APOE p.Leu167del-Related Lipid Disorders – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

Review
In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
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Excerpt

NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.

Clinical characteristics: APOE p.Leu167del is a rare genetic variant described in 38 cases in the literature with a range of clinical phenotypes. Three phenotypes can be associated with the APOE p.Leu167del variant:

  1. Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) characterized by hypertriglyceridemia and splenomegaly. Variable manifestations include thrombocytopenia, liver function abnormalities, and cardiovascular disease

  2. Autosomal dominant hypercholesterolemia (ADH) characterized by markedly elevated LDL cholesterol levels that leads to premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD)

  3. Familial combined hyperlipidemia (FCHL) characterized by variable elevations of total cholesterol, triglycerides, or LDL cholesterol and a high risk of premature ASCVD

It has been suggested that the phenotype associated with the APOE p.Leu167del variant may depend on multiple factors, including sex, APOE genotype, control of hyperlipidemia, gene-gene interactions, gene-environment interactions, or perhaps epigenetic and other non-mendelian effects.

Diagnosis/testing: Diagnosis relies on detection of a heterozygous APOE p.Leu167del pathogenic variant. Determining whether the second APOE allele is the benign variant e2 or the benign variant e3 may be of some clinical predictive value.

Management: Treatment of manifestations: No formal management guidelines exist. Individuals with hyperlipidemia should be treated according to their overall cardiovascular risk profile. Treatment for individuals with documented ASCVD or at high risk of developing ASCVD begins with lifestyle changes (adherence to a heart-healthy diet, exercise, tobacco avoidance, maintenance of a healthy weight) and may also include statin, fibrate, high-dose fish oil, and/or niacin therapy. Although no interventions are known to prevent disease progression, it has been suggested that treatment of dyslipidemia may prevent development of splenomegaly. Splenectomy should be avoided as it may worsen hyperlipidemia. Liver function abnormalities and thrombocytopenia are managed in a routine manner. Diabetes mellitus (if present) should be well controlled.

Surveillance: No formal surveillance guidelines exist. The authors suggest the following:

  1. Lipoprotein profile one year after diagnosis and every 2-5 years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia.

  2. Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every 2-5 years thereafter (if normal)

  3. Platelet count one year after diagnosis and every 2-5 years thereafter (if normal)

Agents/circumstances to avoid: Splenectomy, which may worsen the hypertriglyceridemia. For those with splenomegaly: contact sports given the increased risk for splenic rupture.

Evaluation of relatives at risk: Clarifying the genetic status of relatives at risk of inheriting the APOE p.Leu167del variant allows early adoption of preventive measures and surveillance.

Pregnancy management: In a woman with the APOE p.Leu167del variant, triglyceride levels should be measured when pregnancy is identified and at least one to two times later in pregnancy as severe hypertriglyceridemia (>500 mg/dL) in pregnancy increases the risk for pancreatitis and fetal and maternal death. Before taking a medication during pregnancy, a pregnant woman should discuss with her physician the risks and benefits of that medication.

Genetic counseling: The APOE p.Leu167del variant is inherited in an autosomal dominant manner. The proportion of APOE p.Leu167del-related lipid disorders caused by de novo mutation is unknown. The phenotype associated with the APOE p.Leu167del variant appears to depend on multiple factors. Each child of an affected individual has a 50% chance of inheriting the variant. Prenatal testing for at-risk pregnancies is possible; however, requests for prenatal testing for conditions such as APOE p.Leu167del-related lipid disorders are not common.

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