|Classification and external resources|
|eMedicine||ped/1787 derm/712 article/947781|
Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by homozygous or compound heterozygous mutations in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.:541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine (Tyr). When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.
Untreated PKU can lead to intellectual disability, seizures, and other serious medical problems. The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients. In the United States, the current recommendation is that the PKU diet should be maintained for life. Patients who are diagnosed early and maintain a strict diet can have a normal life span with normal mental development. However, recent research suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology are slightly suboptimal if diet is not supplemented with amino acids.
As an autosomal recessive disorder, two PKU alleles are required for an individual to exhibit symptoms of the disease. Carriers of a single PKU allele do not exhibit symptoms of the disease but appear to be protected to some extent against the fungal toxin ochratoxin A. This accounts for the persistence of the allele in certain populations in that it confers a selective advantage—in other words, being a heterozygote is advantageous.
Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934 when he noticed hyperphenylalaninemia (HPA) was associated with intellectual disability. In Norway, this disorder is known as Følling's disease, named after its discoverer. 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 he had found in eight other patients. He conducted tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that 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. It was recently suggested that PKU may resemble amyloid diseases, such as Alzheimer's disease and Parkinson's disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.
Screening and presentation
PKU is commonly included in the newborn screening panel of most countries, with varied detection techniques. Most babies in developed countries are screened for PKU soon after birth. Screening for PKU is done with bacterial inhibition assay (Guthrie test), immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry (MS/MS). Measurements done using MS/MS determine the concentration of Phe and the ratio of Phe to tyrosine, both of which will be elevated in PKU.
If a child is not screened during the routine newborn screening test (typically performed 2–7 days 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 two 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), as well as a tendency towards 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 intellectual disability, though such clinical disorders are still possible.
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 non-allelic genetic heterogeneity. The PAH gene is located on chromosome 12 in the bands 12q22-q24.1. More than 400 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).
PKU is known to be an autosomal recessive genetic disorder. This means both parents must have at least one mutated allele of the PAH gene. The child must inherit both mutated alleles, one from each parent. Therefore, if both parents are carriers for PKU, there is a 25% chance their child with develop the disorder, a 50% chance their child will be a carrier, and a 25% chance their child will neither develop nor be a carrier for the disease.
Phenylketonuria can exist in mice, which have been extensively used in experiments into finding an effective treatment for it. The macaque monkey's genome was recently sequenced, and the gene encoding phenylalanine hydroxylase was found to have the same sequence that, in humans, would be considered the PKU mutation.
A rarer form of hyperphenylalaninemia occurs when the PAH enzyme is normal, but there is a defect in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4). BH4 (called biopterin) is necessary for proper activity of the enzyme PAH, and this coenzyme can be supplemented as treatment. Those who suffer from PKU as well may also have a deficiency of tyrosine (which is created from phenylalanine by PAH). These patients must also be supplemented with tyrosine to account for this deficiency.
Dihydrobiopterin reductase activity is needed to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form, which is an important cofactor in many reactions in amino acid metabolism. Those with this deficiency may produce sufficient levels of the enzyme phenylalanine hydroxylase (PAH), but since tetrahydrobiopterin is a cofactor for PAH activity, deficient dihydrobiopterin reductase renders any PAH produced unable to use phenylalanine to produce tyrosine. Tetrahydrobiopterin is also a cofactor in the production of L-DOPA from tyrosine and 5-Hydroxy-L-Tryptophan from tryptophan, which must also be supplemented as treatment in addition to the supplements for classical PKU.
Levels of dopamine can be used to distinguish between these two types. Tetrahydrobiopterin is required to convert phenylalanine to tyrosine, but is also required to convert tyrosine to L-DOPA via the enzyme tyrosine hydroxylase. L-DOPA in turn is converted to dopamine. Low levels of dopamine lead to high levels of prolactin. By contrast, in classical PKU (without dihydrobiopterin involvement), prolactin levels would be relatively normal.
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. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic, however most patients are diagnosed via newborn screening.
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). If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. However, as these amino acids are necessary for protein and neurotransmitter synthesis, Phe buildup hinders the development of the brain, causing intellectual disability.
If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by managing and controlling Phe levels through diet, or a combination of diet and medication. Optimal health ranges (or "target ranges") are between 120 and 360 µmol/L, and aimed to be achieved during at least the first 10 years. When Phe cannot 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 intellectual disability, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder.
All PKU patients must adhere to a special diet low in Phe for optimal brain development. "Diet for life" has become the standard recommended by most experts. The diet requires severely restricting or eliminating foods high in Phe, such as meat, chicken, fish, eggs, nuts, cheese, legumes, milk 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. The sweetener aspartame, present in many diet foods and soft drinks, must also be avoided, as aspartame contains phenylalanine.
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. As the child grows up these can be replaced with pills, formulas, and specially formulated foods. (Since Phe 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. 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. 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. After extensive clinical trials, Kuvan has been approved by the FDA for use in PKU therapy. Some researchers and clinicians working with PKU are finding Kuvan a safe and effective addition to dietary treatment and beneficial to patients with PKU.
Dietary supplementation with large neutral amino acids(LNAAs), with or without the traditional PKU diet is another treatment strategy. The LNAAs (e.g. leu, tyr, trp, met, his, iso, val, thr) compete with phe for specific carrier proteins that transport LNAAs across the intestinal mucosa into the blood and across the blood brain barrier into the brain .
Studies have demonstrated that PKU patients given daily supplements of LNAAs have decreased plasma phe levels and reduced brain phe concentrations measured by magnetic resonance spectroscopy.
Another interesting treatment strategy for PKU patients is casein glycomacropeptide (CGMP), which is a milk peptide naturally free of Phe in its pure form CGMP can substitute the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids. The fact that CGMP is a peptide ensures that that the absorption rate its amino acids is prolonged compared to free amino acids and thereby results in improved protein retention and increased satiety compared to free amino acids. Another important benefit of CGMP is that the taste is significantly improved when CGMP substitutes part of the free amino acids and this may help ensure improved compliance to the PKU diet.
Furthermore, CGMP contains a high amount of the phe lowering LNAAs, which constitutes about 41 g per 100 g protein and will therefore help maintain plasma phe levels in the target range.
Other therapies are currently under investigation, including gene therapy and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). In the past, PKU-affected people were allowed to go off diet after approximately eight, then 18 years of age. Today, most physicians recommend PKU patients must manage their Phe levels throughout life.
For women with phenylketonuria, it is essential for the health of their children to maintain low Phe levels before and during pregnancy. 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 child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result. PKU-affected women themselves are not at risk of additional complications during pregnancy.
In most countries, women with PKU who wish to have children are advised to lower their blood Phe levels (typically to between 2 and 6 mg/dL) before they become pregnant, and carefully control their levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general 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 Phe levels will drop, requiring an increased intake to remain within the safe range of 2–6 mg/dL. The mother's daily Phe intake may double or even triple by the end of the pregnancy, as a result. When maternal blood Phe levels fall below 2 mg/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. Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated 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 her Phe levels low. More research is needed. US scientist announced in June 2010 that they would be conducting a thorough investigation on the mutation of genes in the human genome. Their top priority is PKU, as it has become increasingly common, and sufferers often bear children who will be carriers of the recessive gene, and may themselves live past the age of sixty.
The mean incidence of PKU varies widely in different human populations. United States Caucasians are affected at a rate of 1 in 10,000. Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in 100,000 births. A 1987 study from Slovakia reports a Roma population with an extremely high incidence of PKU (one case in 40 births) due to extensive inbreeding.
|Country||Incidence of PKU|
|China||1 in 18,000|
|Finland||<1 in 100,000|
|Ireland||1 in 4,500|
|Japan||1 in 120,000|
|Korea||1 in 41,000|
|Norway||1 in 13,000|
|Turkey||1 in 2,600|
|India||1 in 18,300|
|United States||1 in 15,000|
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