Errors of Inborn metabolism (PKU) Flashcards
Generally describe what is the issue in Phenylketonuria (PKU). Why does this happen?
This is an abnormality of phenylanaline metabolism, resulting in hyperphenylanalinemia. This can be due to a Phenylanaline Hydroxylase (PAH) decrease or a decrease in the tetrahydrobiopterin (BH4) cofactor , preventing conversion of phenylanalyine to tyrosine and accumilation of the former, leading to excess phenyl ketones in urine.
What are the 3 phenylketones?
Phenylacetate, phenyllactate, and phenylpyruvate.
What kind of inheritence pattern in PKU and which is the most common subtype?
It is an autosomal recessive disorder with the vast majority being the bi-allelic defect in the PAH gene.
What are the classic findings of PKU in babies?
Mental and growth retardation, seizures, fair skin, eczema (a kind of rash), musty body odor (caused by phenylacetic acid being excreted in sweat).
What is Maternal PKU and what are the findings seen in the babies?
This is when the mother is non-complaint with her diet (assuming she has PKU herself?) This results in hyperphenylanalinemia which crosses into the placenta and interacts with the fetus, resulting in microcephaly, mental retardation, growth retardation and congenital heart defects.
Assuming the abnormality is in the genes coding for the PAH enzyme (as is the case for 98% of the patients), how can PKU be treated?
Through diet control that decreases phenylanaline intake (contained in aspartame and basically anything that contains proteins like meats nuts and soy), and increase tyrosine intake.
When should PKU be screened for? Why? What are the normal and abnormal values of PKU?
Should be screened in babies 2-3 days after birth because of maternal enzymes during fetal life. Normal is less than 120 micro M, and PKU would be 600+ micro M.
What is “Benign Phenylalanemia?”
There is an increase in phenylalanine but there is still residual normal PAH activity, so the patient is spared the mental retardation and is generally non symptomatic.
Describe the normal pathway of phenylalanine biochemistry in children.
Less than 50% is required for intake in protein synthesis, the rest of it is converted into tyrosine via the enzyme PAH and the cofactor BH4 in the liver, termed the “Hepatic PAH system.”
What is the function of the enzymes tetrahydrobiopterin (BH4) and dihydropteridine reductase (DHPR)?
BH4 is an essential cofactor required for the PAH to turn phenylalanine into tyrosine. DHPR is needed to renew the supply of BH4 by reducing an NADH to NAD+.
Why do we need BH4? If we have a defect in BH4 what would happen?
It is a cofactor for PAH, for tyrosine and triptophan hydroxylation. If we have a defect in BH4 therefore we will also have a defect in the synthesis of neurotransmitters. This only accounts for 2% of cases of PKU, however if this is the case normalizing the diet will do nothing.
What is the main fear of PKU?
It is believed that the excess amounts of phenylalanine produced and its derivitives (phenylketones) leads to brain damage.
Why are 50% of PKU patients termed “BH4 responsive” to BH4 dosing pharmacologically, even though their BH4 is fine to begin with?
50% of patients w/ PKU reacts better with pharmacological administration of BH4, it is believed that it acts like a chaperon protein and prevents the misfolding of the PAH.
