Is there any way to prevent PKU?

PKU is an inherited disorder from autosomal recessive gene. The babies must receive 2 copies of the recessive gene to deveop PKU. The parents will not know if they are PAH mutant gene carrier so there's no way they can free their babies from this disorder. However, it is still important for women to control the Phe level as high Phe level can result in slow growth, small head size and some other disorder in their babies.

Reference:
Editorial team, harvard. (2012). How does one prevent Phenylketonuria PKU.  Retrieved June 12, 2012, from Oh my health: daily dose for better living: http://www.onlymyhealth.com/how-does-one-prevent-phenylketonuria-pku-12977608301

Biochemistry behind phenylketonuria

Metabolic pathway of Phenylalanine

L-Phenylalanine is an essential amino acid that can be taken from diet and is needed for protein synthesis. Phenylalanine hydroxylase (PAH) requires cofactor, tetrahydrobiopterin (BH4) and oxygen to work. PAH together with BH4 catalyses the hydroxylation of L-Phe to L-Tyr.L- Tyr is then converted to Fumarate and then form CO2 and H2O. This metabolism mainly occurs in the liver.

Lack of PAH activity due to genetic defect PAH gene
However, when there is non-functional PAH, L-Phe cannot be converted to L-Tyr. L-Phe will be metabolise by the other 2 pathways, provided that there is no functional PAH. In the other 2 pathways, L-Phe will go through transamination or decarboxylation to form Phenylacetylglutamate, o-hydroxyphenylacetate or phenyl-lactate. The metabolites in the pathway will be released into the bloodstream and bring to the brain. Decarboxylation of L-Phe causes the amount of phenylacetylglutamate(very toxic) to increase. As it accumulates, it can result in alteration in mental status and cognitive impairment. Accumulation of phenyl-lactate will also cause grownth retardation as it causes the myelin level in the verebral hemispheres and the cerebellum to fall. This resulted in the mental retardation in classic PKU.


Lack of PAH activity due to de novo synthesis of BH4 

Classic PKU can also be resulted if the GTP cyclohydrolase I and pyruvoyl tetrahydropterin synthase is not functional as BH4 cannot be formed in the de novo synthesis of BH4.

Lack of PAH activity due to faulty BH4 regeneration pathway- Account for 1-3% of hyperphenylalaninemia
Any mutation in structures of BH4 can lead to a rare form of PKU. This type of PKU is known as ''malignant'' PKU due to the progressive deterioration in neurological function. This deterioration cannot be removed by limiting the phenylalanine dietary intake. Consequence of such problem is defection in neurotransmission. While L-Phe go through the dehydroxylation to form L-Tyr, BH4 is oxidized to BH2 (dihydrobiopterin) by PAH. BH4 is then regenerated by dihydropholate reductase (DHPR). 
   

Regeneration of BH4 from BH2

References:

1. Introduction to Phenylketonuria. Retrived July 1, 2012, from http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/PKU%20Cases/PKU%20biochem%20intro.htm

2. Robin A Williams,Cyril DS Mamotte, John R Burnett. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. National Center for Biotechnology Information. Retrieved July 2, 2012, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423317/

3. Nariman Hossein-Javaheri. (2012). Phenylketonuria. Tangient LLC. Retrieved July 10, 2012, from https://neurowiki2012.wikispaces.com/Phenylketonuria

Effects of PKU on the brain

The cause of neurological disorder caused by PKU  could be due to the myelination or de-myelination as myelination and white matter are affected in the early stage of development. A fall in the myelination levels of neurons and glial cells have been detected. This fall is due to the transformation of oligodendrocytes(a variety of nruroglial) to non-myelinating phenotypes. In periventricular region and the forceps major and carpus callosum minor, the loss of white matter is more visible.In the early development stage, dendrite growth is also affected. 

The PKU patients' gray matter reduce greatly in motor and pre-motor cortex, hippocampus and thalamus but increase in striatum ventral regions. These explain for mental and cognitive abnormalities in PKU patients as damaged motor and pre-motor cortex can lead to damaged motor functions and reduce volume of nueronal cells in the thalamus and hippocampus.

Reference:
Nariman Hossein-Javaheri. (2012). Phenylketonuria. Tangient LLC. Retrieved July 10, 2012, from https://neurowiki2012.wikispaces.com/Phenylketonuria

PKU videos

Here's a video that summarise what PKU is, symptoms in PKU, the dietary control treatment, difficulty to control the diet and importance of treatment.

Next up- a documentary on a 16 years old PKU patient who is able to lead a normal life just like any other 16 years old.

 

References: 

Children Memorial Hospital. Barbara Burton. PKU with Dr Burton. Retrieved June 11, 2012 from http://www.youtube.com/watch?v=DEZ5JzSN2aQ&feature=related

James, Andrew, Thomas, Paul, Matt, Andy. PKU. Retrieved June 11, 2012 from http://www.youtube.com/watch?v=KUJVujhHxPQ&list=PLAC43918F68EE209D&index=3&feature=plpp_video

Kevin's story

an interview video with Kevin who is suffering from PKU.

he's inspiring and living his life to the fullest.

The gray and white matter

Here's the explaination on gray and white matter of the brain.
Next up, effect of PKU on gray and white matter of the brain.

Reference:
Walid Aziz. (2007). Neuroanatomy Tutorial 5 (Gray and White Matter). Retrieved June 11, 2012 from http://www.youtube.com/watch?v=NS8BjcKySF8

The Cures :) Live with Hopes

Today I am going to write about the current cures for Phenylketonuria :)

Dietary therapy is the standard current treatment. 

It involve a strict diet that with extremely low intake of Phe and supplementing Tyr which is the product of phenylalanine metabolism. Phenylalanine metabolism does not occurs in patients suffering from PKU.

Doctors recommend their patients to stick to this diet and PKU formula for life.

This is because PKU formula (devoid of/low in Phe) is essential to provide the body with protein substitution (acts as essential nutritional substitute), additional vitamins and minerals to support normal growth.

In earlier therapeutic protocols, treatment was only continued through the first few years of life, theoretically corresponding to the age at which brain myelination is complete. 

As developmental data accumulated, it became evident that treatment throughout childhood and adolescence was the best course for preserving intelligence. 

In more recent studies, it has been shown that brain MRI abnormalities and electrophysiologic testing abnormalities referable to the central nervous system are observed in adults who are on unrestricted Phe intake. 

Accordingly, it is reasonable to continue treatment into adulthood, and most centers recommend lifelong treatment. 

Strict adherence to the PKU diet is especially important for women during their reproductive years (before conception and throughout pregnancy) because of the risks to the fetus.

Taking supplements such as fish oil to replace the long chain fatty acids missing from a standard phenylalanine-free diet may help improve neurologic development, including fine motor coordination. Other specific supplements, such as iron or carnitine, may be needed.

Another possible addition to the PKU diet may be a supplement called large neutral amino acid therapy powder or tablets. This supplement may block some absorption of phenylalanine. However, this is an emerging treatment that hasn't yet been well-studied.

"Another theory suggests that abnormal brain myelination and deficiency of brain large neutral amino acids may play a role in impaired cognition."  

"Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased."

So, what kind of food should they avoid?

Food rich in Phe such as Milk, Cheese, Peas, Beer, Meat poultry (meat and eggs), Fish, Chocolate candies and also diet soda.
The artificial NutraSweet (Aspartame) also contain Phe, hence any food containing aspartame should also be avoided.
Adults and children with PKU should also have limited portions of low protein food such as desserts.

Medication

The drug called Sapropterin (Kuvan) is for use in combination with a PKU diet. It is an enzyme cofactor and oral form of tetrahydrobiopterin. Tetrahydrobiopterin (BH4) works with phenylalanine hydroxylase to metabolize Phe. It works by increasing the patient's tolerance to Phe as it reduces blood phenylalanine (Phe) levels in patients with hyperphenylalaninemia (HPA) due to tetrahydrobiopterin- (BH4-) responsive PKU.

However, it doesn't work for everyone with PKU.

The drug's efficacy and long-term safety is still under studies.

I will end off with this video.....the video talks abit what we've blogged about PKU. and she is teaching how to make a Fruit smoothie that is friendly to PKU patients! Hahaha :D so there's this recipe book available, called "Low-protein cookery for phenylketonuria" Mentioned in 4:03min inside the video... 
Ok, That's all for today!
CITATION

Gregg, Hanson, Lloyd-Puryear, Rasmussen, A. J. W. ,. M. A. ,. S. A. (2008). Maternal phenylketonuria. Retrieved 6 July, 2012 from http://pediatrics.aappublications.org/content/122/2/445.full

(2011) Phenylketonuria. Retrieved on 6 July, 2012, from Health Guide, by A.D.A.M. Copyright : http://health.nytimes.com/health/guides/disease/phenylketonuria/overview.html

Approved Drugs by FDA, Retrieved 6 July, 2012 from Medilexicon International: http://www.medilexicon.com/drugs/kuvan.php

(2011) Phenylketonuria – MayoClinic.com. Retrieved 7 July, 2012, from Mayo Clinic:http://www.mayoclinic.com/health/phenylketonuria/DS00514/dsection=treatments-and-drugs

Pietz, J (Pietz, J); Kreis, R (Kreis, R); Rupp, A (Rupp, A); Mayatepek, E (Mayatepek, E); Rating, D (Rating, D); Boesch, C (Boesch, C); Bremer, HJ (Bremer, HJ) (1999). Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. Retrieved on 8 July, 2012 from http://cel.webofknowledge.com/InboundService.do?SID=X2i1Po8El41HhomCggI&product=CEL&UT=000079890400009&SrcApp=Highwire&Init=Yes&action=retrieve&Func=Frame&customersID=Highwire&SrcAuth=Highwire&IsProductCode=Yes&mode=FullRecord

The PAH gene mutation

The PAH gene is found on chromosome 12. It has 13 exons and encodes for 452 amino acids. PKU can be resulted by either mutations at the PAH locus or mutations in a number of loci which effect BH₄ synthesis and regeneration.

The mutation is pathogenic as it disrupt the structure and function of the enzyme. There are about 500 disease-causing mutations identified in patients with PKU. The human PAH gene shows great allelic variation . Pathogenic mutation can happens in all PAH gene exons. 

The percentage of different types of mutation that can occur in the gene are as followed:

The classic PKU is resulted by the mutation within the PAH gene, leading to amino acid substitution or premature stop sodon. A number of alleles combination at PAH locus are detected. 3/4 of the European patients have different mutation in their 2 copies of PAH gene. Point mutation in exon 3 of PAH gene from arginine 111 to tryosine 111 is the main cause for mutations in PAH gene. A point mutation by changing a G to A in exons 7 changes glutamate to lysine at protein 280. Replacing nucleotide C to T in exon 9 changes leucine to proline which is the 311th amino acid in the protein sequence. When a thymine replaces cytosine in exon 12, tyrosine 408 is formed instead of arginine 408.

This causes the protein sequence formed to be different and the enzyme will fold differently and become non-functional. As a result, L-Phe cannot be digest by PAH. L-Phe then go through other metabolic pathway and form many toxic metabolites which will accumulate in the body and cause mental retardation.
References:

1. Genetics of Phenylketonuria. Retrived July 1, 2012, from http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/PKU%20Cases/genetics1.htm

2. Robin A Williams,Cyril DS Mamotte, John R Burnett. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. National Center for Biotechnology Information. Retrieved July 2, 2012, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423317/

3. Nariman Hossein-Javaheri. (2012). Phenylketonuria. Tangient LLC. Retrieved July 10, 2012, from https://neurowiki2012.wikispaces.com/Phenylketonuria

How will Phenylketonuria affect the inidividuals suffering from it?

Because Phenylalanine is an Essential amino acid that is inquired through our diet. When PAH (the enzyme to breakdown Phenylalanine) is deficient or is insufficient, phenylalanine will accumulate in blood and body tissues. Accumulation of phenylalanine in all bodies liquids and they are excreted in the urine of the transformation product phenylpyruvate (phenylketon). 

Chronically high levels of phenylalanine cause significant health problems.

Signs and symptoms of PKU vary from mild to severe. 
Mild case of disorder is known as variant PKU or non-PKU hyperphenylalaninemia whereas severe form of this condition is known as classic PKU.

·         Variant PKU
-Face lesser risk of brain damage and their treatment may not require low phenylalanine diet.

·         Classic PKU
--- Children with classic PKU tend to have blue eyes and lighter skin and hair than unaffected family members  (this is because our body process phenylalanine into tyrosine which produce melanine, Melanine cause darker skin and eyes)  and are also likely to have skin disorders such as eczema.

--Infants with classic PKU appear to be normal until they are a few months old.
-Some early symptoms are vomiting, irritability, having eczema-like rashes and a mousy odour to their urine.
-without treatment, these babies develop permanent intellectual disability and suffer from severe brain damages like seizure (Epilepsy), mental retardation and also cause behavioral problems. Other commonly noted features in untreated children include: Small head (microcephaly), prominent cheek and upper jaw bones with widely spaced teeth, poor development of tooth enamel, and decreased body growth.

Babies born to mothers with PKU and uncontrolled phenylalanine levels (women who no longer follow a low-phenylalanine diet) have a significant risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth. These infants may also have a low birth weight and grow more slowly than other children. Other characteristic medical problems include heart defects or other heart problems, an abnormally small head size (microcephaly), and behavioral problems. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.  

Newborn screening, early identification, and management are part of the treatment for PKU and these can lessen the babies’ suffering like vomiting and eczema skin problems. By recognizing phenylketonuria right away can help prevent serious health problems.

References:
(2012). Phenylketonuria. Retrieved June 21, 2012, from Genetics Home Reference, your guide to understand genetic conditions: http://ghr.nlm.nih.gov/condition/phenylketonuria

(1985) Phenylketonuria (PKU). Retrieved June 21, 2012, from MedHelp: http://www.medhelp.org/lib/pku.htm

(2011) Phenylketonuria – MayoClinic.com. Retrieved June 21, 2012, from Mayo Clinic: http://www.mayoclinic.com/health/phenylketonuria/DS00514

[Phenylketonuria Symptoms] Retrieved June 21, 2012, from http://img1.ranker.com/list_img/1/335486/full/phenylketonuria-symptoms.jpg?version=1319277657000 
(2012).  Amino acid metabolism. Retrieved June 21, 2012, from A blockade in the degradation of phenylalanine can lead to mental retardation: http://www.natuurlijkerwijs.com/english/Aminozuurstofwisseling.htm

Phenylketonuria....?

Why is it called Phenylketonuria?

The name of this disease actually come from Phenylalanine & one of the dominant metabolites which contains a ketone group (phenylpyruvate, an alpha-keto acid) circled in red in the pic above.

Introduction to Phenylketonuria. Retrived July 1, 2012, from http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/PKU%20Cases/PKU%20biochem%20intro.htm

What causes Phenylketonuria?

Phenylketonuria (PKU) is an inherited disorder from autosomal recessive gene for metabolism.
 There is mutation in the gene that produces phenylalanine hydroxylase (PAH). PAH is used to break down phenylalanine. Phenylalanine is an amino acid that can be found in many food with protein. The mutation can cause reduction in the enzyme activity or not functioning at all, depending on the severity. When PAH is not working properly, phenylalanine cannot be processed efficiently and will begin to accumulate to toxic level in the human blood and tissue.

Reference:
(2012). Phenylketonuria. Retrieved June 21, 2012, from Wikipedia, the free encyclopedia Web site: http://en.wikipedia.org/wiki/Phenylketonuria#Metabolic_pathways.

(2012). Phenylketonuria. Retrieved June 21, 2012, from Genetics Home Reference, your guide to understand genetic conditions: http://ghr.nlm.nih.gov/condition/phenylketonuria.