phenylketonuria

Definition

Phenylketonuria (PKU) is a rare, inherited, metabolic disorder that can result in mental retardation and other neurological problems. People with this disease have difficulty breaking down and using (metabolizing) the amino acid phenylalanine. PKU is sometimes called Folling's disease in honor of Dr. Asbjorn Folling who first described it in 1934.

Description

Phenylalanine is an essential amino acid. These substances are called "essential" because the body must get them from food to build the proteins that make up its tissues and keep them working. Therefore, phenylalanine is required for normal development. Phenylalanine is a common amino acid and is found in all natural foods. However, natural foods contain more phenylalanine than required for normal development. This level is too high for patients with PKU, making a special low-phenylala-nine diet a requirement.

The incidence of PKU is approximately one in every 15,000 births (1/15,000). There are areas in the world where the incidence is much higher, particularly Ireland and western Scotland. In Ireland the incidence of PKU is 1/4,500 births. This is the highest incidence in the world and supports a theory that the genetic defect is very old and of Celtic origin. Countries with very little immigration from Ireland or western Scotland tend to have low rates of PKU. In Finland, the incidence is less than 1/100,000 births. Caucasians in the United States have a PKU incidence of 1/8,000, whereas Blacks have an incidence of 1/50,000.

Maternal phenylketonuria is a condition in which a high level of phenylalanine in a mother's blood causes mental retardation in her child when in the womb. A woman who has PKU and is not using a special low-phenylalanine diet will have high levels of phenylalanine in her blood. Her high phenylalanine levels will cross the placenta and affect the development of her child. The majority of children born from these pregnancies are mentally retarded and have physical problems, including small head size (microcephaly) and congenital heart disease. Most of these children do not have PKU. There is no treatment for maternal phenylketonuria. Control of maternal phenylalanine levels is thought to limit the effects of maternal phenylketonuria.

Hyperphenylalaninemia is a condition in which patients have high levels of phenylalanine in their blood, but not as high as seen in patients with classical PKU. There are two forms of hyperphenylalaninemia: mild and severe. In the mild form of the disease, patients have phenylalanine blood levels of less than 10 mg/dl, even when eating a normal diet (0.6–1.5 mg/dl is considered the normal range). There are few effects from the mild form of the disease. In the severe form of the hyperphenylalaninemia, patients have higher levels of phenylalanine in their blood. The severe form is distinguished from classical PKU by testing for the presence of phenylalanine hydroxylase (an enzyme that breaks down phenylalanine) in the liver. Classic PKU patients lack this enzyme in their liver, while patients with severe hyperphenylalaninemia have some enzyme activity, but at greatly reduced levels compared with normal persons. Patients with severe hyperphenylalaninemia are treated with the same diet as classical PKU patients.

Tyrosinemia is characterized by high levels of two amino acids in the blood, phenylalanine and tyrosine. Patients with this disease have many of the same symptoms as seen in classical PKU, including mental retardation. Treatment consists of a special diet similar to the diet for PKU. The main difference between the two diets is that patients with tyrosinemia must eat a diet that is low in both phenylalanine and tyrosine.

Tetrahydrobiopterin deficiency disease is another metabolic disorder. Patients with this disease also have high levels of phenylalanine in their blood. Although phenylalanine levels can be controlled by diet, these patients still have mental retardation because they do not make enough of the neurotransmitters dopamine and serotonin, which are essential for proper neurologic function.

— John T. Lohr, PhD

An inborn error of metabolism in which affected individuals lack the liver enzyme needed to metabolize phenylalanine, an amino acid essential for normal growth and development. If untreated, affected individuals may become severely mentally retarded, become microcephalic, have behavioral problems, develop epilepsy, or show other signs of neurological impairment. Phenylketonuria (PKU) is inherited as an autosomal recessive trait and is found in all ethnic groups but most frequently in individuals of northern European descent. Its incidence is about 1 per 14,000 births in the United States.

Newborn screening programs for phenylketonuria have been successful in identifying most cases within a few weeks of birth. A low phenylalanine diet with restriction of proteins, if initiated early in infancy, can prevent the development of severe intellectual and neurological handicaps that would otherwise occur in virtually all untreated cases. See also Protein metabolism.

Definition

Phenylketonuria (PKU) is a rare metabolic disorder caused by a deficiency in the production of the hepatic (liver) enzyme phenylalanine hydroxylase (PAH).

Description

PKU is the most serious form of a class of diseases referred to as hyperphenylalaninemia, all of which involve above normal (elevated) levels of phenylalanine in the blood. The primary symptom of untreated PKU, mental retardation, is the result of consuming foods that contain the amino acid phenylalanine, which is toxic to brain tissue.

PKU is an inherited, autosomal recessive disorder. It is the most common genetic disease involving amino acid metabolism. As of 2004, PKU was incurable, but early, effective treatment can prevent the development of serious mental incapacity.

PKU is caused by the liver's inability to produce a particular type of PAH enzyme. This enzyme converts (metabolizes) the amino acid called phenylalanine into another amino acid, tyrosine. This is the only role of PAH in the body. A lack of PAH results in the buildup of abnormally high phenylalanine concentrations (or levels) in the blood and brain. Above normal levels of phenylalanine are toxic to the cells that make up the nervous system and cause irreversible abnormalities in brain structure and function in PKU patients. Phenylalanine is a type of teratogen (any substance or organism that can cause birth defects in a developing fetus).

The liver is the body's chief protein-processing center. Proteins are one of the major food nutrients. They are generally very large molecules composed of strings of smaller building blocks or molecules called amino acids. About twenty amino acids exist in nature. The body breaks down proteins from food into individual amino acids and then reassembles them into human proteins. Proteins are needed for growth and repair of cells and tissues and are the key components of enzymes, antibodies, and other essential substances.

Pku Effects on the Human Nervous System

The extensive network of nerves in the brain and the rest of the nervous system are made up of nerve cells. Nerve cells have specialized extensions called dendrites and axons. Stimulating a nerve cell triggers nerve impulses (signals) that speed down the axon. These nerve impulses then stimulate the end of an axon to release chemicals called neurotransmitters that spread out and communicate with the dendrites of neighboring nerve cells.

Many nerve cells have long, wire-like axons that are covered by an insulating layer called the myelin sheath. This covering helps speed nerve impulses along the axon. In untreated PKU patients, abnormally high phenylalanine levels in the blood and brain can produce nerve cells with deformed axons and dendrites and cause imperfections in the myelin sheath referred to as hypomyelination and demylenation. This loss of myelin can short circuit nerve impulses (messages) and interrupt cell communication. A number of brain scan studies also indicate a degeneration of the white matter in the brains of older patients who have not maintained adequate dietary control.

PKU can also affect the production of one of the major neurotransmitters in the brain, called dopamine. The brain makes dopamine from the amino acid tyrosine. PKU patients who do not consume enough tyrosine in their diets cannot produce sufficient amounts of dopamine. Low dopamine levels in the brain disrupt normal communication between nerve cells, which results in impaired cognitive (mental) function.

Some research suggests that nerve cells of PKU patients also have difficulty absorbing tyrosine. This abnormality may explain why many PKU patients who receive sufficient dietary tyrosine still experience some form of learning disability.

Behavior and Academic Performance

IQ (intelligence quotient) tests provide a measure of cognitive function. The IQ of PKU patients is generally lower than the IQ of their healthy peers. Students with PKU often find academic tasks difficult and must struggle harder to succeed than their non-PKU peers. They may require special tutoring and need to repeat some of their courses. Even patients undergoing treatment programs may experience problems with typical academic tasks as math, reading, and spelling. Visual perception, visual-motor skills, and critical thinking skills can also be affected. Ten years of age seems to be an important milestone for PKU patients. After these individuals reach age 10, variations in their diets seem to have less influence on their IQ development.

People with PKU tend to avoid contact with others, appear anxious, and show signs of depression. However, some patients may be much more expressive and tend to have hyperactive, talkative, and impulsive personalities. It is also interesting to note that people with PKU are less likely to display such antisocial behaviors as lying, teasing, and active disobedience. It should be emphasized that, as of 2004, research findings were still quite preliminary and more extensive research is needed to clearly show how abnormal phenylalanine levels in the blood and brain might affect behavior and academic performance.

Demographics

One in 50 individuals in the United States has inherited a gene for PKU. About 5 million Americans are PKU carriers. About one in 15,000 babies tests positive for PKU in the United States. Studies indicate that the incidence of this disease in Caucasian and Native American populations is higher than in African-American, Hispanic, and Asian populations.

Causes and Symptoms

PKU symptoms are caused by alterations or mutations in the genetic code for the PAH enzyme. Mutations in the PAH gene prevent the liver from producing adequate levels of the PAH enzyme needed to break down phenylalanine. The PAH gene and its PKU mutations are found on chromosome 12 in the human genome. In more detail, PKU mutations can involve many different types of changes, such as deletions and insertions, in the DNA of the gene that codes for the PAH enzyme.

PKU is described as an inherited, autosomal recessive disorder. The term autosomal means that the gene for PKU is not located on either the X or Y sex chromosome. The normal PAH gene is dominant to recessive PKU mutations. A recessive genetic trait, such as PKU, is one that is expressed—or shows up—only when two copies are inherited (one from each parent).

A person with one normal and one PKU gene is called a carrier. A carrier does not display any symptoms of the disease because the carrier's liver produces normal quantities of the PAH enzyme. However, PKU carriers can pass the PKU genetic mutation on to their children. Two carrier parents have a 25 percent chance of producing a baby with PKU symptoms, and a 50 percent chance having a baby that is a carrier for the disease. Although PKU conforms to these basic genetic patterns of inheritance, the actual expression, or phenotype, of the disease is not strictly an either/or situation. This is because there are at least 400 different types of PKU mutations. Although some PKU mutations cause rather mild forms of the disease, others can initiate much more severe symptoms in untreated individuals. The more severe the PKU mutation, the greater the effect on cognitive development and performance (mental ability).

Untreated PKU patients develop a broad range of symptoms related to severely impaired cognitive function, sometimes referred to as mental retardation. Other symptoms can include extreme patterns of behavior, delayed speech development, seizures, a characteristic body odor, and light body pigmentation. The light pigmentation is due to a lack of melanin, which normally colors the hair, skin, and eyes. Melanin is made from the amino acid tyrosine, which is lacking in untreated cases of PKU. Physiologically, PKU patients show high levels of phenylalanine and low levels of tyrosine in the blood. Babies do not show any visible symptoms of the disease for the first few months of life. However, typical PKU symptoms usually do show up by a baby's first birthday.

Diagnosis

The primary diagnostic test for PKU is the measurement of phenylalanine levels in a drop of blood taken from the heel of a newborn baby's foot. This screening procedure is referred to as the Guthrie test (Guthrie bacterial inhibition assay). In this test, PKU is confirmed by the appearance of bacteria growing around high concentrations of phenylalanine in the blood spot. PKU testing was introduced in the early 1960s and is the largest genetic screening program in the United States. It is required by law in all 50 states. Early diagnosis is critical. It ensures early the treatment PKU babies need to develop normally and avoid the ravages of PKU.

The American Academy of Pediatrics recommends that this test be performed on infants between 24 hours and seven days after birth. The preferred time for testing is after the baby's first feeding. If the initial PKU test produces a positive result, then follow-up tests are performed to confirm the diagnosis and to determine if the elevated phenylalanine levels may be caused by some medical condition other than PKU. Treatment for PKU is recommended for babies that show a blood phenylalanine level of 7 to 10 mg/dL or higher for more than a few consecutive days. Another, more accurate test procedure for PKU measures the ratio (comparison) of the amount of phenylalanine to the amount of tyrosine in the blood.

Subsequent diagnostic procedures (called mutation analysis and genotype determination) can actually identify the specific types of PAH gene mutations inherited by PKU infants. Large-scale studies have helped to clarify how various mutations affect the ability of patients to process phenylalanine. This information can help doctors develop more effective customized treatment plans for each of their PKU patients.

Treatment

The severity of the PKU symptoms experienced by people with this disease is determined by both lifestyle and genetic factors. In the early 1950s, researchers first demonstrated that phenylalanine-restricted diets could eliminate most of the typical PKU symptoms—except for mental retardation. As of 2004, dietary therapy (also called nutrition therapy) is the most common form of treatment for PKU patients. PKU patients who receive early and consistent dietary therapy can develop fairly normal mental capacity to within about five IQ points of their healthy peers. By comparison, untreated PKU patients generally have IQ scores below 50.

Infants with PKU should be put on a specialized diet as soon as they are diagnosed to avoid progressive brain damage and other problems caused by an accumulation of phenylalanine in the body. A PKU diet helps patients maintain very low blood levels of phenylalanine by restricting the intake of natural foods that contain this amino acid. Even breast milk is a problem for PKU babies. Special PKU dietary mixtures or formulas are usually obtained from medical clinics or pharmacies.

Phenylalanine is actually an essential amino acid. This means that it has to be obtained from food because the body cannot produce this substance on its own. Typical diets prescribed for PKU patients provide very small amounts of phenylalanine and higher quantities of other amino acids, including tyrosine. The amount of allowable phenylalanine can be increased slightly as a child grows older.

In addition, PKU diets include all the nutrients normally required for good health and normal growth, such as carbohydrates, fats, vitamins, and minerals. High protein foods such as meat, fish, chicken, eggs, nuts, beans, milk, and other dairy products are banned from PKU diets. Small amounts of moderate protein foods (such as grains and potatoes) and low protein foods (some fruits and vegetables and low protein breads and pastas) are allowed. Sugar-free foods, such as diet soda, which contain the artificial sweetener aspartame, are also prohibited foods for PKU patients because aspartame contains the amino acid phenylalanine.

Ideally, school-age children with PKU should be taught to assume responsibility for managing their diets, recording food intake, and for performing simple blood tests to monitor their phenylalanine levels. Blood tests should be done in the early morning when phenylalanine levels are highest. Infants and young children require more frequent blood tests than older children and adults. The amount of natural foods allowed in a diet can be adjusted to ensure that the level of phenylalanine in the blood is kept within a safe range—2 to 6 mg/dL before 12 years of age and 2 to 15 mg/dL for PKU patients over 12 years old.

A specialized PKU diet can cause abnormal fluctuations in tyrosine levels throughout the day. Thus, some health professionals recommend adding time-released tyrosine that can provide a more constant supply of this amino acid to the body. It should be noted that some PKU patients show signs of learning disabilities even with a special diet containing extra tyrosine. Research studies suggests that these PKU patients may not be able to process tyrosine normally.

For PKU caregivers, providing a diet that is appealing as well as healthy and nutritious is a constant challenge. Many PKU patients, especially teenagers, find it difficult to stick to the relatively bland PKU diet for extended periods of time. Some older patients decide to go off their diet plan simply because they feel healthy. However, many patients who abandon careful nutritional management develop cognitive problems, such as difficulties remembering, maintaining focus, and paying attention. Many PKU health professionals contend that all PKU patients should adhere to a strictly controlled diet for life.

One promising line of PKU research involves the synthesis (manufacturing) of a new type of enzyme that can break down phenylalanine in food consumed by the patient. This medication would be taken orally and could prevent the absorption of digested phenylalanine into the patient's bloodstream.

In general, medical researchers express concern about the great variation in treatment programs available in the early 2000s to PKU patients around the world. They have highlighted the urgent need for consistent international standards for proper management of PKU patients, which should emphasize comprehensive psychological as well as physiological monitoring and assessment.

Pku and Pregnancy

Women with PKU must be especially careful with their diets if they want to have children. They should ensure that phenylalanine blood levels are under control before conception and throughout pregnancy. Mothers with elevated (higher than normal) phenylalanine levels are high risk for having babies with significant birth defects, such as microencephaly (smaller than normal head size), congenital heart disease (abnormal heart structure and function), stunted growth, mental retardation, and psychomotor (coordination) difficulties. This condition is referred to as maternal PKU and can even affect babies who do not have the PKU disease.

Prognosis

Early newborn screening, careful monitoring, and life-long strict dietary management can help PKU patients to live normal, healthy, and long lives.

Parental Concerns

Every state in the United States has mandatory newborn screening programs in place for phenylketonuria, as well as other diseases. Parents who suspect that other genetic diseases may run in their families should speak to their healthcare providers before their baby's birth to ascertain what other screening tests should be run.

Books

Gascon, Generoso G., and Pinar T. Ozand. "Aminoacidopathies and Organic Acidopathies, Mitochondrial Enzyme Defects, and Other Metabolic Errors." In Textbook of Clinical Neurology. Edited by Christopher G. Goetz. Philadelphia: Saunders, 2003.

Rezvani, Iraj. "Defects in Metabolism of Amino Acids." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2004.

Periodicals

Michals-Matalon, K. "Nutrient intake and congenital heart defects in maternal phenylketonuria." American Journal of Obstetrics and Gynecology 187 (August 2002): 441–4.

Organizations

Children's PKU Network. 1520 State St., Suite 111, San Diego, CA 92101–2930. Web site: www.pkunetwork.org.

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. Web site: www.modimes.org.

National PKU News. 6869 Woodlawn Avenue, NE, #116, Seattle, WA 98115–5469. Web site: www.pkunews.org.

[Article by: Marshall G. Letcher, MA Rosalyn Carson-DeWitt, MD]

Phenylketonuria (PKU) is an autosomal recessive disorder that results from phenylalanine hydroxylase (PAH) deficiency. If uncontrolled, PKU leads to mental retardation. The prevalence is approximately 1 in 10,000 in temperate climates and varies by race, with a frequency of 1 in 8,000 in U.S. Caucasians, and 1 in 50,000 in African Americans. Many mutant alleles are present in the population. The high frequency of defective genes suggests that there is an advantage to being a carrier, perhaps due to resistance to natural toxins. Newborn screening (with the Guthrie test) is mandated by law and is critical because the mental retardation is treatable by restricting dietary intake of phenylalanine and/or ingesting a form of phenylalanine ammonia lysase, a plant enzyme. Unfortunately, the offspring of affected mothers are typically mentally retarded, even when the child's endogenous PAH activity is adequate.

(SEE ALSO: Congenital Anomalies; Genetic Disorders; Genetics and Health; Newborn Screening)

Bibliography

Scriver, C. R.; Eisensmith, R. C.; Woo, S. L. C.; and Kaufman, S. (1994). "The Hyperphenylalaninemias of Man and Mouse." Annual Review of Genetics 28:141–165.

— HARRY W. SCHROEDER, JR.

A hereditary disease that prevents the proper metabolism of phenylalanine, an amino acid. When phenylalanine is not metabolized properly, poisonous substances can build up in the body, causing brain damage and mental retardation. The effects of PKU can be controlled by a special diet.

"PKU" redirects here. For other uses, see PKU (disambiguation).

Phenylketonuria
Classification and external resources
ICD-10	E70.0
ICD-9	270.1
OMIM	261600 261630
DiseasesDB	9987
MedlinePlus	001166
eMedicine	ped/1787 derm/712
MeSH	D010661

Phenylketonuria (PKU) is an autosomal recessive genetic disorder characterized by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH).^[1]:541 This enzyme is necessary to metabolize the amino acid phenylalanine ('Phe') to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which is detected in the urine.^{[citation needed]}

Since its discovery there have been many advances in its treatment. It can now be managed by the patient with little or no side effects, just inconvenience with managing the treatment. If however the condition was left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. Historically, PKU has been treated with a low-phenylalanine diet. Research now has proved that diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Phe levels to a safe range and monitoring diet and cognitive development. Lowering of phenylalanine levels to a safe range may be achieved by combining a low phenylalanine-diet with protein supplements. There is currently no cure for this disease, although some treatments are available with varying success rates. PKU is generally detected through newborn screening and diagnosed by a geneticist. PKU clinics around the world provide integrative care for PKU patients to optimize phe levels, dietary intake and cognitive outcomes.

Contents 1 History 2 Screening and presentation 3 Pathophysiology 3.1 Classical PKU 3.2 Tetrahydrobiopterin-deficient hyperphenylalaninemia 4 Metabolic pathways 5 Treatment 6 Maternal phenylketonuria 7 Incidence 8 In relationships 9 See also 10 References 11 External links

History

Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934^[2] when he noticed that hyperphenylalaninemia (HPA) was associated with mental retardation. In Norway, this disorder is known as Følling's disease, named after its discoverer.^[3] Dr. Følling was one of the first physicians to apply detailed chemical analysis to the study of disease. His careful analysis of the urine of two affected siblings led him to request many physicians near Oslo to test the urine of other affected patients. This led to the discovery of the same substance that he had found in eight other patients. The substance found was subjected to much more basic and rudimentary chemical analysis (taste). He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude the compound contained a benzene ring. Further testing showed the melting point to be the same as phenylpyruvic acid, which indicated that the substance was in the urine. His careful science inspired many to pursue similar meticulous and painstaking research with other disorders.

Screening and presentation

Blood is taken from a two-week old infant to test for phenylketonuria

PKU is normally detected using the HPLC test, but some clinics still use the Guthrie test, part of national biochemical screening programs. Most babies in developed countries are screened for PKU soon after birth.^[4]

If a child is not screened during the routine Newborn Screening test (typically performed at least 12 hours and generally 24–28 hours after birth, using samples drawn by Neonatal heel prick), the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenylacetate, one of the ketones produced). In most cases a repeat test should be done at approximately 2 weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed.

Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities and seizures, and severe learning disabilities are major clinical problems later in life. A "musty or mousy" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed.

In contrast, affected children who are detected and treated are less likely to develop neurological problems or have seizures and mental retardation, though such clinical disorders are still possible.

Pathophysiology

Classical PKU is caused by a mutated gene for the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine to other essential compounds in the body. Other, non-PAH mutations can also cause PKU. This is an example of genetic heterogeneity.

Classical PKU

The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than four hundred disease-causing mutations have been found in the PAH gene. PAH deficiency causes a spectrum of disorders including classic phenylketonuria (PKU) and hyperphenylalaninemia (a less severe accumulation of phenylalanine).^[5]

PKU is an autosomal recessive genetic disorder, meaning that each parent must have at least one mutated allele of the gene for PAH, and the child must inherit two mutated alleles, one from each parent. As a result, it is possible for a parent with PKU phenotype to have a child without PKU if the other parent possesses at least one functional allele of the PAH gene; but a child of two parents with PKU will always inherit two mutated alleles, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU^[6]. The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence which in humans would be considered the PKU mutation.^[7]

Tetrahydrobiopterin-deficient hyperphenylalaninemia

A rarer form of hyperphenilalaninemia occurs when PAH is normal but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH₄) by the patient.^[8] This cofactor is necessary for proper activity of the enzyme.

Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to convert phenylalanine to tyrosine, but it is also required to convert tyrosine to DOPA (via the enzyme tyrosine hydroxylase), which in turn is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four different genes. These types are known as HPABH4A, HPABH4B, HPABH4C, and HPABH4D.^[9]

Metabolic pathways

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include phenylacetate, phenylpyruvate and phenethylamine^[10]. Elevated blood phenylalanine and detection of phenylketones in the urine is diagnostic.

Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood-brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). Excessive phenylalanine in the blood saturates the transporter. Thus, excessive levels of phenylalanine significantly decrease the levels of other LNAAs in the brain. But since these amino acids are required for protein and neurotransmitter synthesis, phenylalanine accumulation disrupts brain development, leading to mental retardation.^[11]

Treatment

If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling phenylalanine (Phe) levels through diet, or a combination of diet and medication. When phenylalanine can't be metabolized by the body, abnormally high levels accumulate in the blood and are toxic to the brain. When left untreated, complications of PKU include severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning and abnormal behavior such as ADHD.

All PKU patients must adhere to a special diet low in phenylalanine for at least the first 16 years of their lives. This requires severely restricting or eliminating foods high in phenylalanine, such as meat, chicken, fish, nuts, cheese, legumes and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid.

Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low phenylalanine diet. These can be replaced as the child grows up such as pills, formulas, and specially formulated foods. (Since phenylalanine is necessary for the synthesis of many proteins, it is required for appropriate growth but levels must be strictly controlled in PKU patients). In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented.)

The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in certain patients.^[12][13] The company BioMarin Pharmaceutical has produced a tablet preparation of the compound sapropterin dihydrochloride (Kuvan),which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges. ^[14] Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat.^[15] After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial to patients with PKU.^[16][17]

There are a number of other therapies currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). Previously, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. Today most physicians recommend that PKU patients need to manage their Phe levels throughout life.

Maternal phenylketonuria

Phenylketonuria is inherited in an autosomal recessive fashion

For women affected with PKU, it is essential for the health of their child to maintain low phenylalanine levels before and during pregnancy.^[18] Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The result is that the child may develop congenital heart disease, growth retardation, microcephaly and mental retardation.^[19] PKU-affected women themselves are not at risk from additional complications during pregnancy.

In most countries, women with PKU who wish to have children are advised to lower their blood phenylalanine levels (typically to between 2 and 6 micromol/deciliter) before they become pregnant and carefully control their phenylalanine levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, generally monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood phenylalanine levels will drop, requiring an increased phenylalanine intake to remain within the safe range of 2-6 micromol/dL. The mother's daily phenylalanine intake may double or even triple by the end of the pregnancy as a result. When maternal blood phenylalanine levels fall below 2 micromol/dL, anecdotal reports indicate that the mothers may suffer adverse effects including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.^[20] Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated that an exclusive diet of breast milk for PKU babies may alter the effects of the deficiency, though during breastfeeding the mother must maintain a strict diet to keep their phenylalanine levels low. More research is needed.

Incidence

The incidence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations from 1 in 4,500 births among the population of Ireland^[21] to 1 in 13,000 births in Norway^[22] to fewer than one in 100,000 births among the population of Finland.^[23] Turkey, at 1 in 2600, has the highest incidence rate in the world. The illness is also more common in Italy and China, as well as in Yemeni populations^[24].

In relationships

It was discovered in 2007 that those with this disorder will discharge a concentrated amount of phenylalanine in breast milk and semen.^{[citation needed]} If these bodily fluids are transferred between two individual phenylketonurics, there is a significant health risk to the receiving partner. The risk, however, has been determined to be statistically insignificant (for each exchange of bodily fluid, the risk is 1 in 15,000 squared, or, 1 in 225,000,000.) Since there have been no reported cases, the risk is theoretical. It was noted, however, that since the rise of the Internet, people coping with this disorder have sought each other out, so the increased social interaction may become a cause for concern.^{[citation needed]}

See also

• Tetrahydrobiopterin deficiency

References

1. ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. ISBN 0-7216-2921-0. 
2. ^ Folling, A. (1934). "Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet". Ztschr. Physiol. Chem. 227: 169–176. 
3. ^ Centerwall, S. A. & Centerwall, W. R. (2000). "The discovery of phenylketonuria: the story of a young couple, two affected children, and a scientist.". Pediatrics 105 (1 Pt 1): 89–103. doi:10.1542/peds.105.1.89. PMID 10617710. http://pediatrics.aappublications.org/cgi/content/full/105/1/89. 
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External links

• Phenylketonuria at the Open Directory Project
• National PKU News
• Videos, Blogs, PKU Community
• Online PKU Community
• Online PKU-Diet calculator

v • d • e Inborn error of amino acid metabolism (E70-72, 270) K→acetyl-CoA Lysine/straight chain Glutaric acidemia type 1 · type 2 · Hyperlysinemia · Pipecolic acidemia · Saccharopinuria Leucine Maple syrup urine disease · Isovaleric acidemia · 3-Methylcrotonyl-CoA carboxylase deficiency · 3-hydroxy-3-methylglutaryl-CoA lyase deficiency Tryptophan Hypertryptophanemia G G→pyruvate→citrate Glycine Sarcosinemia · D-Glyceric acidemia · Glutathione synthetase deficiency Glycine→Creatine: GAMT deficiency G→glutamate→ α-ketoglutarate Histidine Carnosinemia · Histidinemia · Urocanic aciduria Proline Hyperprolinemia · Prolidase deficiency Glutamate/glutamine SSADHD G→propionyl-CoA→ succinyl-CoA Valine Maple syrup urine disease · Hypervalinemia · Isobutyryl-CoA dehydrogenase deficiency Isoleucine Maple syrup urine disease · Beta-ketothiolase deficiency · 2-Methylbutyryl-CoA dehydrogenase deficiency Methionine Hypermethioninemia · Homocystinuria · Cystathioninuria General BC/OA Propionic acidemia · Methylmalonic acidemia · Methylmalonyl-CoA mutase deficiency G→fumarate Phenylalanine/tyrosine Phenylketonuria Tetrahydrobiopterin deficiency · 6-Pyruvoyltetrahydropterin synthase deficiency Tyrosinemia Type II tyrosinemia · Type III tyrosinemia/Hawkinsinuria · Alkaptonuria/Ochronosis · Type I tyrosinemia Tyrosine→Melanin Albinism: Ocular albinism (1) · Oculocutaneous albinism (Hermansky–Pudlak syndrome) · Waardenburg syndrome Tyrosine→Norepinephrine Dopamine beta hydroxylase deficiency G→oxaloacetate Urea cycle/Hyperammonemia (arginine, aspartate) N-Acetylglutamate synthase deficiency · Carbamoyl phosphate synthetase I deficiency · Ornithine transcarbamylase deficiency/translocase deficiency · Citrullinemia · Argininosuccinic aciduria · Argininemia Transport/ IE of RTT Solute carrier family: Cystinuria · Hartnup disease · Lysinuric protein intolerance · Iminoglycinuria other/general/unknown: Oculocerebrorenal syndrome · Fanconi syndrome · Cystinosis Other Trimethylaminuria · 2-Hydroxyglutaric aciduria · Fumarase deficiency see also Amino acid metabolism enzymes, intermediates see also Urea cycle enzymes, intermediates

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