Lecithin:cholesterol Acyltransferase Deficiency

A number sign (#) is used with this entry because Norum disease is caused by homozygous or compound heterozygous mutation in the lecithin:cholesterol acyltransferase gene (LCAT; 606967) on chromosome 16q22.

The LCAT gene is also mutant in fish-eye disease (136120).

Description

Lecithin:cholesterol acyltransferase deficiency is a disorder of lipoprotein metabolism and causes a typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure.

Clinical Features

In Norway, Norum and Gjone (1967) described an error of lipid metabolism in sisters with normochromic anemia, proteinuria, and corneal deposits of lipid. Total serum cholesterol was elevated, almost all of it being free cholesterol. Lack of plasma lecithin:cholesterol acyltransferase was postulated. Gjone and Norum (1968) reported the clinical features in 3 adult sisters who showed only traces of esterified cholesterol in the serum. All had proteinuria and anemia. Total cholesterol, triglyceride, and phospholipid were increased. Lysolecithin of serum was decreased. Foam cells were present in the bone marrow and in the glomerular tufts of the kidney. The tonsils were normal. The liver was not enlarged and there was no evidence of liver disease which might account for a defect in cholesterol esterification. The anemia is hemolytic and associated with an increased content of cholesterol in red cells. Patients may succumb to renal failure.

Borysiewicz et al. (1982) described a family from County Mayo, Ireland, with 3 affected sisters and a brother who was probably affected. They stated that 10 families and a total of 21 affected persons had previously been identified. The patients had the typical triad of diffuse corneal opacities, target cell hemolytic anemia, and proteinuria with renal failure.

Vergani et al. (1983) reported an asymptomatic 18-year-old Italian patient who came to medical attention because of proteinuria. His father had had myocardial infarction at age 38 and died suddenly at age 48. The proband showed corneal opacities with intensification near the limbus resembling corneal arcus. Sakuma et al. (1982) and Murayama et al. (1984) described Japanese patients. Weber et al. (1987) described the first German patient. They stated that previously 18 families with a total of 35 affected persons had been reported.

In India, Muthusethupathi et al. (1999) described 2 brothers in their thirties who presented with renal failure and were found to have corneal opacities. One had bilateral corneal clouding; the other had bilateral sensorimotor peripheral neuropathy. The older brother underwent renal transplantation and was doing well 9 years after operation. Both patients had anemia with target cells, and the bone marrow in 1 patient showed 'sea-blue' histiocytes. This was the first report of LCAT deficiency from India.

Biochemical Features

In patients with familial LCAT deficiency from Norway, Ireland, Germany, and Italy, Humphries et al. (1988) used polyclonal antibodies to study the LCAT protein. The patients had low levels of nonfunctional LCAT in their serum as measured by rocket immunoelectrophoresis. The molecular weight of the residual protein was identical to that in normal plasma, as judged by immunoblotting.

Clinical Management

Many patients with renal failure require kidney transplantation. Although favorable long-term results have been reported, Flatmark et al. (1977) reported that morphologic changes may develop in the donor kidney within 6 months of transplant.

Inheritance

LCAT deficiency is an autosomal recessive disorder (Gotoda et al., 1991).

Population Genetics

Albers and Utermann (1981) reviewed the families with LCAT deficiency that had been observed in various parts of the world. Obligate heterozygotes in families in Norway, Canada, and France have shown normal LCAT activities. However, in a family from Sardinia, Albers and Utermann (1981) found half-normal enzyme levels. Heterogeneity is further indicated by the fact that whereas Norwegian homozygotes had about 5% of the normal level of enzyme activity, very low-level or undetectable enzyme activity was found in patients of other ethnic origin. In a Canadian kindred of Swedish and Italian extraction, Frohlich et al. (1982) described methods for identifying heterozygotes.

Pathogenesis

LCAT facilitates the removal of excess cholesterol from peripheral tissues to the liver. A lack of LCAT activity would be expected to lead to accumulation of free cholesterol in the tissues. The gene encoding LCAT on chromosome 16 is the site of the mutation in both Norum disease and fish-eye disease (136120). In fish-eye disease, there is a specific inability of LCAT to esterify cholesterol in HDL, a deficiency of alpha-LCAT function.

According to Norum et al. (1989), there is apparently no increased risk of premature atherosclerotic cardiovascular disease in either form of LCAT deficiency. This is remarkable in light of the markedly low levels of HDL cholesterol, apoA-I (APOA1; 107680), and apoA-II (APOA2; 107670) in both disorders. Rader et al. (1994) attributed this to markedly accelerated catabolism of apolipoprotein A-II. Normally, there are several subclasses of apoA-I containing particles within HDL, including particles that contain both apoA-I and apoA-II and those that contain apoA-I but not apoA-II. Several lines of evidence suggest that the latter subclass (with only apoA-I) may be a specific 'anti-atherogenic' particle within HDL.

Mapping

Teisberg and Gjone (1974) reported data suggesting close linkage of the alpha-haptoglobin locus and the LCAT locus on chromosome 16. In 3 sibships LCAT deficiency seemed to travel with the alpha-Hp-1 allele. The lod score was about 2.81 at a recombination fraction of 0. The linkage disequilibrium strongly favored close linkage. The mutation was thought to have occurred in rural Norway at least 250 to 300 years ago.

Molecular Genetics

Humphries et al. (1988) studied the structure of the LCAT gene in patients with familial LCAT deficiency using a cDNA clone. Enzymatic digestion of DNA samples from the patients produced LCAT gene fragments which were indistinguishable from those found in normal individuals, thus excluding large deletion or rearrangement of the gene.

In the Italian patient with familial LCAT deficiency reported by Vergani et al. (1983), Taramelli et al. (1990) found a C-to-T transition in the fourth exon of the LCAT gene (606967.0001), resulting in a substitution of arginine for tryptophan at position 147 of the mature protein.

Animal Model

Hoeg et al. (1996) generated transgenic rabbits that overexpressed the human LCAT gene. These animals had 15-fold greater plasma LCAT activity and a 6.7-fold greater plasma HDL concentrations than nontransgenic animals. When fed a cholesterol-rich diet, the total cholesterol/HDL cholesterol ratio rose only 2-fold in the transgenic animals, compared with 12-fold in the control animals. The LCAT transgenic animals were protected from diet-induced atherosclerosis as determined by both quantitative planimetry and quantitative immunohistochemistry of the aortas. Hoeg et al. (1996) suggested that LCAT may be a target for therapy to prevent atherosclerosis.

Sakai et al. (1997) established a mouse model for human LCAT deficiency by targeted disruption of the LCAT gene in mouse embryonic stem cells. Homozygous LCAT-deficient mice were healthy at birth and fertile. Compared with age-matched wildtype littermates, the LCAT activity in heterozygous and homozygous knockout mice was reduced by 30% and 99%, respectively. LCAT deficiency resulted in significant reductions in the plasma concentrations of total cholesterol, HDL cholesterol, and apoA-I in LCAT -/- mice, and moderately so in LCAT +/- mice. Plasma triglycerides were significantly higher only in male homozygous knockout mice. After 3 weeks on a high-fat and high-cholesterol diet, LCAT -/- mice had significantly lower plasma concentrations of total cholesterol, reflecting lower levels of both proatherogenic apoB-containing lipoproteins as well as HDL, compared with controls.

To examine the effect of LCAT deficiency on HDL structure and composition and adrenal cholesterol delivery, Ng et al. (1997) created Lcat-deficient mice by gene targeting. The HDL in the Lcat-deficient mice was reduced in its plasma concentration (92%) and cholesteryl ester content (96%). The HDL particles were heterogeneous in size and morphology and included numerous discoidal particles, mimicking those observed in LCAT-deficient humans. The adrenals of the male Lcat -/- mice were severely depleted of lipid stores, which was associated with a 2-fold upregulation of the adrenal scavenger receptor class B type I (CD36L1; 601040) mRNA. Ng et al. (1997) concluded that LCAT deficiency, like apoA-I deficiency, is associated with a marked decrease in adrenal cholesterol delivery and supports the hypothesis that adrenal scavenger receptor class B type I expression is regulated by the adrenal cholesterol.