Phenylketonuria

Phenylketonuria is a clinical syndrome that includes mental retardation with cognitive and behavioral disorders that are caused by an increase in the level of phenylalanine in the blood. The primary cause is insufficient activity of phenylalanine hydroxylase. The diagnosis is based on the detection of a high level of phenylalanine and a normal or low level of tyrosine. Treatment consists of a lifelong diet with a low content of phenylalanine. The prognosis is excellent with timely diagnosis.

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What causes phenylketonuria?

Phenylketonuria is most common among the white population and is relatively less common among Ashkenazi Jews, Chinese and blacks. Type of inheritance is autosomal recessive; the frequency is about 1/10 000 births among the white population.

Excess phenylalanine, supplied with food (ie, which is not used for protein synthesis), normally turns into tyrosine by the action of phenylalanine hydroxylase; tetrahydrobiopterin (BH4) is a necessary cofactor for this reaction. If as a result of one or more mutations develop deficiency or lack of phenylalanine hydroxylase, there is accumulation of phenylalanine, which comes with food; the main organ, suffering from an elevated level of phenylalanine, is the brain, due to a violation of myelination. Part of the excess phenylalanine is converted to phenylketones, which are excreted in the urine, which led to the name phenylketonuria. The degree of deficiency of the enzyme and hence the severity of hyperphenylalanineemia varies among patients, depending on the specific mutation.

Symptoms of phenylketonuria

Most of the children are born normal, but they develop symptoms of phenylketonuria slowly for several months, which is associated with the gradual accumulation of phenylalanine. A distinctive feature of phenylketonuria in the absence of treatment is a marked delay in mental development. Children also exhibit severe hyperactivity, gait disturbance and psychosis, as well as an unpleasant, mouse body odor resulting from urinary excretion and then phenylacetic acid (the product of the breakdown of phenylalanine). Patients also tend to have lighter skin, hair and eyes than healthy members of the family, some may have a rash similar to infantile eczema.

Forms of phenylketonuria

Despite the fact that almost all cases (98-99%) of phenylketonuria are a consequence of a deficiency of phenylalanine hydroxylase, phenylalanine can also accumulate if BH4 is not synthesized due to a deficiency of dehydrobipterinsyntheticase or is not restored due to a deficiency of dihydropteridine reductase. In addition, since BH4 is also a co-factor for tyrosine hydroxylase, which is involved in the synthesis of dopamine and serotonin, the BH4 deficiency disrupts the synthesis of neurotransmitters, causing neurological symptoms, regardless of the accumulation of phenylalanine.

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Diagnosis of phenylketonuria

In the United States and many developed countries, all newborns are screened for phenylketonuria 24-48 hours after birth, using one of several screening methods in the blood; at reception of the results differing from normal, the diagnosis is confirmed by direct measurement of a level of phenylalanine. In classical phenylketonuria, the level of phenylalanine in the patients often exceeds 20 mg / dl (1.2 μmol / L). In case of partial deficiency, the level of phenylalanine is usually less than 8-10 mg / dL if the child receives regular food (the level of more than 6 mg / dL indicates the need for treatment); differential diagnosis with classical phenylketonuria requires the determination of the activity of the hepatic phenylalanine hydroxylase, in which its level is 5-15% of the normal, or mutational analysis, identifying the lung mutations of the gene. The deficiency of BH4 differs from other forms of phenylketonuria by increasing the concentration of biopterin or neopterin in urine, blood or CSF or in all these biological fluids; the detection of this form is important, since the standard treatment of phenylketonuria does not prevent brain damage in these cases.

In children from families with a positive family history, phenylketonuria can be detected prenatally when using a direct study of mutations after chorion biopsy or amniocentesis.

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Treatment of phenylketonuria

Treatment consists of a lifelong restriction of the intake of phenylalanine food. All natural proteins contain about 4% phenylalanine, so the diet should include low-protein foods (for example, fruits, vegetables, certain cereals); protein hydrolyzate, processed to remove phenylalanine; and mixtures of amino acids that do not contain phenylalanine. Examples of commercial products that do not contain phenylalanine are XPhe products (XP Analog for infants, Maxamaid XP for children 1 to 8 years, XP Maxamum for children older than 8 years); Phenex I and II; PhenilFree I and II; PKU1, 2, 3; PhenylAde (various); Loflex; PlexylO. A small amount of phenylalanine is necessary for growth and metabolism; It is injected additionally with measured portions of natural protein in the form of milk or low-protein products.

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

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

What prognosis does phenylketonuria have?

If adequate treatment begins in the first days of the child's life, phenylketonuria does not develop. Treatment of phenylketonuria, started after 2-3 years, can be effective only for controlling severe hyperactivity and an uncontrollable convulsive syndrome. Children born to mothers with poorly controlled phenylketonuria (ie, having a high level of phenylalanine) during pregnancy, have a high risk of developing microcephaly and delayed development.