phenylketonuria Flashcards
what is phenylketonuria
an inherited defiency in metabolism. A deficiency in the enzyme phenylalanine hydroxylase
what dose phenylalanine hydroxylase normally do ?
it converts S-Phe to S-Tyr
so without this enzyme you get a build up of S-phe in the cells and reduced levels of S-Tyr
what does a build up of S-Phe cause in cells?
it causes toxic changes in cells such as microcenchalpy ( small brain size) and mental retardation.
- increase in reactive O2 species leading to inflammation and damage
is neonatal screening done?
yes due to the high incidence risk
what is pathway is PAH involved in?
dopamine to noradrenalin and adrenaline pathway with happens in the liver
- its also used in the tyrosine synthesis pathway
what other co factors and co substrates are involved in the conversion ?
S-Phe to S-tyr
cosubstate O2 is needed and the cofactor tetrahydrobipetrin
and the enzyme PAH
what is the structure of the enzyme ?
its a tetramer with each monomer possessing catalytic regulatory and tetramization domains
how is phenolketonuria diagnosed?
after birth all children are screened and mass spec of S-phe levels are taken and quantified
why are other levels of amino acids and metabolites also taken?
to see the differentiation of PKU and BH4 deficiency
e.g S-tyr levels are also taken
what can CNS levels of S-phe show?
exposure of S-phe to th braun and progression of the disease
what can decreased levels of S-try mean?
Decreased levels of neurotransmitters (NO) so unstable moods and seizures
also decreased levels of melanin in the skin
what are patients with PKU prone to ?
Prone to fractures due to poor bine metabolism although this could be due to a restricted diet
what is the diet for people with PKU?
low S-phe diets
- avoid foods high in amino acids such as meat or diary
- must take Vitamin d and b12 and S-tyr supplements
- avoid things such as sweeteners which contain aspartame
what are some of the treatment options ?
- large neutral amino acids (lannas)
- sapropertin
- gene therapy
- enzyme therapy
- probiotics
how do large neutral amino acids work?
increased levels of LNAAs mean less S-phe gets absorbed form the digestive system so lower levels of S-phe in the blood
they also compete for the amino acid transporters across the BBB so less S-phe is espoused to the brain having a positive influence on decision making
what are some examples of LNNAs?
tyrosine , tryptophan and other branched aliphatic amino acids
what is sapropterin ?
it works as its the cofactor that the enzyme PAH uses and its given as a HCL salt
Which patients do saporetin work best for and why ?
it works best for patients with milder PKU as
how does saporetin work ?
it works as a cosubrate by binding to the enzyme and stabilising it so its degraded to a lesser extent, increasing enzyme activity and decreasing S-phe levels
how does gene therapy work?
it works by replacing missing enzyme expression of wild type enzyme in targeting tissues.
what are the issues of gene therapy ?
issues with safety concerns and requires as safe vector as adenovirus to give to patients
how does enzyme replacement therapy work?
it directly replaces the missing enzyme PAH
Why is enzyme therapy hard to do ?
its a tetrameter and needs allot of cofactor to work
and its hard to target the correct organelle and tissue.
how does using an alternative enzyme work?
Using an enzyme called PAL which degrades S-phe in the blood. so lower concentrations
what does PAL stand for ?
bacterial phenylalanine ammonia liase
why is PAL easier to use than PAH?
It needs no cofactors to work so easier to use
What are some of the specifications to give PAL?
it must be given IV - to avoid dgergation by proteases in the stomach
dosing is gender specific
expensive as it must be administered by staff
risk of infection
how do probiotics work?
probiotics can contain bacteria that express the recombinant enzyme potentially allowing drug delivery to the lower digestive system . As the bacteria can survive the acidic conditions of the stomach and lyse in the lower intestines which have an alkali pH to release the enzyme. The enzyme then decreases S-phe levees in the digestive system.
