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Biochemistry Case 6- Phenylketonuria

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on 11 February 2015

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Transcript of Biochemistry Case 6- Phenylketonuria

Characteristics of Children Who Have PKU
The Background on Patient P.Y.
4 month old
Recently arrived in US from Eastern Europe
Has become less than normally attentive to her surroundings
Delayed psychomotor maturation
Tremor of her extremities
Gross twitching
The Metabolic Defects Responsible for causing Phenylketonuria
-Phenylalanine needs to be converted to tyrose.
-Enzyme responsible for this is
phenylalanine hydroxylase.
-Phenylalanine hydroxylase uses
tetrahydrobiopterin (BH4)
-BH4 is the electron donor for the enzyme
What molecules are responsible for the adverse effects?
Biochemistry Case Study 6
1. High phenylalanine concentration
Normal: 1 mg/dL
Classic PKU: >20 mg/dL
Patient: 30 mg/dL
2. Low tyrosine concentration
Patient: 2 mg/dL
3. Urea contains phenolic acids and ketones.
Patients: both
4. Musty odor
5. Fair skin
Metabolism of Phenylalanine and Tyrosine
1.Phenylalanine is an essential amino acid.
2. Phenylalanine can be used to make macromolecules.
3. It can be oxidized by phenylalanine hydroxylase to tyrosine.
4. Tyrosine can be used to make macromolecules.
5. It is also involved in the biosynthesis of melanin, catecholamines, norepinephrine, epinephrine, and thyroid hormone.
Two pathways to get rid of excess phenylalanine:
1. Convert phenylalanine to tyrosine (main route)
2. Transamination to phenylpyruvate and then to other phenolic acids
Excess Phenylalanine
Phenylalanine builds up in the body if there is an inadequate PAH activity, which causes a condition called hyperphenylalaninemia.
Now, the only way to get rid of phenylalanine is to convert it to phenolic acids.
The disease is called phenylketonuria because one of the dominant metabolites contains a ketone, phenylpyruvate, which is an alpha-keto acid
Two reasons for a lack of PAH activity: 1. Defective PAH gene. 2. There is an inadequate amount of the cofactor tetrahydrobiopterin (BH4).
Traditional treatment for phenylketonuria consists of a phenylalanine restricted diet.
Phenylalanine is toxic to brain tissue.
Since the liver cannot metabolize Phe to Tyr, restricting the amount of phenylalanine dietary intake, if PKU is caught early enough, can prevent devastating damage to the brain.
Sapropterin, a synthetic form of tetrahydrobiopterin (BH4) (a cofactor of PAH), can lower blood Phe levels.
Food prominent in our diet and high in Phe include:
Foods high in protein such as:
Milk and dairy products
Red meat, chicken, and fish
Artificial sweeteners such as aspartame
Foods to Avoid
Foods that are encouraged for patients suffering from Phenylketonuria include:
The Phenylketonuria Diet
If the genetic defect involving PAH is caught shortly after the child’s birth and a strict diet is established before serious mental deficiencies have set in, the outlook for patient’s affected is surprisingly good.
If the condition goes untreated or if the diet is not strictly adhered to, brain damage can occur and quickly exacerbate.
Mental retardation can develop within the first year of life.
Typical Prognosis
This defect occurs 1 in 20 thousand individuals
On the human chromosome the defect is in the position 12 q 22-24.1
In Northern Europeans (40%) a G-A transition at the 5' donor splice site results in an absence of the C terminus
20% of Northern Europeans have a mutation on Exon 12 involving a C->T transition substitute tryptophan for arginine
Defects in PAH enzyme
BH4 is the electron donor for the PAH enzyme
BH4 transfers electrons to oxygen to form tyrosine and dihydropiopterim (QH2)
BH4 gets regenerated from QH2 by an NADH dependent reaction that is catalyzed by dihydrobiopteridine reductase (DHPR) found widely in the brain
Defects in BH4 Electron Donor
Defects begin in BH4 metabolism, this process synthesizes GTP using septitern reactions 3 and 4
When BH4 is defective tyrosine can not be hydroxylated to tryptophan
Neurotransmitter production is decreased causing convulsions and neurological deterioration
What Can Make BH4 Defective?
Phe, Tyr, and Trp are transported across the blood-brain barrier by the L-type amino acid carrier
Abnormally high levels of Phe can produce hypomyelination or demyelination

- Increased Phe concentration competes with Tyr and Trp

tryptophan - serotonin
tyrosine - catecholamines

* disturbed brain development and function
Physiological Consequences of PKU
- interrupts transmission of neurotransmitters
- Results in learning disability
Today all newborns are screened for PKU because it has in the past been a leading cause of mental retardation
Early testing can prevent long term neurological damage and mental retardation
Excessive Phenylalnine in the body is toxic to the brain and cognitive development
causing epilepsy, intellectual disability, and behavior problems
* Substrate for catecholamine (dopamine, norepinephrine, epinephrine) synthesis
* Rate of catecholamine synthesis is dependent on substrate concentration
* Low dopamine levels impair cognitive function
* dopamine controls behavior and cognition, motivation, working memory, and learning
Texas Law on Testing Infants for PKU
Texas DSHS Newborn Screening Program
-Screens for 28 different disorders
-Required except for parents with religious reasons
-Most children with disorders are from healthy families and tend to appear healthy.

2 rounds of screening tests for certain inheritable and other disorders
-Blood from baby’s heel 24-48 hrs after birth
-Blood sample taken 1-2 weeks later

Guthrie bacterial inhibition assay, Fluorometric analysis, and Tandem mass spectroscopy
Specimen collection kits are usually covered by insurance companies
Guthrie Test
Developed by Dr. Robert Guthrie in the early 1960s

Agar diffusion microbial assay for PKU

Growth of Bacillus subtilis ATCC 6051 in a minimum culture medium containing phenylalanine, phenylpyruvic acid, and phenyllactic acid despite the presence of an inhibitor, B-2-thienylalanine

If test results are “out of range,” the healthcare provider will be notified for additional testing
Letcher M. Phenylketonuria. Gale Encyclopedia of Medicine, 3rd ed. 2006. http://www.encyclopedia.com/doc/1G2-3451601244.html. Accessed November 05, 2012.
Fernstrom JD. Role of precursor availability in control of monoamine biosynthesis in brain. Physiol Rev. 1983;63(2):484-546.
Nelson DL, Cox MM. Amino acid oxidation and production of urea. In: Lehninger Principles of Biochemistry. 5th ed. New York, NY: W.H. Freeman and Company; 2008.
Newborn screening – frequently asked questions. Texas Department of State Health Services. http://www.dshs.state.tx.us/lab/nbsFAQ.shtm. Updated July 26, 2012. Accessed November 15, 2012.
Phenylketonuria: screening and management. US Department of Health & Human Services National Institutes of Health. http://consensus.nih.gov/2000/2000phenylketonuria113html.htm. Updated October 18, 2000. Accessed November 15, 2012.
Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatr. 1963;32(3):338-343. http://pediatrics.aappublications.org/content/32/3/338. Accessed November 5, 2012.
Musty odor in wet diaper

Lab results:
Phenylalanine concentration
= 30 mg/dL
Tyrosine concentration
= 2 mg/dL
Urine tested positive for phenolic acids
FeCl3 detected ketones in urine
How PKU affects CNS
PKU = missing phenylalanine hydroxylase (PAH)
PAH converts Phenylalanine to Tyrosine
Mutated PAH causes build up of Phenylalanine in blood
Retardation in axonal maturation, hypomyelination
Genetics of PKU
PKU is an autosomal recessive disease
Both parents have to be carriers of mutated genes on PheOh
Number of mutations found… and counting
269 missense point mutations
23 nonsense mutations
10 silent mutations
D143G variant
Asp 143
Located at active site
May be involved in controlling co-factor access to active site
Mutation of Asp 143
Aspartic acid glycine
Population Distribution
Mutations in Europe
Scandinavia – R408W-H2, Y414C
Britain and Ireland – R408W-H1, F39L
Germany and Austria – R408W-H2
Eastern Europe – R408W, R158Q
Italy and Spain – R252W, R158Q
Anh Le
Eva Coulson
Tyler Skeeler
Cesna Yap
John Park
Based on lab values, the patient clearly has some defect in the PAH enzyme.
The patient is unable to metabolize Phe to Tyr.
The patient is only four months old so, while the level of Phe is alarming, disastrous effects could still be potentially minimized.
The patient should be started on a very restricted diet and undergo further testing in the next several weeks.
Quick Review
PKU is an inherited genetic disorder in which a defect exists in the phenylalanine hydroxylase.
This defect prevents the metabolism of Phe to Tyr.
The metabolism of Phe by PAH requires the cofactor BH4 to deliver reducing equivalents needed for the reaction.
This is the area of research in developing drugs to treat this disorder.
A synthetic form of BH4, Sapropterin, could be the answer for PKU patients in the future.
Quick Review
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