ChemPath: Metabolic Screening and Disorders 1 Flashcards
Which database keeps track of all inherited metabolic disorders?
OMIM
What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?
Lack of end-product
Build-up of precursors
Abnormal or toxic metabolites
What are the criteria for inherited metabolic disorder screening (Wilson and Junger)?
- It has to be an important health problem
- Must be accepted treatment
- Facilities for diagnosis and treatment
- Latent or early symptomatic stage
- Suitable test or examination
- Test should be acceptable to the population
- Natural history is understood
- Agreed policy on whom to treat as patients
- Economically balanced
- Continuing process (keep updating what is screened for)
What is phenylketonuria caused by?
- Phenylalanine hydroxylase deficiency
- This enzyme is responsible for conerting phenylalanine to tyrosine
- Deficiency results in an accumulation of phenylalanine which is toxic
Which abnormal metabolites are produced in PKU?
Phenylpyruvate
Phenylacetic acid (detected in the urine)
What is the main consequence of untreated PKU?
Low IQ
How is PKU investigated?
Blood phenylalanine level
Describe the treatment of PKU.
- Monitor the diet and ensure that the patient is having enough phenylalanine (but not too much)
- This must be started within the first 6 weeks of life
When is the Guthrie test performed in the UK?
5-8 days after birth
What is congenital hypothyroidism usually caused by?
- Thyroid dysgenesis or agenesis
NOTE: diagnosis is based on high TSH
Describe the pathophysiology of MCAD deficiency.
- This is a fatty acid oxidation disorder
- The carnitine shuttle transports fats into the mitochondria where it will be broken down into smaller and smaller chains by the process of fatty acid oxidation
- Without MCAD, you will not produce acetyl-CoA from fatty acids, which is necessary in the TCA cycle to produce ketones (which spares glucose)
- Fat is used when fasting in between meals in order to spare your glucose stores
- In MCAD deficiency, the patient is unable to break down fats so they become very hypoglycaemic in between meals and this can kill
What is the screening test for MCAD deficiency?
Measuring C6-C10 acylcarnitines by tandem MS
Outline the treatment of MCAD deficiency.
Make sure the child never becomes hypoglycaemic, and hence reliant on fats as a source of energy.
What is homocystinuria caused by?
Failure of remethylation of homocysteine
What are the clinical features of homocystinuria?
- Lens dislocation
- Mental retardation
- Thromboembolism
Which conditions are currently being trialled for inclusion in the newborn screening programme?
- Homocystiinuria
- Isovaleric acidaemia
- Glutaric aciduria type I
- Maple syrup urine disease
- Long-chain acyl-CoA dehydrogenase deficiency
How many classes of cystic fibrosis are there?
6
Outline the pathophysiology of cystic fibrosis.
- Failure of the cystic fibrosis transmembrane conductance regulator means that chloride ions cannot move into the lumen from the cells, resulting in increased water absorption and very thick secretions
What is the screening test for cystic fibrosis?
High serum immune reactive trypsinogen
Describe the process of screening and diagnosis of cystic fibrosis.
- If IRT > 99.5th centile in 3 bloodspots, move on to mutation detection
- There are >500 mutations that can cause cystic fibrosis, but FOUR are very common
- If you detect 2/4 mutations, diagnose CF
- If you detect 1/4 mutations, extend test to panel of 28 mutations
- If you detect 0/4 mutations, repeat IRT at day 21-28
