J. Alick Little

Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency.

In a kindred with three hyperlipidemic subjects who had premature atherosclerosis and complete deficiency of hepatic lipase activity, we had previously identified a novel structural hepatic lipase gene variant. We now report the identification of three more hepatic lipase gene mutations in this family and demonstrate that compound heterozygosity for two hepatic lipase mutations (designated S267F and T383M) underlies hepatic lipase deficiency.

Familial Hepatic Lipase Deficiency

We have described a kindred with familial hepatic lipase (HL) deficiency [1]. The proband presented with marked hyperlipoproteinemia and β-VLDL and was originally thought to have Type III hyperlipoproteinemia. However, he was investigated further because of an unusually high proportion of triglyceride in low density and high density lipoproteins and a slightly reduced post-heparin lipolytic activity. Subsequently he, his brother and other family members were discovered to have a marked reduction in hepatic lipase, with gross changes in plasma lipoprotein composition and premature vascular disease. Characterization of the lipoprotein abnormalities has allowed us to evaluate the role of HL in human lipoprotein metabolism and to make inferences about the relationships between the composition of their lipoproteins and atherogenicity.

Studies of Male Survivors of Myocardial Infarction IV. Serum Lipids and Five-Year Survival

This study examined life expectancy and serum lipids in 120 men with atherosclerotic coronary heart disease. Five-year survival from onset of infarction was 79 per cent. No relationship could be demonstrated between survival and the level of the total serum cholesterol, Std. Sf 0–12, 12–20, 20–100, and 100–400 lipoproteins. Survival for patients with an infarct less than 6 months before entry into the study was shorter, despite serum lipid levels the same as the remainder of the group.Although the age of onset of coronary disease is influenced by serum lipid levels, survival subsequent to infarction is not. This paradox suggests that serum lipids affect rate of atherogenesis in the long preclinical stage but in the short clinical stage other factors determine survival.

Studies of Male Survivors of Myocardial Infarction VIII. The Electrocardiogram and Ten-Year Survival*

Abstract The relation of electrocardiographic findings to survival over a ten year period was studied in 101 men aged 30 to 70 years, who had a myocardial infarction at least three months previous to entry into the study and were free of other disease. Age at onset of clinical coronary disease did not influence the electrocardiographic pattern, nor was it related to prognosis. A rate greater than 90 was associated with a poorer prognosis only after 80 months. Ventricular premature beats tended to be associated with a better prognosis for the first five years and a worse one thereafter. Survival was not affected by the complete disappearance of previous electrocardiographic abnormalities, by the site of infarction, anterior or posterior, or by its type, transmural or non-transmural. It is concluded that the electrocardiogram is of little help in predicting long term prognosis in survivors of myocardial infarction.

Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (P=0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (P=0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F.

Familial Chylomicronemia Due to Mutations in Apolipoprotein CII: Apolipoprotein CII-Toronto and Apolipoprotein CII-St. Michael

In this article, we present a summary of our work in establishing the molecular defect in two separate families that were characterized as having familial chylomicronemia due to a deficiency of apolipoprotein CII (apoCII).