Familial Hypercholesterolemia

From Iusmgenetics

Contents 1 Familial Hypercholesterolemia 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

[edit] Familial Hypercholesterolemia

[edit] General background information

• 1 / 500
• 5% of MI pts younger than 60yo
• Demonstrates gender-dependence

[edit] Mode of inheritance

• Autosomal dominant (LDL receptor mutations, apoprotein B100 mutations)
• Semi-dominant (homozygotes: childhood MIs)
• Some haploinsufficiency and dominant-negative mutations.

• LDL receptor, Apoprotein B100 = AD
• ARH adaptor protein = AR (rare)
• PCSK9 protease = AD (rare)

[edit] Single important gene

• LDL receptor
• Apoprotein B100
• ARH adaptor protein
  • Rare
• PCSK9 protease
  • Rare, autosomal dominant, gain of function
• These are all examples that cause locus heterogeneity

[edit] Etiology

• LDL receptor: loss of function (see below for classes)
  • The LDL receptor is supposed to bind the LDL, bring it into the cell, drop it off in the endosome, and thus let it be converted to free cholesterol for use by the cell.
• Apoprotein B100: loss of function
  • Apoprotein B100 is supposed to surround a cholesterol ester core ball-o-cholesterol and facilitate binding to the LDL receptor.
• ARH adaptor protein: loss of function
  • ARH adapter protein is required for clustering the LDL receptors (bound to apoprotein B100 and cholesterol stuff) into the clathrin pits.
• PCSK9 protease: gain of function
  • PCSK9 is a protease that degrades the LDL receptor.
  • A dominant mutation
  • Gain of function

• Three classes of mutations:
  • Class 1 interrupts receptor synthesis
  • Class 2 interrupts receptor transport to the cell surface
  • Class 3 interrupts receptor binding of LDL
  • Class 4 interrupts receptor clustering in coated pit
  • Class 5 interrupts receptor discharge of LDL into endosome

What are "private" mutations?

• Some mutations cause a dominant negative effect.

[edit] Pathogenesis

[edit] Phenotypic information

• Early onset atherosclerotic heart disease
  • Age and sex dependent
• Elevated serum cholesterol
• Elevated LDL (low density lipoprotein) cholesterol
• Xanthomas
  • Tendons, skin, eyelids (yellow and fatty)
  • 50% of pts
• Homozygotes have very high lipids and childhood miocardial infarctions
  • semi-dominant

[edit] Diagnosis

[edit] Treatment

• Heterozygotes are less severe in phenotype and more likely to respond to treatment.
  • More readily treated because they are making at least some LDL receptor.
  • One response to elevated cholesterol is upregulation of the endogenous receptor.
• Genotype affects how well treatments work.
• There are two main strategies in treating familial hypercholesterolemia: deplete bile and inhibit HMG-CoA reductase.
• Bile contains cholesterol (or some intermediate) and is normally reabsorbed in the gut.
  • So we provide bile acid-binding resin so that the pt passes the bile (and the cholesterol within) and thus reduces their cholesterol levels.
• HMG-CoA reductase makes cholesterol out of acetyl CoA.
  • HMG-CoA reductase inhibitors (statins) reduce the amount of cholesterol made by the hepatocytes of the pt.

[edit] Recent research

[edit] 5 important facts

[edit] Not to be confused with

[edit] Questions and answers