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Homozygous Tangier disease and cardiovascular disease
C Serfaty-Lacrosniere1, F Civeira, A Lanzberg
1Lipid Research Laboratory, Endocrinology Division, New England Medical Center, MA.
Insights
Tangier disease, a rare genetic disorder, significantly increases cardiovascular disease (CVD) risk in homozygotes, with peripheral neuropathy also being a common complication. Lipid-lowering drugs may not effectively raise HDL cholesterol but can manage other lipid levels.
Area of Science:
- Lipidology
- Genetics
- Cardiovascular Medicine
Background:
- Tangier disease is an autosomal co-dominant disorder characterized by severe deficiency of high density lipoprotein (HDL) cholesterol and apolipoprotein A-I.
- Homozygotes exhibit abnormal lipid profiles, including low HDL and LDL cholesterol, and mild hypertriglyceridemia.
- Cholesterol ester deposition occurs in various tissues, leading to characteristic clinical manifestations.
Observation:
- This study assessed cardiovascular disease (CVD) prevalence in 54 homozygous Tangier disease cases, including 3 new cases and autopsy data.
- Peripheral neuropathy was the most frequent clinical finding (54%), significantly higher than in controls.
- CVD was observed in 20% of Tangier patients versus 5% of controls, with 44% of patients aged 35-65 showing CVD evidence.
Findings:
- Homozygous Tangier disease is associated with a significantly increased risk of cardiovascular disease (CVD), particularly in middle-aged and elderly individuals.
- Peripheral neuropathy is a major clinical feature in Tangier disease patients.
- Standard lipid-lowering therapies showed limited efficacy in raising HDL cholesterol but effectively reduced triglyceride and LDL cholesterol levels.
Implications:
- Tangier disease homozygotes face a substantial CVD burden, necessitating proactive cardiovascular risk management.
- The findings highlight the complex interplay between genetic lipid disorders and atherosclerosis.
- Further research into novel therapeutic strategies targeting HDL metabolism and CVD prevention in Tangier disease is warranted.
Abstract:
Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (+/- S.D.) lipid values of all cases were as follows: total cholesterol 68 +/- 30 mg/dl (32% of normal), triglycerides 201 +/- 118 mg/dl (162% of normal), HDL cholesterol 3 +/- 3 mg/dl (6% of normal) and LDL cholesterol 50 +/- 38 mg/dl (37% of normal). The most common clinical finding in these subjects (n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects (n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls (P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group (P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes.(ABSTRACT TRUNCATED AT 400 WORDS)