At a Glance
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
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?
What Lab Results Are Absolutely Confirmatory?
At a Glance
Tangier Disease is a very rare recessive disorder caused by mutations in the adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1) gene that impairs ABCA1 function. As ABCA1 effluxes excess cell cholesterol and phospholipid during the biogenesis of high-density lipoprotein (HDL), such mutations result in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Specifically, Tangier mutations prevent the ABCA1-dependent transfer of cholesterol and phospholipid onto Apolipoprotein A1 (ApoA1), which is the rate-limiting step in HDL biosynthesis.
In patients with Tangier Disease, cells that undergo large lipid fluxes, such as macrophages, will accumulate cholesterol, resulting in the formation of "foam cells," an early hallmark of atherosclerosis. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop premature cardiovascular disease. Only 50-100 cases have been identified worldwide, and both genders are equally affected. The build-up of cholesterol within cells can, in itself, be toxic, causing cell death or impaired cell function.
Clinical manifestations of Tangier Disease are related to cholesteryl ester deposits in reticuloendothelial tissues (tonsils or pharyngeal lymph follicles, lymph nodes, thymus, spleen, liver, bone marrow, cornea, lungs, intestinal mucosa, skin, and gall bladder) and to peripheral neuropathy. The latter is the most frequent symptom that leads to the identification of adults with Tangier disease and is thought to be due to abnormal lipid deposition in Schwann cells. The extent and tissue location of cholesteryl ester accumulation varies among Tangier patients, and symptoms vary in severity from subclinical and transient to quite disabling:
Enlarged, orange-yellow tonsils
Neurological abnormalities (in more than half of Tangier patients) - peripheral neuropathy with diminished or absent reflexes
Sensory abnormalities - widespread dissociated loss of pain and temperature sensitivity, paresthesia, and stabbing pains
Possible motor abnormalities (e.g., progressive focal muscle weakness), ptosis, muscle atrophy
Thrombocytopenia (blood counts 30,000-120,000 cells per microliter)
Clouding of the cornea (in patients older than 20 years of age)
Early-onset atherosclerosis (dependent on specific mutation and especially relevant in the presence of additional cardiovascular risk factors)
The lipid profile in Tangier patients shows low serum total cholesterol (TC), normal to high triglyceride (TG) levels (200-400 mg/dL), and little or no circulating HDL-C (<5% of normal). This profile, together with the hyperplastic orange-yellow tonsils, is pathognomonic for the disorder. In addition, plasma ApoA1 concentrations are extremely low (<3% of normal) because of the lack of mature, lipid-rich HDL (alpha-HDL), which have electrophoretic alpha-mobility and represent the majority of HDL in normal plasma. Chylomicron remnants may also be abnormal in Tangier Disease.
Obligate heterozygotes have no clinical symptoms and are characterized at the biochemical level by half-normal serum levels of HDL-C, ApoA1, and half-normal lipid efflux from fibroblasts.
Fasting (10-14 hours) measurement of HDL-C, ApoA1, TC, and TG should be ordered.
At least 50 ABCA1 gene mutations have been identified, leading to Tangier disease or its allelic disorder familial hypoalphalipoproteinemia (FHA). FHA is associated with moderately low HDL-C (20-35 mg/dL) and predisposition to coronary heart disease. Sequence variants in ABCA1 may also contribute to variations in plasma HDL-C concentrations in the general population. Family studies are important to demonstrate that HDL deficiency is of genetic origin, because the Tangier phenotype is mimicked in some secondary forms of HDL deficiency (ApoA1 deficiency, LCAT deficiency, fish eye disease).
Cellular cholesterol efflux can be either ApoA1-mediated or HDL-mediated. Tangier patients generally show a 50-60% decrease in both effluxes. Electrophoretic separation of the plasma lipoproteins shows the absence, or marked reduction, in alpha-migrating HDL and ApoA1. On immunoblotting, residual amounts of ApoA1 are found in pre-beta-HDL, but virtually none in alpha-HDL. Alternatively, quantification of lipids in fractions obtained by sequential or density-gradient ultracentrifugation may confirm the virtual absence of HDL. A decreased HDL size may also occur (as detected by nuclear magnetic resonance spectroscopy).(
Test Results Indicative of the Disorder
|Plasma HDL-C||<5% of normal value (<5 mg/dL)|
|Plasma ApoA1||<3% of normal value (< 5 mg/dL)|
|Plasma TG||normal or elevated (200-400 mg/dL)|
|Plasma TC||low (<150 mg/dL mg/dL)|
Changes in lipid turnover can influence ABCA1 turnover, such as those associated with type 2 diabetes mellitus. Here, elevated free fatty acids and low plasma HDL levels accelerate the degradation of ABCA1 and decrease ApoA1-mediated lipid efflux. Impaired cholesterol efflux from macrophages will, thus, contribute to the enhanced atherosclerosis associated with type II diabetes.
Lifestyle factors may contribute to decreased circulating levels of HDL-C (e.g., sedentary lifestyle, smoking, obesity, or a diet enriched in carbohydrates). Pharmacological doses of niacin (vitamin B3) are known to repress hepatic very-low-density lipoprotein (VLDL) secretion and raise HDL levels.
What Lab Results Are Absolutely Confirmatory?
The unique appearance of the tonsils makes this disease diagnosable from examination of the oropharynx. The tonsils are enlarged with a distinct orange or yellowish-gray color. The tonsil tissue can be shown by microscopic examination to contain large foam cells located mostly in the fibrous septa, but also in the follicles. Patients may have had a history of recurrent "tonsillitis," which led to removal of the tonsils, in which case small plaques or tags of mucosa may remain with the same appearance to aid in diagnosis.
The biochemical hallmark of Tangier disease is the absence of alpha-migrating HDL and ApoA1-containing lipoproteins. This is due to the increased catabolism of HDL, defective maturation of HDL, and impaired efflux of cellular cholesterol, resulting from the dysfunctional ABCA1 transporter.
The exclusive presence of ApoA1 in pre-beta-HDL, together with the failure of Tangier plasma to convert ApoA1 into alpha-HDL, are specific biochemical features that distinguish Tangier disease from other familial HDL deficiency syndromes (e.g., ApoA1 deficiency, LCAT deficiency, fish eye disease).
The low plasma TC levels in Tangier disease are similar to those observed in patients with abetalipoproteinemia, but the presence of normal to elevated TG levels and absence of HDL in Tangier plasma readily differentiate these two disorders.
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