Gene defects affecting cholesterol metabolism can lead to a variety of inherited disorders. These defects can impact how the body synthesizes, transports, and processes cholesterol, leading to various dyslipidemias and associated health issues. Some of the most notable gene defects related to cholesterol metabolism include:
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Familial Hypercholesterolemia (FH):
- Genes Involved: The most common genetic causes of FH are mutations in the LDLR gene, which encodes the low-density lipoprotein receptor, leading to elevated levels of LDL cholesterol. Other genes, such as APOB (apolipoprotein B) and PCSK9, can also be implicated.
- Pathophysiology: These mutations cause a reduced ability to clear LDL cholesterol from the bloodstream, resulting in increased cholesterol levels and a higher risk of cardiovascular diseases.
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Sitosterolemia:
- Genes Involved: Mutations in ABCG5 and ABCG8 genes which encode transporters involved in intestinal cholesterol and phytosterol absorption.
- Pathophysiology: This condition leads to the accumulation of plant sterols in the body, causing atherosclerosis and other cardiovascular issues, as well as tendon xanthomas.
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Cholesterol Ester Storage Disease (CESD):
- Genes Involved: Mutations in the LIPA gene, which encodes lysosomal acid lipase.
- Pathophysiology: Deficiency in this enzyme leads to impaired breakdown of cholesteryl esters and triglycerides, resulting in their accumulation in various tissues.
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Smith-Lemli-Opitz Syndrome (SLOS):
- Genes Involved: Mutations in the DHCR7 gene, which encodes 7-dehydrocholesterol reductase.
- Pathophysiology: This condition leads to a deficiency of cholesterol and an accumulation of 7-dehydrocholesterol, resulting in developmental anomalies and other health issues.
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ApoE Deficiency:
- Genes Involved: Mutations in the APOE gene, which encodes apolipoprotein E, a key component in the metabolism of fats in the body.
- Pathophysiology: This deficiency can lead to abnormalities in lipid metabolism and an increased risk of cardiovascular diseases.
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Xanthomatosis:
- Genes Involved: Various gene mutations can affect lipid metabolism, leading to xanthomas due to elevated cholesterol levels.
- Pathophysiology: Cholesterol deposits accumulate in the skin and tendons, signaling underlying dyslipidemia.
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Hypobetalipoproteinemia:
- Genes Involved: Mutations in the APOB gene can lead to low levels of apolipoprotein B, impairing chylomicron and LDL formation.
- Pathophysiology: This condition results in very low levels of LDL cholesterol in the blood.
In summary, genetic defects in cholesterol metabolism can significantly impact cardiovascular health and may present with various clinical manifestations. Diagnosis often involves genetic testing, family history assessment, and lipid profile evaluation. Treatment may include lifestyle changes, dietary modifications, and pharmacotherapy to manage cholesterol levels effectively.