ABETALIPOPROTEINEMIA

  • Genetics and Mechanism
    • Autosomal recessive disorder.
    • Caused by mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein.
    • Leads to abnormal production and secretion of apolipoprotein B (apo B) and apo B–containing lipoproteins.
    • Insufficient lipidation of nascent particles prevents normal synthesis and secretion of chylomicrons (intestine) and VLDL (liver).
  • Clinical Presentation
    • Usually presents in infancy with:
      • Fat malabsorption
      • Hypocholesterolemia
      • Acanthocytosis (crenated RBCs)
    • Later in life:
      • Deficiencies in fat-soluble vitamins (A, D, E, K)
      • Neurologic complications: atypical retinitis pigmentosa, posterior column neuropathy, myopathy
      • Retinal changes, peripheral neuropathy, ataxia, lordosis (from muscular weakness), sensory motor neuropathy, mental retardation
    • Children appear malnourished, show growth retardation.
    • Some develop hepatic steatosis and cirrhosis (possibly related to medium-chain triglyceride therapy).
  • Laboratory Findings
    • Absence of plasma apo B–containing lipoproteins
    • Extremely low plasma cholesterol (<50 mg/dL)
  • Pathophysiology
    • Microsomal triglyceride transfer protein is essential for loading triglycerides and phospholipids into the lumen of the endoplasmic reticulum.
    • Without it, chylomicrons & VLDL cannot form or be secreted → fat malabsorption & lipid-poor plasma.
  • Treatment
    • Lipid-poor diet to address digestive intolerance (low daily fat intake, e.g., 5 g/day in children).
    • Provide dietary essential fatty acids (e.g., vegetable oils).
    • High-dose fat-soluble vitamins (A, D, E, K) supplementation.

TANGIER DISEASE

  • Genetics and Mechanism
    • Autosomal dominant disorder.
    • Mutations in ABCA1 (adenosine triphosphate–binding cassette transporter-1 gene).
    • ABCA1 crucial for cholesterol efflux from cells onto nascent HDL → decreased cholesterol efflux → low plasma HDL levels.
    • Homozygotes: almost absent plasma HDL.
    • Heterozygotes: ~50% normal HDL levels.
  • Clinical Presentation
    • Named for the kindred on Tangier Island (Chesapeake Bay).
    • Orange-colored tonsils (cholesterol deposits).
    • Corneal opacities.
    • Hepatosplenomegaly (due to foam cell accumulation).
    • Peripheral neuropathy.
    • Increased risk for premature coronary disease.
  • Laboratory Findings
    • Very low to absent HDL cholesterol.
    • Low total cholesterol.
    • Overaccumulation of macrophage cholesteryl esters (foam cells).
  • Treatment
    • No disease-specific treatment currently available.
    • Management focuses on general measures for cardiovascular risk reduction.

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