Hypoalphalipoproteinemia, Primary, 2

A number sign (#) is used with this entry because of evidence that primary hypoalphalipoproteinemia-2 is caused by homozygous, compound heterozygous, or heterozygous mutation in the APOA1 gene (107680) on chromosome 11q23.

Description

Primary hypoalphalipoproteinemia-2 characterized by dysfunctional apoA-I production, resulting in undetectable levels of apoA-I in serum and in markedly low levels of serum high density lipoprotein cholesterol (HDL-C), is generally an autosomal recessive disorder associated with extensive atherosclerosis, xanthomas, and corneal opacities (summary by Tanaka et al., 2018).

Primary hypoalphalipoproteinemia-2 characterized by half the normal plasma apoA-I and HDL-C levels is inherited as an autosomal dominant trait (Yamakawa-Kobayashi et al., 1999). Heterozygous individuals may develop xanthomas and corneal opacities, but most do not have increased cardiovascular risk (Rader and deGoma, 2012).

For a discussion of genetic heterogeneity of primary hypoalphalipoproteinemia, see 604091.

Clinical Features

Funke et al. (1991) studied an otherwise healthy 42-year-old man for massive corneal clouding resembling that described in patients with fish-eye disease (see 136120). He had complete absence of plasma HDL, and apoA-I was not present in HDL particles. There was no history in the patient or in his family of premature coronary artery disease and no evidence of consanguinity.

Hiasa et al. (1986) reported a 55-year-old Japanese woman, born of consanguineous parents, with severe coronary arteriosclerosis and skin xanthomas on her neck, elbow joints, knee joints, and thighs. ApoA-I, apoA-III, and HDL-C were undetectable. Matsunaga et al. (1991) studied this patient and confirmed the presence of apoA-III. They noted that the patient's father died of a cerebrovascular disease at age 70, and her mother died of unknown causes at age 64.

Ng et al. (1994) reported a Canadian kindred segregating complete apoA-I deficiency. The 34-year-old Caucasian proband, the product of a consanguineous marriage, initially presented at the age of 30 years because of xanthelasmata. In the same year, she was diagnosed with bilateral cataracts requiring cataract extraction in the right eye. She also had bilateral subretinal lipid deposition with exudative proliferative retinopathy complicated by bilateral retinal detachments, which were treated surgically. She had a longstanding history of mild imbalance, i.e., unsteadiness. Examination showed mildly thickened Achilles tendons and mild midline cerebellar ataxia. One sister had had a mild myocardial infarction at age 34. Another sister with angina had cerebellar ataxia. High density lipoprotein cholesterol was very low and apoA-I was undetectable.

Romling et al. (1994) reported a Sicilian woman, born to first-cousin parents, who developed bilateral periorbital xanthelasmas during her first pregnancy at age 22. The xanthelasmas did not progress after delivery. The woman had absent apoA-I and low HDL-C, but no signs of coronary artery disease or other atherosclerosis.

Inheritance

Borecki et al. (1986) studied 16 kindreds ascertained through probands clinically determined to have primary hypoalphalipoproteinemia characterized by low HDL cholesterol but otherwise normal blood lipids. They concluded that 'these families provided clear evidence for a major gene.'

Moll et al. (1986) measured apoA-I levels in families ascertained through cases of hypertension or early coronary artery disease. They concluded that the findings supported 'a major effect of a single genetic locus on the quantitative variation of plasma apoA-I in a sample of pedigrees enriched for individuals at risk for coronary artery disease.'

Using a radioimmunoassay, Moll et al. (1989) measured plasma apoA-I levels in 1,880 individuals from 283 pedigrees. Complex segregation analysis suggested heterogeneous etiologies for the individual differences in adjusted apoA-I levels observed. The authors concluded that environmental factors and polygenic loci account for 32% and 65%, respectively, of the adjusted variation in a subset of 126 families. In the other 157 pedigrees, segregation analysis strongly supported the presence of a single locus accounting for 27% of the adjusted variation.

Pathogenesis

The major protein constituent of HDL, apoA-I, provides structure to the HDL particle, mediates the initial required step in HDL assembly, lipidation by ABCA1 (600046), and promotes activation of LCAT (606967). Autosomal recessive apoA-I deficiency is due to deletions of the apoA-I gene or truncating mutations early in the coding portion of the gene in both apoA-I alleles. As a result, the apoA-I protein is not synthesized or secreted, leading to absent apoA-I in plasma and very low levels of HDL-C. Missense mutations in the apoA-I gene, which are almost always heterozygous, affect the structure of the apoA-I protein, often leading to impaired function and/or increased metabolism and low levels of apoA-I and HDL-C (Rader and deGoma, 2012).

Clinical Management

Autosomal recessive apoA-I deficiency is generally associated with markedly increased atherosclerotic cardiovascular disease and should be managed with aggressive reduction of LDL-C and non-HDL-C. Autosomal dominant hypoalphalipoproteinemia is generally not associated with clinical sequelae requiring specific treatment (Rader and deGoma, 2012).

Population Genetics

To determine the frequency of de novo hypoalphalipoproteinemia in the general population due to mutation of the APOA1 gene, Yamakawa-Kobayashi et al. (1999) analyzed sequence variations in the APOA1 gene in 67 children with a low HDL-C level. These children were selected from 1,254 school children through a school survey. Four different mutations with deleterious potential, 3 frameshifts and 1 splice site mutation, were identified in 4 subjects. The plasma apoA-I levels of the 4 children with these mutations were reduced to approximately half of the normal levels and were below the first percentile of the general population distribution (80 mg/dl). The frequency of hypoalphalipoproteinemia due to a mutant APOA1 gene was estimated at 6% in subjects with low HDL-c levels and 0.3% in the Japanese population generally.

Molecular Genetics

Lack of detectable plasma apolipoprotein A-I can be due to DNA deletions, rearrangements, or nonsense or frameshift mutations within the APOA1 gene resulting in a lack of apoA-I secretion (summary by Schaefer et al., 2010).

In an otherwise healthy 42-year-old man with massive corneal clouding, Funke et al. (1991) identified a homozygous 1-bp deletion in the APOA1 gene (107680.0014) as the basic defect responsible for complete absence of HDL from the plasma and corneal opacities. Heterozygous carriers of the deletion, including the proband's mother and 3 of this children, showed approximately half-normal HDL cholesterol concentrations.

In the Japanese woman with apoA-I deficiency, xanthomas, and premature atherosclerosis reported by Hiasa et al. (1986), Matsunaga et al. (1991) identified homozygosity for a nonsense mutation in the APOA1 gene (Q84X; 107680.0015).

By genomic DNA sequencing of the APOA1 gene in affected members of a Canadian family with apoA-I deficiency, Ng et al. (1994) identified homozygosity for a nonsense mutation (Q23X; 107680.0017), which the authors designated as Q(-2)X.

In a Sicilian woman, born to first-cousin parents, who developed bilateral periorbital xanthelasmas during her first pregnancy at age 22, Romling et al. (1994) identified homozygosity for a nonsense mutation (Q32X; 107680.0019) in the APOA1 gene. The xanthelasmas did not progress after delivery.

In a 67-year-old Japanese male with corneal opacities, coronary artery disease, and low apoA-I and HDL-C levels, Huang et al. (1998) identified a homozygous mutation in the APOA1 gene (V156E; 107680.0022).

In 3 healthy Japanese individuals, including a 10-year-old proband and her 34-year-old mother and 36-year-old maternal aunt, with low levels of apoA-I and HDL-C levels, Nakata et al. (1993) identified a heterozygous mutation in the APOA1 gene (107680.0018).

Combined ApoA-I and ApoC-III Deficiency

In certain patients with premature atherosclerosis, Karathanasis et al. (1987) demonstrated a DNA inversion containing portions of the 3-prime ends of the APOA1 and APOC3 genes, including the DNA region between these genes (see 107680.0011). The breakpoints of this DNA inversion were found to be located between the fourth exon of the APOA1 gene and the first intron of the APOC3 gene; thus, the inversion results in reciprocal fusion of the 2 gene transcriptional units. The absence of transcripts with correct mRNA sequences causes deficiency of both apolipoproteins in the plasma of these patients, leading to atherosclerosis.

Exclusion Studies

By genetic linkage analysis using RFLPs in the APOA1/C3/C4 gene cluster, Kastelein et al. (1990) showed that the mutation causing familial hypoalphalipoproteinemia (familial HDL deficiency) in a family of Spanish descent was not located in this cluster.