FA Oxidation

Question 1

Zelwegger’s syndrome

Answer 1

• VLCFA accumulation
• defective peroxins (peroxisome biogenesis), so lack of peroxisomes
• Ineffective targeting of proteins to peroxisomes
• Sx: CNS swelling & hepatomegaly; also affects other tissues

Question 2

CPT-1 deficiency

Answer 2

• Liver primary effects
• FA oxidation decreased
• Hypoketotic
• Hypoglycemic
• Lethal

Question 3

CPT-II deficiency

Answer 3

• Myocytes primary affected
• FA oxidation reduced in skeletal & cardiac muscles
• Cardiomyopathy
• Sx:
  
  • Muscle pain, cramps following prolonged exercise
  • Muscle necrosis & myoglobinuria
• Dx: cultured fibroblasts & enzyme assay
• DDx: muscle biopsy for elevated muscle triglyceride; whereas McArdle’ disease will show increased glycogen
• Rx: High CHO/low fat diet, avoid fasting

Question 4

Acyl-carnitine translocase deficiency

Answer 4

• Sx:
  
  • muscle weakness
  • hypoglycemia
  • hyperammonemia
  • cardiomyopathy

Question 5

MCAD deficiency

Answer 5

• Reduction in E production from ß-oxidation and causes severe hypoglycemia & hypoketonemia
• MCFA metabolites, including acyl-carnitines) readily detected in urine
• No KB, i.e. hypoketosis
• Sx:
  
  • vomiting
  • hepatomegaly
  • coma, death
• linked to 10% of cases of sudden infant death syndrome (SIDS)

Question 6

Refsum disease

Answer 6

• aka Phytanic Acid Storage Syndrome
• accumulation of Phytanic acid in plasma, blood cells & tissues
• Phytanic acid alpha-hydroxylase def.
• Sx:
  
  • progressive neuro sx.
  • tremors
  • unsteady gait
  • defective night vision
  • Peripheral nerves show segmental demyelination with hypertrophy due to concentric Shwann cell proliferation
• Rx: Diet devoid of chlorophyll-containing foods
  
  • Refsum’s disease is only lipid storage disorder that can be controlled by diet

Question 7

Plasma membrane carnitine transporter deficiency, i.e. failure in myocyte uptake of carnitine

Answer 7

• Na+-dependent transport membrane protein defect -> defect in carnitine transport into cytosol of muscle & heart cells
• Renal tubule cells also affected, being involved in reabsorbing glomerular filtrate carnitine
  
  • Failure of reabsorbing glomerular filtrate carnitine leads to excessive carnitine loss in urine
• Low intracell carnitine levels in affected tissues
• Low plasma levels b/c kidneys fail to reabsorb carnitine from filtrate
• Compromises acyl-oxidation in heart
• Sx vary from mild muscle cramps to severe muscle weakness (life-threatening)
• Rx:
  
  • Dietary carnitine therapy raises blood carnitine levels which in turn forces carnitine into cells in a non-specific manner
  • Diet low in LCFA
  • Avoid fasting
  • Diet supplemented by MCFA that do NOT rely on carnitine transport
• AR

Question 8

Secondary carnitine deficiency

Answer 8

1. Metabolic disorders:
   
   • FA oxidation disorders -> accumulation of acyl-carnitines which are excreted by kidneys, depleting carnitine pool
   • defects in mitochondrial chain which comprises ATP synthesis
2. Iatrogenic response: Pt taking meds that produces an adverse side effect on carnitine metabolism

• Rx:
  
  • Strenuous physical activity restriction
  • Snacking regularly on carb-rich foods to avoid hypoglycemia

Question 9

Jamaican vomiting sickness

Answer 9

• Unripe ackee fruit contain Hypglycin (rare a.a.)
  
  • Hypoglycin -> Methylenecyclopropylacetyl-CoA
• Methylenecyclopropylacetyl-CoA: irreversible inhibitor of short- & medium chain acyl-CoA dehydrogenases
• Sx:
  
  • hypoglycemia
  • vomiting
  • convulsions
  • metabolic coma

Question 10

Methylmalonic aciduria

Answer 10

• Defect in step:

1. B12 deficiency
2. Instrinsic factor from stomach
3. Defect in methylmalonyl CoA Mutase
4. Defect in coenzyme form of B12

• Used to DDx between Vit. B12 deficiency and Folate deficiency