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Phenylketonuria

Phenylketonuria Evidence supports the theory that an unknown disease causing mental retardation surfaced among wives and slaves of Vikings in Ireland and Scotland long ago. Despite this Celtic origin, it was not until 1934 that a biochemist named A. Folling from Norway discovered phenylketonuria through urine testing. He correctly identified the disease as one in which the body cannot handle phenylalanine, an essential amino acid found in protein. Then in 1947, George Jervis, an American scientist presented that the exact cause of PKU was an enzyme found in the liver called phenylalanine hydroxylase (PAH). Discovery of a mutant PAH enzyme made it possible to start searching for treatments for the condition. It is now commonly accepted that Phenylketonuria, often called PKU for short, is an inborn error of protein metabolism. In other words, the body is unable to produce proteins or enzymes needed to convert certain toxic chemicals into nontoxic products. The inability of the body to complete this process can lead to neurological damage. Phenylketonuria involves one particular part of a protein, the amino acid called phenylalanine, or PHE for short. When an individual eats food-containing protein, various enzymes break down the protein into amino acids used for the body’s growth and repair of its tissues. Everyone needs a certain amount of PHE to perform these functions. Most of the time the unused PHE is then converted to another amino acid. In the case of PKU, the disorder is inherited when a baby inherits two mutant genes for the enzyme phenylalanine hydroxylase. A mutant gene for PKU occurs as a result of a mutation at the PAH locus, 12q24 which is considered to be a large gene being 90 kb long with 13 exons and encoding a polypeptide of 452 amino acids. 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. Most PAH variants are single-base substitutions such as missense, nonsense, and splicing mutations. This mutation causes a near or complete deficiency of the enzyme phenylalanine hydroxylase, which converts phenylalanine into another amino acid, tyrosine. As a result, PHE accumulates in the blood and in other parts of the body, which prevents the brain from developing normally. A normal blood phenylalanine level is about 1 mg/dl. With PKU, levels range from 6 to 80 mg/dl but are usually greater than 30 mg/dl. Phenylketonuria is a single gene disorder, meaning that, a mutant or abnormal gene causes the disorder. PKU is inherited in an autosomal recessive fashion. This means that the affected individual must have two defective genes in order to have the disorder. People with only one copy of the defective gene are called carriers and show no symptoms of having the disease. In order for a child to inherit PKU, both parents must be carriers. When this occurs, there is a twenty-five percent chance of their producing an affected child and a twenty-five percent chance that both of the normal genes will be passed on. There is also a fifty-percent chance that a baby will inherit the PKU gene from one parent and the normal gene from the other, making the baby a carrier like his or her parents. These chances remain the same for each pregnancy and males and females are equally likely to inherit this disease. Other characteristics of an autosomal recessive genetic disorder that apply to PKU include clustering of the disease phenotype among siblings and consanguineous mating accounts for five percent of the cases of PKU. The prevalence of Phenylketonuria in the United States is approximately 1 in 10,000 to 15,000 births, which is most commonly present in Caucasians. Approximately 1 person in 50 has inherited a PKU allele. This means that some 5 million people in the United States are carriers. Internationally, the disease frequency varies by population. Turkey has the highest incidence in the world with approximately 1 in 2600 births. However, the disease is also common among people of north European descent and less common among Jewish, Asian, and African-American families. Tests available for the detection of phenylketonuria include a enzyme assay to detect the carrier state in parents, chorionic villus sampling to detect fetal PKU, and PKU screening which is mandatory in most states in the United States. Testing is imperative since there are no known signs of Phenylketonuria present in a newborn baby. Untreated PKU can cause symptoms that include: eczema, microcephaly (small head), tremors, spasticity, unusual hand posturing, seizures, hyperactivity, delayed mental and social skills, mental retardation, a “mousy odor” detected on the individual’s breath, skin, and urine, and light coloration (light complexion, blond hair, and blue eyes) in the first year of life. The longer the disease goes on undiagnosed and untreated the more severe the symptoms and mental retardation become in the child. For this reason, testing must be done to determine whether or not the child is affected with PKU. In the 1960s, based on work funded for by the March of Dimes, a test was developed for Phenylketonuria by Dr. Robert Guthrie. All states now routinely test all babies for Phenylketonuria at about 3 days of age, before they ever even leave the hospital. The Guthrie test, which costs on average $1.25, involves pricking the heel of the baby to obtain a few drops of blood. The blood is placed on filter paper and is then sent to a laboratory to find out if it has more than a normal amount of phenylalanine by examining the bacterial metabolism of Bacellus subtiles. If the test results show phenylalanine levels exceed 4 mg/dl then the patient is reported to the health care provider and more testing is completed to determine whether the baby truly has PKU. Repeated testing is important because there are variant types of PKU for which treatment differs. If a child is diagnosed as having phenylketonuria, then examination by a metabolic specialist would be beneficial, as well as an evaluation by a nutritionist and a genetic counselor. Screening and visits with medical professionals should be taken very seriously because with each passing day the chance of irreversible mental damage increases. The development of a screening test for PKU was a huge step toward preventing mental retardation as a result of a metabolic disorder, but sadly there are more than 100 more rare metabolic disorders that lead to mental retardation for which newborn screening is unavailable. Treatment should be obtained immediately after a child is diagnosed with phenylketonuria. There are two different types of treatment that the child will require. The most important form of treatment will be diet, followed by medical care. Mental retardation can usually be prevented if a phenylalanine free diet is started before the fourth week of life. The goal of PKU treatment is to maintain the blood level of phenylalanine between 2 and 10 mg/dl. Some phenylalanine is needed for growth but in much lower amounts than normal. Certain symptoms will be present if the child is not getting the necessary amount of PHE and these include mental and physical sluggishness, loss of appetite, anemia, rashes, and diarrhea. A PKU diet should be prescribed by a doctor, designed by a dietician, administered by parents, and monitored and changed over time as the child’s nutritional needs change due to growth, changing tastes, and eating habits. Foods such as meat, fish, chicken, turkey, milk, cheese, ice cream, yogurt, eggs, beans, nuts, peanut butter, and Nutra sweet are not allowed because they are high in phenylalanine. Fruits, fruit juices, vegetables, vegetable juices, breads, cereals, crackers, potato chips, popcorn, and other special low protein foods are allowed but should be eaten in regulated amounts. Soda, Kool-Aid, lemonade, popsicles, jelly, gum drops, suckers, tapioca pudding, and hard candy are “free foods” and can be consumed without worry. A child with PKU has a special drink often called Lofenalac or Phenylfree, which has most of the artificial protein substitutes, vitamins, and minerals that a child needs for growth with little or no PHE. The taste and the smell of the drink are objectionable but PKU children usually acquire a taste for the drink at and early age and grow up drinking it. The food program used to treat those with PKU typically costs around $10,000 a year or more. Health departments may pay for the formula in some states and in other states insurance may cover the cost of the food. However, a lot of insurance companies do not cover this cost since it is considered nutritional rather than medical therapy. Individuals with PKU should remain on a restricted diet throughout childhood and adolescence, and perhaps throughout life. Until recently, doctors believed that children with PKU could discontinue their special diet around age 6 when brain growth was completed. However, these children did not develop as rapidly and had more behavioral and learning disabilities. Therefore, until research provides alternative treatments, all people with PKU are being advised to remain on a restricted diet indefinitely in order to maintain a safe level of phenylalanine. The second type of treatment for PKU involves medical care. A neonate with PKU should see a physician 1-2 times a week and older children and adults should see theirs’ once a month to have their phenylalanine level checked. A psychologist should also evaluate developmental testing on young children at regular intervals to ensure that they are maturing properly. It would also be a good idea for the patient and parents to visit a nutritionist experienced with PKU whenever possible. As you can see, there is not any miracle medication that a child can take when they are young that would rid them of phenylketonuria, but having this disorder is not life threatening and thousands of people are diagnosed each year with this disease and live long and normal lives (minus the phenylalanine in the diet). Since the diet and constant blood testing to determine the level of phenylalanine in the blood is started so early in life, it becomes second nature to the child and usually is not a problem for the child growing up. The next area of concern for females with phenylketonuria is called maternal PKU. Women with PKU who have been properly treated throughout childhood and adolescence can develop normally, lead normal lives, and have normal I.Q.s. When a woman with PKU is ready to have children, she should speak to a metabolic specialist at least six months before trying to become pregnant to discuss treatment and follow-up exams. Women who go on a special diet to control the phenylalanine levels in their blood before, during, and after her pregnancy can have unaffected babies. The phenylalanine level of a pregnant women should be monitored weekly to ensure that it is in a safe range for the baby. The recommended phenylalanine level for pregnant women is in the range of 2-6 mg/dl. However, if the women with PKU are no longer on their diet and decide to have children, high blood levels of phenylalanine are devastating to the fetus. In untreated cases, infants born to untreated women have 93% risk for mental retardation and a 72% risk for microcephaly. Low birth weight, characteristic facial features, or congenital heart disease are other results of untreated pregnancies. This is very serious since these birth defects due to an uncontrolled diet in the mother are separate from the actual inherited condition. Most moms with PKU will not have kids with PKU. Brain and other damage happens before birth to babies born to PKU moms and cannot be fixed or helped with a diet since the baby does not even have the condition. These problems would be permanent. The affected mother could also have a spontaneous abortion because of the disease. If a woman with PKU were to have an unplanned pregnancy as long as she was able to bring down her PHE to a safe level within the first eight weeks of her pregnancy her chances of having a healthy baby are still good. Even though immense progress has been made since the discovery of PKU in 1934, there are still obstacles to overcome and more information to be learned. Current treatment, as discussed before, is best suited by means of a phenylalanine-free diet however other approaches are being studied that would eliminate this strict diet. A plant enzyme called phenylalanine ammonia-lyase has been studied over the years with mice and seems to be a promising addition to the diet therapy because it is shown to lower levels of phenylalanine by 50 percent in mice after only seven days. 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. Unfortunately, methods for an effective gene transfer are yet to be found. Others are trying to develop a genetically engineered version of the missing enzyme which, when taken orally, can degrade phenylalanine in the digestive tract before it is absorbed into the body. This would allow PKU patients to relax their diet if not eliminate it completely. Research is also being conducted on the long-term outcome for children who were born from maternal PKU pregnancies so that these children can reach their full cognitive potential. With continuous research and studies, the outlook for patients with phenylketonuria is promising. Bibliography: Bibliography:  http://medhlp.netusa.net/lib/pku.htm  http://www.emedicine.com/PED/topic1787.htm  http://www.nlm.nih.gov/medlineplus/ency/article/001166.htm  http://thearc.org  http://www.tdh.state.tx.us/newborn/what_pku.htm  http://www.ncbi.nlm.nih.gov/Omim/  Medical Genetics, 2nd ed. (revised for 2000), by Jorde, Carey, Bamshad and White  CDC: Morbidity and Morality Weekly Report. February 15, 2002, Vol. 51, No. 6, pgs.117-119.

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