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Phenylketonuria

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"PKU" redirects here. For other uses, see PKU (disambiguation).
Phenylketonuria
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Phenylketonuria (PKU) is an autosomal recessive metabolic 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.[2]

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 the inconvenience of managing the treatment. If, however, the condition is left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. In the past, PKU was treated with a low-phenylalanine diet. Latter-day research now has shown that diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Ph 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; however, some treatments are available with varying success rates. In general, PKU is detected through newborn screening and diagnosed by a geneticist. PKU clinics around the world provide care for PKU patients to optimize phe levels, dietary intake, and cognitive outcomes.

History

Phenylketonuria was discovered by the Norwegian physician Ivar Asbjørn Følling in 1934[3] 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.[4] 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.[5]

If a child is not screened during the routine newborn screening test (typically performed 6 -14 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 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).[6]

PKU is known to be an autosomal recessive genetic disorder. This means that 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, it is not impossible for a parent with the disease to have a child without it if the other parent possesses one functional allele of the gene for PAH. Yet, a child from two parents with PKU will inherit two mutated alleles every time, and therefore the disease.

Phenylketonuria can exist in mice, which have been extensively used in experiments into an effective treatment for PKU.[7] The macaque monkey's genome was recently sequenced, and it was found that the gene encoding phenylalanine hydroxylase has the same sequence that, in humans, would be considered the PKU mutation.[8]

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.[9] This cofactor is necessary for proper activity of the enzyme. The coenzyme (called biopterin) can be supplemented as treatment.

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 L-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.[10]

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.[11] Elevated blood just because 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). 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, phenylalanine buildup hinders the development of the brain, causing mental retardation.[12]

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 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 mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioral problems 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, eggs, nuts, cheese, legumes, cow 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. 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. As the child grows up, these can be replaced with 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.[13][14] 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.[15] 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.[16] 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.[17][18]

There are several other therapies currently under investigation, including gene therapy, large neutral amino acids, and enzyme substitution therapy with phenylalanine ammonia lyase (PAL). In the past, PKU-affected people were allowed to go off diet after approximately 8, then 18 years of age. Today most physicians recommend that PKU patients must 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.[19] 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.[20] PKU-affected women themselves are not at risk from additional complications during pregnancy.

In most countries, women with PKU that 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, 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 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.[21] 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. US scientist have recently announced (June 2010) that they will be conducting thorough investigation on the mutation of genes in the human genome. Their top priority is Phenylketonuria as it has become increasingly common, due to the fact that sufferers often live past the age of sixty and often bear children (carriers of the recessive gene).

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[22] to 1 in 13,000 births in Norway[23] to fewer than one in 100,000 births among the population of Finland.[24] 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.[25]

See also

References

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  25. ^ http://emedicine.medscape.com/article/947781-overview

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