3. Amino acid metabolism disorders Flashcards
What is creatinine?
Breakdown product of creatine and creatine phosphate in muscle.
What is creatinine used as a clinical marker for?
- Estimate of muscle mass - produced at constant rate depending on muscle mass (unless muscle is wasting)
- Indicator of renal function - filtered via kidneys into urine; raised level on damage to nephrons
Why is striae formation a symptom of Cushing’s syndrome?
Excess cortisol… excessive protein breakdown… weakens skin structure… striae formation.
Name 2 enzymes that are routinely measured in plasma as part of liver function test.
- Alanine aminotransferase (ALT) - converts alanine to glutamate
- Aspartate aminotransferase (AST) - converts glutamate to aspartate
Give examples of conditions which would cause particularly high levels of ALT and AST.
Conditions that cause extensive hepatocyte necrosis, eg.
- viral hepatitis
- autoimmune liver diseases
- toxic injury
- acute liver failure from ingestion of death cap mushrooms (Amanita phalloides)
Describe the genetic basis of defects in the urea cycle.
- Autosomal recessive mutation in either of the 5 urea cycle enzymes.
- Complete enzyme loss is always fatal but partial losses occur in 1/30,000 liver births.
What do inherited urea cycle enzyme defects cause?
- Hyperammonaemia (high blood [NH4+])
2. Accumulation and/or excretion of particular urea cycle intermediate(s)
What are the symptoms of inherited urea cycle diseases?
Depends on extend of defect and amount of protein eaten. Include:
- vomiting
- lethargy
- irritability
- mental retardation
- severe cases: seizures, coma and eventually death
What are the treatments for urea cycle defects?
- low protein diets
- diets in which keto acids of essential amino acids are used to replace the amino acids themselves (keto acids are converted to amino acids using some of the NH4+ - lower its tissue concentration)
Apart from an inherited mutation, give a cause of hyperammonaemia.
Can arise as secondary consequence of liver disease such as cirrhosis - liver’s ability to remove NH3 from the portal blood is impaired.
Why might defects in the urea cycle cause mental retardation?
Causes accumulation of ammonia, which is readily diffusible and extremely toxic to brain:
- Disruption of cerebral blood flow and alteration of blood-brain barrier
- Interferes with metabolism of excitatory amino acid NTs (eg glutamate and aspartate)
- Interferes with TCA cycle (reacts with a-ketoglutarate to form glutamate)
- Interferes with amino acid ttransport and protein synthesis
- pH effects (alkaline)
How are inherited diseases of amino acid metabolism detected at birth?
Heel prick test
How common are inherited diseases involving amino acid metabolism defects?
- > 50 diseases involving total, or more commonly partial loss of enzyme activity,
- Rare individually but collectively constitute a significant portion of paediatric genetic disease.
Why do disorders in amino acid metabolism usually only have clinical consequences when the affected enzymes is involved in amino acid breakdown rather than synthesis?
- Sufficient amino acids are normally supplied in diet to overcome any defects in their synthesis.
- But defect in breakdown allows the amino acid/breakdown products to accumulate - may be toxic themselves or may be metabolised to toxic products.
What are the general symptoms of accumulation of toxic amino acids/breakdown products?
What does treatment usually involved?
Mental retardation and developmental abnormalities
Restricting the amount of a particular amino acid in diet.
