metabolic disorders and screening Flashcards
causes of defect in enzyme activity
- lack of enzyme
- reduced enzyme activity due to:
1. defects of post-translational modification,
2. assembly
3. transportation - defects of cofactor activation
general effect of deficiency of enzyme activity
lack of end product
build up of precursers
abnormal, toxic, metabolites
* Km – how high concentration of substrate has to be, before enzyme interested.
* If get high conc of substrates can get enzyme interested -> toxic metabolies
* These factors are biological hallmarks
criteria to screen for a metabolic disease
- Important health problem
- Accepted treatment
- Facilities for diagnosis and treatment
- Latent or early symptomatic stage - no point screening if early sx
- Suitable test or examination
- Test should be acceptable to the population
- Natural history understood
- Agreed policy on whom to treat as patients
- Economically balanced
- Continuing process - update what screen for
pathway involved in phenylketonuria
Phenylalanine is essential amino acid – normally metabolised through tyrosine
If phenylalanine hydroxylase is deficient -> build up of phenylalanine = toxic
Also get phenylpyruvate and phenylacetic acid – abnormal metabolites of phenylalanine
Phenylacetic acid seen in urine
problem with phenylketonuria (PKU)
phenylalanine is toxic to CNS - low IQ less than 50
no physical sx
it is common
dx and mx of phenylketonuria
Test is to measure blood phenylalanine
Cant do genetic test – too many mutations
Cant get rid of phenylalanine – it is an essential amino acid, so need some.
Treatment has to be started within 1st 6wks of life - expensive
sensitivity =
true +ve / total disease present
specificity =
true -ve / total disease absent
positive predictive value =
true +ve / +ve test
negative predictive value =
true -ve / total -ve
is sensitivity or specificity more important in screening
sensitivity - unethical to miss cases - better to have false +ves
how do we screen for inherited metabolic disorders
guthrie test on day 5-8
heal prick form posterior medial 1/3 of foot
what is the positive predictive value for PKU guthrie test
80%
how is congenital hypothyroidism screened for and what is the usual cause
guthrie - look for gigh TSH
PPV = 60-70%
usually dysgenesis/agenesis of thyroid gland
features of congenital hypothyroidism
- large tongue,
- mottling of face,
- umbilical hernia,
- hoarse cry.
- High TSH.
Treatable with thyroxine.
pathology of CF
6 classes of defect.
Failure of Cl- ion movement from inside epithelial cell into lumen
-> increased reabsorption of Na+ /H2O
-> viscous secretions
-> ductule blockage
screening for CF
how does mass spectrometry work
Ionise molecule
Then fragment it in a controlled way
Bits of molecules can separate on mass and charge
Unique footprint to molecule
If further fragement twice -> tandem mass spec
Can pick up a lot of abnormal metabolites
MCADD pathway
Break down fatty acids in mitochondiroa
If MCAD missing – don’t produce acetyl CoA – used for TCA cycle or for producing ketones – both spare glucose.
Use fat when fasting, to spare glucose.
what is homocystinuria
failure of methylation of homocysteine - causes:
* lens dislocation,
* mental retardation
* thromboembolism at early age.
wales screen for this
