phenylketonuria

Question 1

what is phenylketonuria

Answer 1

an inherited defiency in metabolism. A deficiency in the enzyme phenylalanine hydroxylase

Question 2

what dose phenylalanine hydroxylase normally do ?

Answer 2

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

Question 3

what does a build up of S-Phe cause in cells?

Answer 3

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

Question 4

is neonatal screening done?

Answer 4

yes due to the high incidence risk

Question 5

what is pathway is PAH involved in?

Answer 5

dopamine to noradrenalin and adrenaline pathway with happens in the liver
- its also used in the tyrosine synthesis pathway

Question 6

what other co factors and co substrates are involved in the conversion ?

Answer 6

S-Phe to S-tyr
cosubstate O2 is needed and the cofactor tetrahydrobipetrin
and the enzyme PAH

Question 7

what is the structure of the enzyme ?

Answer 7

its a tetramer with each monomer possessing catalytic regulatory and tetramization domains

Question 8

how is phenolketonuria diagnosed?

Answer 8

after birth all children are screened and mass spec of S-phe levels are taken and quantified

Question 9

why are other levels of amino acids and metabolites also taken?

Answer 9

to see the differentiation of PKU and BH4 deficiency

e.g S-tyr levels are also taken

Question 10

what can CNS levels of S-phe show?

Answer 10

exposure of S-phe to th braun and progression of the disease

Question 11

what can decreased levels of S-try mean?

Answer 11

Decreased levels of neurotransmitters (NO) so unstable moods and seizures
also decreased levels of melanin in the skin

Question 12

what are patients with PKU prone to ?

Answer 12

Prone to fractures due to poor bine metabolism although this could be due to a restricted diet

Question 13

what is the diet for people with PKU?

Answer 13

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

Question 14

what are some of the treatment options ?

Answer 14

• large neutral amino acids (lannas)
• sapropertin
• gene therapy
• enzyme therapy
• probiotics

Question 15

how do large neutral amino acids work?

Answer 15

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

Question 16

what are some examples of LNNAs?

Answer 16

tyrosine , tryptophan and other branched aliphatic amino acids

Question 17

what is sapropterin ?

Answer 17

it works as its the cofactor that the enzyme PAH uses and its given as a HCL salt

Question 18

Which patients do saporetin work best for and why ?

Answer 18

it works best for patients with milder PKU as

Question 19

how does saporetin work ?

Answer 19

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

Question 20

how does gene therapy work?

Answer 20

it works by replacing missing enzyme expression of wild type enzyme in targeting tissues.

Question 21

what are the issues of gene therapy ?

Answer 21

issues with safety concerns and requires as safe vector as adenovirus to give to patients

Question 22

how does enzyme replacement therapy work?

Answer 22

it directly replaces the missing enzyme PAH

Question 23

Why is enzyme therapy hard to do ?

Answer 23

its a tetrameter and needs allot of cofactor to work

and its hard to target the correct organelle and tissue.

Question 24

how does using an alternative enzyme work?

Answer 24

Using an enzyme called PAL which degrades S-phe in the blood. so lower concentrations

Question 25

what does PAL stand for ?

Answer 25

bacterial phenylalanine ammonia liase

Question 26

why is PAL easier to use than PAH?

Answer 26

It needs no cofactors to work so easier to use

Question 27

What are some of the specifications to give PAL?

Answer 27

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

Question 28

how do probiotics work?

Answer 28

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.