Inherited Syndromes of Low LDLC Abetalipoproteinemia

Abetalipoproteinemia is a rare autosomal recessive disease caused by mutations in the gene encoding microsomal transfer protein (MTP) (11), a protein that transfers lipids to nascent chylomicrons and VLDL in the intestine and liver, respectively. Plasma levels of cholesterol and triglyceride are extremely low in this disorder, and no chylomicrons, VLDL, LDL, or apoB are detectable in plasma (12). Obligate heterozygotes have normal plasma lipid and apoB levels. Abetalipoproteinemia usually presents in childhood with diarrhea and failure to thrive and is characterized clinically by fat malabsorption, spinocerebellar degeneration, pigmented retinopathy, and acanthocy-tosis. The initial neurological manifestations are loss of deep tendon reflexes, followed by decreased distal lower extremity vibratory and proprioceptive sense, dysmetria, ataxia, and the development of a spastic gait, often by the third or fourth decade. Patients with abetalipoproteinemia also develop a progressive pigmented retinopathy presenting with decreased night and color vision, followed by reductions in daytime visual acuity and ultimately progressing to near blindness.

Most clinical manifestations of abetalipoproteinemia result from defects in the absorption and transport of fat-soluble vitamins. Vitamin E and retinyl esters are normally transported from enterocytes to the liver by chylomicrons, and vitamin E is dependent on VLDL for transport out of the liver and into the circulation. As a consequence of the inability of these patients to secrete apoB-containing particles, patients with abetalipoproteinemia are markedly deficient in vitamin E and are also mildly to moderately deficient in vitamins A and K. Treatment consists of a low-fat, high-caloric, vitamin-enriched diet accompanied by large supplemental doses of vitamin E. It is imperative that treatment be initiated as soon as possible to obviate the development of the neurological sequelae.

Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia generically refers to low LDL-C levels that have a genetic basis. Historically, it has been used to refer to low LDL-C because of mutations in apoB (13,14). There are a range of missense mutations in apoB that have been shown to reduce secretion and/or accelerate catabolism. Individuals heterozygous for these mutations have LDL-C levels less than 100mg/dL. They appear to be protected from the development of atherosclerotic vascular disease. There are rare patients who have mutations in both apoB alleles and have plasma lipids similar to those in abetal-ipoproteinemia, but a less severe neurological phenotype.

More recently, loss-of-function mutations in PCSK9 have been shown to cause low LDL-C levels (usually less than 80 mg/dL) and are therefore another molecular cause of familial hypobetalipoproteinemia (15,16). The mechanism is uncertain but presumably results in the upregulation of the hepatic LDL receptor and increased catabolism of LDL. This condition, which is much more common in people of African descent, provided the opportunity to demonstrate that the effects of lifelong low LDL-C levels are a substantial reduction in with no other adverse consequences (17). This strongly supports the concept that aggressive LDL-C reduction is associated with long-term substantial reduction in cardiovascular risk.

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