Phenylketonuria

Phenylketonuria is a clinical syndrome of mental retardation with cognitive and behavioral impairment caused by elevated blood phenylalanine levels. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is based on finding high phenylalanine levels and normal or low tyrosine levels. Treatment consists of lifelong adherence to a low-phenylalanine diet. The prognosis is excellent with timely diagnosis.

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What causes phenylketonuria?

Phenylketonuria is most common among whites and is relatively uncommon among Ashkenazi Jews, Chinese, and blacks. The inheritance pattern is autosomal recessive; the incidence is approximately 1/10,000 births among whites.

Excess dietary phenylalanine (i.e., that which is not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is an essential cofactor for this reaction. If phenylalanine hydroxylase is deficient or absent as a result of one or more mutations, dietary phenylalanine accumulates; the main organ affected by elevated phenylalanine levels is the brain, due to impaired myelination. Some of the excess phenylalanine is converted to phenylketones, which are excreted in the urine, giving rise to the name phenylketonuria. The degree of enzyme deficiency, and hence the severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.

Symptoms of phenylketonuria

Most children are born normal but slowly develop symptoms of phenylketonuria over several months due to the gradual accumulation of phenylalanine. The hallmark of untreated phenylketonuria is severe mental retardation. Children also have severe hyperactivity, gait disturbances, and psychosis, as well as an unpleasant, mousy body odor due to the excretion of phenylacetic acid (a breakdown product of phenylalanine) in the urine and sweat. Patients also tend to have lighter skin, hair, and eyes than healthy family members, and some may develop a rash similar to infantile eczema.

Forms of phenylketonuria

Although virtually all cases (98-99%) of phenylketonuria result from phenylalanine hydroxylase deficiency, phenylalanine can also accumulate if BH4 is not synthesized due to dehydrobeptorin synthetase deficiency or is not regenerated due to dihydropteridine reductase deficiency. In addition, because BH4 is also a cofactor for tyrosine hydroxylase, which is involved in the synthesis of dopamine and serotonin, BH4 deficiency impairs neurotransmitter synthesis, causing neurologic symptoms independent of phenylalanine accumulation.

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Diagnosis of phenylketonuria

In the United States and many developed countries, all newborns are screened for phenylketonuria 24 to 48 hours after birth using one of several blood screening methods; if abnormal results are obtained, the diagnosis is confirmed by directly measuring the phenylalanine level. In classic phenylketonuria, patients often have phenylalanine levels greater than 20 mg/dL (1.2 μmol/L). In partial deficiency, phenylalanine levels are usually less than 8 to 10 mg/dL if the infant is on a normal diet (levels greater than 6 mg/dL indicate the need for treatment); differential diagnosis with classic phenylketonuria requires a hepatic phenylalanine hydroxylase activity test showing levels of 5 to 15% of normal or mutation analysis identifying mild mutations in the gene. BH4 deficiency is distinguished from other forms of PKU by elevated levels of biopterin or neopterin in urine, blood, or cerebrospinal fluid, or all of these; detection of this form is important because standard treatment for PKU does not prevent brain damage in these cases.

In children from families with a positive family history, phenylketonuria can be detected prenatally using direct mutation testing after chorionic villus sampling or amniocentesis.

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Treatment of phenylketonuria

Treatment consists of lifelong restriction of dietary phenylalanine. All natural proteins contain about 4% phenylalanine, so the diet should include low-protein foods (eg, fruits, vegetables, certain grains); protein hydrolysate processed to remove phenylalanine; and amino acid mixtures that do not contain phenylalanine. Examples of commercial phenylalanine-free products are XPhe products (XP Analog for infants, XP Maxamaid for children 1 to 8 years old, XP Maxamum for children over 8 years); Phenex I and II; PhenilFree I and II; PKU1, 2, 3; PhenylAde (various); Loflex; PlexylO. A small amount of phenylalanine is needed for growth and metabolism; it is supplemented with measured portions of natural protein in the form of milk or low-protein products.

Regular monitoring of blood phenylalanine levels is necessary; the recommended level is 2-4 mg/dL (120-240 μmol/L) for children under 12 years of age and 2-10 mg/dL (120-600 μmol/L) for children over 12 years of age. Nutritional planning and treatment should be initiated in women of childbearing age before pregnancy to ensure a good outcome for the child.

In children with BH4 deficiency, treatment also includes tetrahydrobiopterin 1-5 mg/kg orally 3 times daily; levodopa, carbidopa, and 5OH tryptophan and folic acid 10-20 mg orally once daily in cases of dihydropteridine reductase deficiency. However, the goals and approaches to treatment are the same as for phenylketonuria.

What is the prognosis for phenylketonuria?

If adequate treatment is started in the first days of life, phenylketonuria does not develop. Treatment of phenylketonuria started after 2-3 years may be effective only for controlling severe hyperactivity and intractable seizures. Children born to mothers with poorly controlled phenylketonuria (i.e., with high phenylalanine levels) during pregnancy have a high risk of developing microcephaly and developmental delays.