Phenylketonuria: Pku Essay, Research Paper

Danielle Woods

Genet 351, K. Owens

Research paper

Phenylketonuria: PKU

Phenylketonuria also known as PKU once had irrevocable and detrimental damage to the people it effected. Babies that were born with the genetic disorder were certain to suffer from severe mental retardation and behavioral disorders because no one knew what was causing the symptoms. Until 1934 when a biochemist and doctor named A. Folling from Norway discovered the disease through urine testing.(Mange,4) He identified that it was a hereditary disease which causes the affected person’s body to not be able to handle a substance called phenylalanine (phe), an essential amino acid found in protein. After Folling’s discovery of the disease, in 1947 George Jervis, an American scientist finally presented that the exact cause was an enzyme found in the liver called Phenylalnine hydroxylase (PAH). PAH is responsible for converting excess phenylalanine into tyrosine and other useful amino acids. Tyrosine is an essential amino acid that makes proteins, hormones and neurotransmitters that control brain functions. The discovery of the mutant PAH enzyme made it possible to start searching for a treatment. It was reasoned that by removing foods which contained phe from the affected person’s diet and giving them vitamin supplements would stop the toxic effect of excess phe and its derivatives in the body. Doctors quickly saw profound effects in the diet therapy and now patients, when treated soon after birth can develop normally by sticking to a medical diet.(Mange, 346)

PKU is a autosomal recessive inherited condition with phenotypic characteristics that prevent affected individuals from normally metabolizing phenylalanine (phe). Untreated, this hereditary biochemical disorder prevents normal brain development and usually results in severe mental retardation. Other phenotypic symptoms are skin rash, seizures, excessive restlessness, irritable behavior and sometimes a musty or mousy body odor.(Clarke) The age of onset for these symptoms is approximately two to three months after birth. Treatment that is started after developmental damage has already occurred will only prevent further damage from happening and will help take care of the odor, rash and restlessness. Fortunately, detection of the condition shortly after birth, through the use of a routine blood screening procedure, which replaced the “wet diaper” test in 1964, has become standard practice in every state and Canadian Province since 1991. The blood test screens for phe levels in the blood plasma. When a baby has a high level of phe, confirmatory tests are preformed during a 3 week period, a diagnosis is established and diet treatment begins as soon as possible. Prenatal screening is rare and expensive because the PAH enzyme is only found in the liver it is not available in amniotic fluid, however skin cells may be examined by checking for mutations in the DNA.(Clarke)

Even though placing the baby on a phenylalanine-restricted diet with in the first few weeks of life, and maintaining good diet control thereafter during developmental years is effective in preventing symptoms, PKU can still cause problems if diet is not maintained into adulthood. This is especially true for women with PKU. It is important for women to maintain the medical diet during their childbearing years because of the harmful effects that high levels of phe can have on the unborn child of a PKU mother. Maternal PKU effects offspring with conditions such as mental retardation, small brain size, congenital heart disease, low birth weight and spontaneous abortion.(Mange 347) Studies are still inconclusive in identifying whether preconception treatment of mothers with PKU have produced offspring with average physical and intellectual skills. This is because the children in this extensive study are not yet old enough to be adequately screened.

There are 5 types of identified PKU conditions that range from a mild to severe defect in the PAH enzyme. Classical PKU, where there is close to total absence in activity of the PAH enzyme accounts for approximately 60 percent of all PKU cases and is the most severe. The PAH location or locus is on the tip of the long arm of chromosome 12. Its map location is 12q22-24.1 and it is considered to be a large gene being 90 kb long with 13 exons and encoding a polypeptide of 452 amino acids.(Scriver,144) Genetically, PKU is not always caused by a single gene defect because there are two other enzymes produced by different genes that can effect the efficiency of PAH. However, mutation within the PAH gene is the main determinant of PKU.(Guldburg,71) There are over 365 identified possible mutant alleles that play a role in PKU and 105 of the mutations are found on the gene encoding for PAH. Fortunately, two-thirds of all mutant alleles are confined within four haplotypes. Most PAH variants are single-base substitutions such as missense, nonsense and splicing mutations. Common examples of these single-base substitutions would be a splicing mutation in intron 12, missense mutations in exons 7,9 and 12 or a deletion in the region of exons 1 and 2. (Clarke, 47)

Throughout the world,” PKU is one of the most common defects of amino acid metabolism and is also one of the most common metabolic, inherited disorders effecting brain development.”(p346,Mange) PKU affects about 1 in 10,000-15,000 newborns in the United States and Europe and about 1 in 16,500 in China. There are also particular groups that are more frequently affected, 1 in 2,600 among Turks and 1 in 4,000 among the Irish. Similarly, groups with a rare frequency are the Ashkenazi Jews, Finns, African Americans and Japanese. In Caucasians the carrier frequency of PKU averages to 1 in 50 males and females which indicates no discrimination between genders. It is not yet certain why there are differences among groups in the population or whether environment influences frequency rates.(p346-47,Mange) However, evidence has surfaced that supports PKU being of Celtic origin. It is believed that it was brought from Ireland and Scotland, which have the highest frequency rates, with wives and slaves of the Vikings.

Even though immense progress has been made since PKU’s discovery in 1934, there are still obstacles to overcome and more information to be learned. Current treatment of PKU is done with strict diet therapy, however other approaches are being studied. A plant enzyme called phenylalanine ammonia-lyase has been studied over the years with mice and seems to be a promising addition to diet therapy because it has shown to lower phe levels in mice by 50 percent after seven days.(Bickel,20) Another possibility to cure PKU is liver transplantation. Even though liver disease is not a characteristic of PKU and not a usual treatment approach, a ten year old boy with PKU and unrelated liver disease had a liver transplant which in turn cured him of PKU.(Bickel, 22) Research involving gene therapy is still underway. A gene clone expressing human PAH and a PKU animal model, a mouse, have been developed because the mouse has a 90 percent homology with the human PAH gene.(Bickel,24) Unfortunately, methods for an effective gene transfer have yet to be found. However, with the continuous Research and studies that are being conducted the outlook for people with PKU is promising.

Bickel, H. 1997. Early diagnosis and treatment of inborn errors of metabolism

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Clarke, J.T. 1996. A Clinical Guide to Inherited Metabolic Diseases. Cambridge University Press, Cambridge.

Guldberg, P., A European multicenter study of Phenylalanine hydroxlase deficiency: classification of 105 mutations and a general system for genetype-based prediction of metabolic phenotype. 1998, American Journal of Human Genetics, Jul;63(1): 71-9.

Mange, Elaine J. Mange, Arthur P. Basic Human Genetics. 2nd ed. 1999. Sinauer Associates, Inc., Massachusetts: p 4, 346-50.

Scriver, C.R. 1994. The Hyperphenylalaninemias. Annual Review of Genetics

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