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.
Name 2 major inherited diseases of amino acid metabolism.
- Phenyketonuria (PKU)
2. Homocystinuria
What is the genetic basis of PKU? Which enzyme is affected?
Autosomal recessive mutation of phenylalanine hydroxylase (chromo 12).
What is the function of phenylalanine hydroxylase?
Oxidises phenylalanine to tyrosine (1st step in phenylalanine metabolism)
What is the consequence of a deficiency in phenylalanine hydroxylase?
- Accumulation of phenylalanine in tissues and blood… transaminated to phenylpyruvate… produce phenylketones (eg. phenylacetate, phenyllactate)… excreted in urine (musty smell).
- Tyrosine deficit… affects pathways for production of: NA, adrenaline, dopamine, melanin, thyroid hormone and protein synthesis.
How is PKU diagnosed and treated?
- Diagnosed by detection of phenyketones in urine or measurement of blood [phenylalanine] - normally <0.1 mmol/L but can >1.0 mmol/L in disease.
- Treatment =
- low phenylalanine diet (avoid artificial sweeteners and high protein foods such as meat, milk and eggs)
- high tyrosine diet (becomes essential amino acid)
What are the symptoms of untreated PKU?
- Severe intellectural disability
- developmental delay
- microcephaly
- seizures
- hypopigmentation (decreased melanin production due to tyrosine absence)
Why is untreated PKU associated with brain development inhibition?
- Phenylpyruvate inhibits pyruvate uptake into mitochondria so interferes with energy metabolism in the brain.
- Affects signalling in brain as tyrosine is a precursor of many NTs (NA, adrenaline, dopamine).
- High serum [phenylalanine] actually decreases brain [phenylalanine] by saturating/blocking LNAAT transporter.
What is homocystinuria? Which enzyme is involved in Type 1?
- Rare autosomal recessive defect in methionine metabolism.
- Type 1 = deficiency in cystathionine beta-synthase (CBS) enzyme.
What is the function of the CBS enzyme?
Converts homocysteine to cystathionine, which is further converted to cysteine.
What are the consequences of chronically elevated plasma [homocysteine]?
Disorders of connective tissue, muscle, CNS and the CVS (mechanisms not fully understood).
How is type 1 homocystinuria detected?
- Elevated levels of homocysteine and methionine in plasma
2. Presence of homocystine (oxidised form of homocysteine) in urine
Why is homocystinuria easily misdiagnosed as Marfan’s syndrome? How are the 2 conditions differentiated?
In children, symptoms are very similar.
Marfan’s = lack of expression of fibrillin-1 protein in CT
Homocystinuria = disruption of fibrillin-1 protein structure
Differentiated by neurological symptoms in homocystinuria.
What is the treatment for homocystinurias?
- Low methionine diet( avoid milk, meat, fish, cheese, eggs, nuts and peanut butter)
- Cysteine, VitB6, betaine, B12 and folate supplements
Why are Vit B6 and B12, betaine and folate supplements part of the treatment for homocystinuria?
- Betaine, Vit B12 and folate promote reconversion of homocysteine to methionine (involved in DNA metabolism so more reconversion pathways than homocysteine).
- Vit B6 is required as a co-factor for activity of CBS enzyme (when low level expression). If complete absence of CBS, increase cysteine in diet.
What is the effect of the lack of cysteine production in homocystinuria?
Increased susceptibility to oxidative stress as cysteine is required for glutathione activity in ROS protection.
Why does homocystinuria cause neurological symptoms?
breakdown products (metabolites) of methionine are toxic
Why is homocystinuria associated with increased risk of early onset CVD?
- excess homocysteine damages collagen and elastic fibres in CT by binding to protein lysine residues - can cause aortic dilation or valve prolapse
- homocysteine = pro-thrombotic, can cause blood clot formation
