Familial dysbetalipoproteinemia (Fredrickson's type III hyperlipidemia, autosomal recessive, incidence approximately 1:2,000) results from a defect in the metabolism of chylomicrons and VLDL remnants, whose uptake into the liver is mediated by apolipoprotein E (Apo E). Remnants are degradation products of plasmatic lipoprotein metabolism and are among the most atherogenic lipid particles. Affected patients therefore have a very high vascular risk (arterial occlusive disease, CHD, stroke). Cutaneous or tuberous xanthomas are frequently found, hand line xanthomas are pathognomonic. Biochemically, one finds an increased serum concentration of beta-VLDL with concomitant elevation of triglycerides and total cholesterol. Diet is the treatment of choice. However, recent studies have shown that the use of HMG-CoA reductase inhibitors (e.g., statins) also yields good results.
The molecular mechanisms of type III hyperlipidemia are not yet clearly understood. The prerequisite seems to be homozygosity for the E2 allele of apolipoprotein E. Two polymorphisms in the APOE gene result in the amino acid exchanges Cys112Arg (rs429358) and Arg158Cys (rs7412), giving rise to the three isoforms ApoE2, ApoE3, and ApoE4 (allele frequency: E2: 4% to 13%, E3: 62% to 86%, and E4: 7% to 29%). ApoE2 exhibits decreased LDL receptor binding properties, resulting in accumulation of remnants and consequent increases in total cholesterol and triglycerides. However, only about 4% of individuals homozygous for APOE2 develop type III hyperlipidemia (low penetrance). This requires secondary factors such as hypothyroidism, estrogen deficiency, obesity, alcohol consumption, type 2 diabetes mellitus, pregnancy, or the use of certain medications (e.g., olanzapine). Approximately 10% of patients with type III hyperlipidemia carry other causative variants in the APOE gene. Some of these rare causative APOE variants, such as p.(Arg145Cys), follow a dominant mode of inheritance with complete penetrance. Characteristic of these dominantly inherited variants is, for example, an absent or reduced modulation of receptor binding (e.g., of the LDL receptor) by LPL-induced changes in the composition of triglyceride-rich lipoproteins. Therefore, complete sequencing of the APOE gene could also be considered.
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