Familial apolipoprotein A-I and C-III deficiency, variant II.

The biochemical, clinical, and genetic features were examined in the proband (homozygote) and heterozygotes (n = 17) affected with familial apolipoprotein A-I and C-I11 deficiency, variant I1 (previously described as apolipoprotein A-I absence). The proband was a 45-year-old white female with mild corneal opacification and significant three-vessel coronary artery disease (CAD), who died shortly after bypass surgery. Autopsy findings included significant atherosclerosis in the coronary and pulmonary arteries and the abdominal aorta as well as extra- cellular stromal lipid deposition in the cornea. No reticuloendo- thelial lipid deposits in the liver, bone marrow, or spleen were noted (unlike Tangier disease). Laboratory features included marked high density lipoprotein (HDL) deficiency and undetec- table plasma apolipoproteins (apo) A-I and C-111. The per- centage of plasma cholesterol in the unesterified form was normal at 30%. The activity and mass of 1ecithin:cholesterol acyltransferase (LCAT) were 42% and 36% of normal, respec- tively, and the cholesterol esterification rate was 43% of normal. Deficiencies of plasma vitamin E and essential fatty acid (linoleic, C18:2) were also noted. Evaluation of plasma lipopro- teins and apolipoproteins in 37 kindred members revealed 17 heterozygotes with HDL cholesterol values below the 10th percentile of normal. Of these, all had apoA-I levels more than one standard deviation below the normal mean, and 37.5% had a similar decrease in apoC-I11 values. Mean (* SD) plasma HDL cholesterol, apoA-I, and apoC-I11 values (mgldl) in heterozygotes were 54.0%, 62.4%, and 79.2% of normal, respec- tively. No evidence of CAD was observed in 10 heterozygotes 40 years of age or less; however, CAD was detected in 3 of 7 hetero- zygotes over 40 years of age, one of whom died at age 56 years of complications of myocardial infarction and stroke. The inheritance pattern in this kindred was autosomal codominant. ApoA-I isolated from a heterozygote had an isoelectric focusing pattern and amino acid composition similar to normal. Utilizing DNA isolated from two obligate heterozygotes, no abnormalities in the apoA-I or apoC-I11 genes were detected by Southern blot analysis utilizing specific probes following restriction enzyme digestion. The data indicate that familial apolipoprotein A-I and C-I11 deficiency, variant 11, is similar to variant I (described by Norum et al. 1982. N Engl. J. Med. 306: 1513-1519), but differs at the clinical level (lack of xanthomas), the biochemical level (lack of detectable apoA-I, lower apoA-I1 level), and at the gene level. Our data are consistent with the view that apoA-I is essential for HDL formation but not for LCAT activation, and that apolipoproteins A-I and C-I11 may be important for vita- min E and essential fatty acid intestinal absorption. Schaefer,