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PKU and metabolic disorders (PKU (Treatment (Avoid foods that are high in…
PKU and metabolic disorders
Pathological samples
Blood spot
Helps diagnose before the disease develops
Used in newborn screening
Screens for PKU
PKU results from phenyalanine hydroxylase
EDTA blood samples
When plasma is isolated the urgency of samples determines whether or not assayed immediately
Plasma has to be isolated from whole blood. RBC's produce ammonia, deamination of amino acids by gamma glutamyl transferase
Specialist tests
Congenital glycosylation defects
Numerous roles in body
Glycosylation - adding carbs to lipids & proteins
Can occur when glycosyl (carb group) is attached to nitrates
Can have multiple organ affects and can present in all effected organs
Autosomal recessive and can cause seizures (ataxyia)
Transferrins
used to diagnose a patient with CGD
glycoprotein that carries iron
ER or Golgi
Less sialic acid residues in defect
Isoelectric focussing
move to anode as negatively charged
reaches pH where no charge and movement stops (isoelectric point) Defect has lower isoelectric point
pH gradient in gel
abnormal pattern indicative of defect
MRC disorders
Systemic but many patients present with neurological dysfunctions
decreased ATP and cellular dysfunction
complex 1 decrease in abs at 340nm
measure mitochondrial marker enzyme (citrate synthase)
MCADD
Causes sudden infant death syndroe
Screened for
Can't break fatty acids into ketones
Metabolic disease
A disturbance in metabolism such as a breakage or blockage in the pathway and substrates and metabolites build up
Need a mutation in both maternal and paternal genes in order to present
MRCD
O2 is final e- acceptor in oxidative phosphorylation & makes H2O
ROS are toxic and require antioxidants to balance them out
May be under diagnosed
Most of MRC is coded for by mitochondrial DNA
Mitochondrial DNA
Homoplasmy (normal DNA)
Heteroplasmy (normal and mutant DNA)
Mutant load increases with age
Can damage cell if exceeds threshold
1000's of copies
Only present when mutant load passes threshold
Needs number of tests to confidently diagnose
Neurological presentation - CSF tested
Systemic presentation - plasma tested
Can test mtDNA in blood for mutations and replication is controlled by POLG polymerase gamma
Ragged red fibres indicative of MRCD as cells make more mitochondria
No cure but can be stabilised via antioxidants and can be prevented
PKU
Deficiency in phneylalanine hydroxylase where sufferer is unable to make tyrosine
substrate (tyrosine) is used to diagnose
A stable diagnostic marker is required for newborn screening
Can be caused by co-factor tetrahydrobiopterin
brain has deficit of large amino acids in the brain as phenyalanine competes with them for transport into the brain
Lipid peroxidation is caused by ROS
Measured TBARS as stable end product
decrease in coQ10 and deficit in activity of GSH peroxidase
Treatment
Avoid foods that are high in protein
Can also be prescribed sapropterin which helps to lower levels of phenylalanine
diet contains very low levels of phenylalaninne
Main way to treat is via diet
Treatment must commence as soon as possible after birth to have the best effect and to avoid any issues such as brain damage
if untreated it can eventually cause delayed development
behavioral and emotional problems
neurological problems, such as tremors and seizures
MCADD
Medium chain fatty acids added to a carnitine group which is removed from mitochondria & cell into blood
Results in accumulation of fatty acids joined to carnitine
Unable to metabolise medium chain fatty acids
Low Glucose leads to low ketones
Unable to make ketones, once glycogen is broken down can't make glucose
Ketone bodies essential to provide brain with energy when glucose levels are low