 4 patients (see, e.g., 604774.0005 and 604774.0007) as well as heterozygous mutations in 4 patients. (One of the compound heterozygous patients was the proband from the kindred previously reported by Musunuru et al. (2010).) Compared to ANGPTL3 mutation-negative individuals from the cohort, homozygotes and compound heterozygotes had significantly lower levels of total, LDL, and HDL cholesterol and TG, whereas ANGPTL3 heterozygotes had lower TG levels but similar levels of total, LDL, and HDL cholesterol, suggesting that gene dosage affects only the TG plasma levels. In addition, 1 of the 3 mutation-positive patients who underwent ultrasound examination was found to have fatty liver, indicating that the absence of fatty liver might not be a discriminating factor for ANGPTL3 mutations versus other genetic causes of FHBL.

In the probands of 9 hypocholesterolemic families from a small town in Italy, who were negative for causative mutations in the MTP, PCSK9, NPC1L1 (608010), and ANXA2 (151740) genes, Minicocci et al. (2012) identified the S17X mutation in the ANGPTL3 gene (604774.0001), present in heterozygosity in 7 probands and in homozygosity in 2. Screening of family members revealed 20 additional individuals carrying the S17X mutation, 4 homozygotes and 16 heterozygotes; all but 3 heterozygous carriers showed a hypocholesterolemic phenotype. In 1 hypocholesterolemic spouse, heterozygosity for a 2-bp deletion in the ANGPTL3 gene was identified; however, segregation of the variant with hypocholesterolemia could not be determined because her son was unavailable for study. Sequencing of ANGPTL3 in 46 additional hypocholesterolemic residents of the town identified 6 carriers of the S17X mutation, 2 homozygous and 4 heterozygous, and 1 individual with a 3-bp deletion; screening the remaining population identified 26 more heterozygous carriers of the S17X variant. The prevalence of ANGPTL3 variants in the whole population sample was 9.4%; in hypocholesterolemic individuals, prevalence was 15.2%. All the S17X alleles shared the same haplotype, suggesting that the S17X mutation arose from a common ancestor. Only homozygous carriers showed comprehensive reduction of plasma lipoproteins; in heterozygous carriers, significant reduction was limited to total and HDL cholesterol levels. No differences were observed in plasma noncholesterol sterols between carriers and noncarriers, and there was no association detected between familial combined hypolipidemia and the risk of hepatic or cardiovascular disease. Minicocci et al. (2012) concluded that hypobetalipoproteinemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

Dewey et al. (2017) sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. They identified 13 different loss-of-function variants in 43 (0.33%) patients with coronary artery disease and in 183 (0.45%) controls (adjusted OR, 0.59; 95% CI, 0.41 to 0.85; p = 0.004). They then performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from 4 population studies. In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. The results were confirmed in the follow-up studies.