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
features of CF
Lungs – recurrent infection
Pancreas –malabsorption, steatorrhoea, diabetes
Liver – cirrhosis
blood in CF in a neonate
high blood immune reactive trypsin
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
what is screened for in the UK
PKU from 1969
Congenital hypothyroidism added 1970
Sickle cell disease added 2006
Cystic fibrosis added 2007
Medium chain AcylCoA dehydrogenase (MCADD) added 2009
how is mitochondrial fatty acid B-oxidation screened for (MCADD)
acylcarnitine levels by tandem MS
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.
consequence of MCADD
cot death - cant break down fat
