Fish-Eye Disease

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

Norum disease (245900) is an allelic disorder.

Clinical Features

In Sweden, Carlson and Philipson (1979) described a man and his 3 daughters with a disorder called 'fish-eye' in their home village because corneal opacities gave their eyes the appearance of those of boiled fish. Two living sisters showed the same dyslipoproteinemia, characterized by normal serum cholesterol but raised serum triglycerides, raised VLDL, and strikingly high LDL triglycerides. In HDL, cholesterol was reduced. Corneal opacities (of less dense nature) occur in Tangier disease (HDLDT1; 205400) and LCAT deficiency (Norum disease), but both of these were excluded by normal electrophoretic mobility of HDL and normal LCAT activity, respectively. Visual impairment was almost the only clinical problem.

Carlson (1979) reported a second case, in a 70-year-old woman referred to him by ophthalmologist Philipson. The woman was in general good health. Corneal clouding was noted before age 20, but she worked as a hairdresser until age 65. Parents and 5 sibs were free of eye disease.

Cases of fish eye disease were also observed in Canada by Frohlich et al. (1987); Kastelein et al. (1992) stated that the father's maternal side of the family had been traced back to Sweden. A fourth family of Dutch descent was reported by Kastelein et al. (1992).

Funke et al. (1991) described the biochemical and genetic presentation of 2 homozygotes from a German family with fish-eye disease and their relatives. They demonstrated vertical transmission of a decrease in the specific activity of LCAT. Two brothers, 57 and 68 years old, had massive bilateral corneal opacities that almost completely covered the irides. There were several consanguineous marriages in their family history. In their village, the kindred was known to have been affected with 'sick eyes' for several generations. The younger brother suffered from angiographically assessed 2-vessel coronary disease, and the elder brother suffered from angina pectoris. Family history, however, was not compatible with an increased prevalence of myocardial infarction. All 5 children of the 2 presumed homozygotes were heterozygotes.

Pathogenesis

Carlson and Holmquist (1985) and Holmquist and Carlson (1987) demonstrated that the defect in fish-eye disease is deficiency of high density lipoprotein lecithin:cholesterol acyltransferase activity. Alpha-LCAT, deficient in this condition, is specific for HDL, whereas beta-LCAT, also deficient in Norum disease (245900), is specific for combined VLDL and LDL (Carlson and Holmquist, 1985). Thus, fish-eye disease is one form of LCAT deficiency. In fish-eye disease, the HDL of plasma contains only about 20% cholesteryl esters relative to total cholesterol as compared to 75 to 80% in control HDL. In fish-eye disease plasma, however, there is a normal cholesteryl ester percentage as well as a normal plasma cholesterol esterification rate as a result of the activity of beta-LCAT.

Molecular Genetics

By restriction enzyme analysis of the apoA-I gene, Rees et al. (1984) could demonstrate no major deletion or insertion in 2 patients with fish-eye disease.

The mutations in fish-eye disease and in Norum disease are in the same gene, that encoding LCAT, located on chromosome 16. In the family described by Funke et al. (1991), direct sequencing of DNA segments of the LCAT gene amplified by PCR led to the identification of a homozygous mutation, ACA to ATA, resulting in the substitution of threonine for isoleucine at codon 123 (606967.0005).