Defects in Synthesis of Apolipoprotein A-I

At a Glance

Hypoalphalipoproteinemia, or low levels of high-density lipoprotein cholesterol (HDL-C), is quite prevalent in the United States, according to the third National Health and Nutrition Examination Survey (NHANES III). Approximately 35% of adult men have HDL less than 40 mg/dL and 39% of women have HDL less than 50 mg/dL. The common, mild forms of hypoalphalipoproteinemia have no characteristic physical findings, but patients may have premature coronary heart or peripheral vascular disease, as well as a family history of low HDL cholesterol levels and early-onset coronary heart disease (CHD).

Hypoalphalipoproteinemia occasionally results from mutations in the ApoA-I/ApoC-III/ApoA-IV gene complex on chromosome 11q23. In some families, a gene inversion has resulted in deletion of the whole cluster, leading to a severe reduction in HDL levels and premature atherosclerosis. The ApoA-I gene encodes the major structural protein of HDL.

There are upwards of 13 different functionally deleterious mutations of APOA1 that cause decreased HDL-C and ApoA-I levels and are variably associated with corneal opacities in addition to premature CHD, elevated triglyceride levels, and xanthomas.

However, in some individuals, certain missense mutations may affect the generation of the ApoA-I molecule. These mutations are a very rare cause of low HDL-C levels (usually 15-30 mg/dL). Such subjects may be healthy, especially those with the APOA1 Milano variant inherited as an autosomal dominant trait, which leads to reduced HDL-C and LDL-C and has been reported to be cardioprotective. Other than corneal opacities, most of these patients do not exhibit many clinical features related to the APOA1 mutations. Other APOA1 mutations have been found in association with systemic amyloidosis, and the mutant APOA1 gene has been located within the amyloid plaque.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Familial hypoalphalipoproteinemia is a relatively common disorder and is often associated with decreased ApoA-I production or increased Ap A-I catabolism. The molecular diagnosis can be made by electrophoresis of the plasma apolipoproteins and/or DNA analysis to identify the specific mutation.

Tests Results Indicative of the Disorder

Criteria for the definition of familial hypoalphalipoproteinemias are a low HDL-C level (below the 10th percentile) in the presence of normal VLDL-C and LDL-C levels, an absence of diseases or factors to which hypoalphalipoproteinemia may be secondary, and the presence of a similar lipoprotein pattern in a first-degree relative. HDL-C in plasma is almost undetectable in persons with the familial apo A-I deficiency caused by deletions of the APOA1 gene, the HDL-C level being less than 10 mg/dL. ApoA1 values are also markedly reduced. Heterozygotes tend to have less severe reductions in HDL-C and apoA1.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Treatment with the following drugs may affect plasma HDL levels: probucol, androgens or progestins, high-dose thiazide diuretics, and high-dose beta-blockers. A very low-fat diet will also contribute to low HDL levels. Cholestatic liver disease and primary biliary cirrhosis in the early stages may result in HDL-C increases, but, as disease progresses, HDL-C values decrease and may reach undetectable levels.

What Lab Results Are Absolutely Confirmatory?

HDL-C in plasma is almost undetectable in persons with the familial ApoA-I deficiency caused by deletions of the APOA1 gene, the HDL level being less than 10 mg/dL. Heterozygotes tend to have less severe reductions in HDL. Serum apoA1 concentration will also be markedly reduced, often paralleling the HDC-C concentrations.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

HDL-C and serum apoA1 concentration should be ordered to confirm a diagnosis of familial hypoalphalipoproteinemia. Other non-genetic causes of decreased HDL-C, such as liver disease and drug interactions, should be ruled out. Genetic sequencing to identifying disease causing mutations or deletions will confirm the diagnosis of familial hypoalphalipoproteinemia.

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