Drew and Cody's Paper

Cody Dennis & Drew Smith

Phenylketonuria, better known by PKU, is an inborn error of the metabolism of the amino acid phenyalanine (Phe). Without proper treatment PKU can lead to some serious phenotypical problems such as growth problems and poor skin pigmentation and also severe mental retardation and seizures. These effects can be controlled simply by dietary restriction. Recent research has led to a better understanding of the genetics of PKU allowing possible ways of controlling PKU aside from strict diet control.

Phenylketonuria or PKU was first expressed by a Norwegian physician, Asbjorn Folling, who first started studying PKU when a mother of two intellectually impaired children asked if the smell of their urine had anything to do with their impairment.⁸ Folling was able to describe PKU as he was the first physician who used chemical methods when studying medicine. Folling ran chemical tests on the urine making sure it wasn’t due to any medications than he ran the test every other day in order to insure his results. He ran more analysis of extracting and purifying the responsible compound, in order to establish a melting point for the compound. Oxidation of the compound produced a compound that smelled of benzoic acid, which Folling hypothesized to be phenylpyruvic acid.⁸ The compound was then mixed with phenylpyruvic acid and the melting point remained the same proving his hypothesizes.
Folling then ran the same test on 430 intellectually impaired children in local institutions and came up with eight more individuals that shared similar symptoms and whose tests also came back positive⁸. Then when Folling ran Family studies on the children who tested positive he found there to be an inherited recessive autosomal trait. Folling then in his findings suggested the name ‘imbecillitas phenylpyruvica’ for the disease but was renamed ‘phenylketonuria’ thereafter.⁸
Our understanding of PKU has increased drastically since it was discovered. The metabolic block and enzyme deficiency was discovered by Jervis¹¹, soon after the connection between Phe intake and enhanced prognosis was revealed. The Canadian Pediatrician Robert Gurthrie developed the first screening tests for PKU, but the establishment of the PAH Mutation Analysis Consortium Database in 1996 was the biggest advancement in the study of PKU¹.

Newborns are now being screen tested. Blood is taken and is tested for the correct measurement of Phe concentration. This test has proven to be quite accurate. Urine is another way to test this, but it is actually not an excepted PKU screening method⁹. If the results are positive (an elevated level of Phe) then the child has HPA. Of the children that do experience consistent HPA, 98% have it because of a mutation at the PAH locus⁹. “Differential diagnosis of PKU from the disorders of synthesis or recycling of BH4 may involve various testing regimes including BH4 loading tests, measurement of urine and plasma pterin metabolites and neurotransmitter metabolites as well as blood spot dihydropteridine reductase measurement.” ¹ Other ways of screening are molecular tests. This includes Southern blotting, restriction enzyme digestion, detection of mutations by sequencing and multiplex ligation probe amplification¹.

The treatment of PKU is having a low Phe diet. This is achieved by reducing or normalizing the Phe concentrations which prevents abnormal psychological changes and neurological changes. The neurological changes have been detected within a month after birth, therefore the diet of a low Phe should be started right away and should be continued until the child has reached their neural development maximum.
Older women also need to have a Phe restriction if they have PKU and are contemplating starting a family, particularly during pregnancy, as elevated blood Phe concentrations are dangerous for the fetus. A low Phe diet is used for treatment usually in the small amounts of Phe coming from breast milk or commercial infant formula that is considered a safe intake for babies¹⁰. Children that are older have their protein intake controlled. The amount of protein allowed in their diet is determined by their levels of Phe concentration. “Foods such as eggs, milk, cheese, meat, poultry, fish, dried beans and legumes which are high in protein are excluded from the diet.”¹ However, without these foods, the child would not receive enough protein in their daily intake for growth requirements. Dietitians help with keeping a balance in the child’s body. They do this by making food diaries and adjusting the child’s diet when needed¹⁰.
Daily blood tests are also taken and supplements are given to the child that contains essential amino acids. These supplements would be taken daily by the child. There are benefits of a Phe-restricted, low protein diet, including: avoidance of increased Phe concentrations, improved neurological and psychological performance, and prevention of neurological damage¹. With these dietary treatments can com problems like compliance with diet, and an imbalance of dietary nutrients¹².

PKU is an autosomal recessive inborn error of Phe metabolism resulting from a deficiency of phenyalalnine hydroxylase (PAH).1 PAH is responsible for converting Phe to Tyr. The PAH gene is located on chromosome 12 and contains 13 exons.2 Various types of mutations of all 13 exons have been identified to cause PKU.3
People who suffer from PKU have two recessive genes that cause the PAH gene mutation, one from each parents. Since it requires two recessive genes to be expressed, most people who might have one recessive gene will never know it until it is passed on. Some PAH mutations are more severe than others depending upon their effect on the enzyme structure and function.4 The severity of the mutation does not play as critical a role in the expression of the symptoms of PKU as dietary control does. This is because the blood concentration of Phe is controlled by its dietary intake.1

Strict dietary control is still the best option for controlling PKU, but an increasing desire from PKU patients to control the disorder without a strict diet has led to trials with alternate therapy.
One such emerging therapy option is BH4 therapy. Recent clinical studies have shown that some children with PKU respond to being administered an orally active form of BH4, sapropterin dihydrochloride.5 Patients with more severe forms of PKU do not respond to BH4 therapy at all. Enzyme replacement therapy is being tested for treatment of this case. The enzyme replacement therapy involves the substitution of PAH with Phe ammomia-lyase. This process has been practiced only in laboratories with animals, such as mice, and has showed sufficient but short-lived drops in Phe concentration.6
Somatic gene therapy is also being tested in labs as an alternate device for handling PKU. It has not been tested on humans because, as of now, because the therapy involves the administration of immunosuppressant agents.7
Although advances are being made with alternate therapies, strict dietary control is still the leading therapy for PKU treatment.

Works Citied
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(3) PAH: Phenylalanine hydroxylase locus knowledgebase. http://www.pahdb.mcgill.ca/ (Accessed 10 March 2009).
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(6) Sarkissian, CN; Shao, Z; Blain, F; Peevers, R; Su, H; Heft, R, et al. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc Natl Acad Sci USA. 1999;96:2339–44.
(7) Ding, Z; Harding, CO; Thöny, B. State-of-the-art 2003 on PKU gene therapy. Mol Genet Metab. 2004;81:3–8.
(8)Følling, I. The discovery of phenylketonuria. Acta Pediatr Suppl. 1994;407:4–10.
(9)Scriver, CR; Kaufman, S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B. , editors. The Metabolic and Molecular Bases of Inherited Disease. 8. New York: McGraw-Hill; 2001. pp. 1667–724.
(10)Michals-Matalon, K. Developments in phenylketonuria. Topics Clin Nutr. 2001;16:41–50.
(11)Jervis, GA. Studies on phenylpyruvic oligophrenia: the position of the metabolic error. J Biol Chem. 1947;169:651–6.
(12)Hanley, WB. Adult Phenylketonuria. Am J Med. 2004;117:590–5.

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