|
 |
Phenylketonuria - PKU |
 |
| |
Condition: Phenylketonuria - PKU
This disorder is caused by the child's inability to break down phenylalanine. If not treated, this condition can lead to mental retardation, but the simple practice of avoiding foods with phenylalanine can lead to a normal life. On the order of one in 20,000 children has this disorder.
More technical information from the Mountain States Genetic Network:
The practice of newborn screening was originally developed to detect PKU. All states screen for PKU. The incidence is 1:10-15,000 Caucasian births; it occurs infrequently in other ethnic groups. PKU is due to a recessively inherited defect in which the body cannot use the amino acid phenylalanine properly. Phenylalanine, which comes from all dietary protein, accumulates in the blood. Most abnormalities in the metabolism of the amino acid phenylalanine are caused by mutations in the gene which is responsible for the production of the enzyme phenylalanine hydroxylase. Phenylalanine, an essential amino acid, is normally converted to tyrosine by this enzyme, which uses tetrahydrobiopterin as a cofactor. Normal metabolism of phenylalanine results in a serum concentration between 30µ M and 180µ M (0.5-3 mg/dL).
Clinical Features
Classical phenylketonuria is a disorder in which the blood phenylalanine concentration rises above 1200µ M (20 mg/dL) on a normal diet. Without treatment, 95% of affected individuals develop severe mental retardation. Other symptoms may include hyperactivity, spasticity, seizures, eczema, and autistic-like behavior. Physical findings are nondiagnostic. In addition to a marked elevation of blood phenylalanine, phenylketones may be produced when the blood level is above 1200µ M (20mg/dL). These compounds have a peculiar, mousey odor, sometimes noticeable in untreated patients.
Hyperphenylalaninemia refers to any consistent elevation of phenylalanine levels, including classical PKU. If cases of classical PKU are excluded, this includes levels between 240µ M and 1200µ M (4-20 mg/dL). These may be caused by liver damage, transient tyrosinemia of prematurity, mutation of the phenylalanine hydroxylase gene, disorders of cofactor synthesis or regeneration, or maternal PKU.
The cause of hyperphenylalaninemia must be determined if proper treatment is to be provided. Treatment by dietary restriction alone is inadequate for a tetrahydrobiopterin cofactor defect. The cofactor is necessary not only for normal activity of phenylalanine hydroxylase, but also for activity of the tyrosine and tryptophan hydroxylase which synthesize serotonin and dopamine.
Laboratory Tests
There are a variety of laboratory tests used in screening for PKU. Elevated levels of phenylalanine are most often detected using a bacterial inhibition (Guthrie) assay, a semiquantitative test. A level equal to 240µ M (4 mg/dL) or greater is usually considered abnormal and requires further testing. Chromatographic and fluorometric tests are used in some states. The likely causes of a positive screen and the actions to be taken in response to a positive screen vary according to the laboratory protocol and should be checked with your individual state screening program. Refer to the directory for newborn screening laboratory and follow-up contacts and metabolic physician consultants for your state.
Newborn screening test results must be confirmed before a specific diagnosis can be made. A quantitative tyrosine level should also be obtained to exclude hepatic causes of hyperphenylalaninemia. Urine and serum pterins should be measured to diagnose cases of dihydropteridine reductase deficiency or a defect in tetrahydrobiopterin synthesis.
Treatment
With early treatment, symptoms of classical phenylketonuria are preventable. Treatment should be started as soon as possible after birth, once phenylalanine elevations are confirmed and other possible causes excluded. Minimal levels requiring treatment are controversial, but in most clinics are 600µ M to 900µ M (10-15 mg/dL).
Dietary restriction of phenylalanine is the mainstay of therapy in most cases. Treatment should continue indefinitely. Because phenylalanine is an essential amino acid, it is necessary to consume a minimal amount, which must be carefully monitored and adjusted periodically with growth. A special medical food containing amino acids (except phenylalanine), vitamins, and iron is necessary in conjunction with a carefully prescribed and monitored diet to prevent protein/calorie malnutrition, osteoporosis, and catabolism.
Late treatment of PKU is variably effective. Behavior may improve, but reversal of mental retardation does not. Discontinuation of treatment is associated with variable loss of intellectual functioning, hyperactivity, and onset of seizures and other neurological signs.
Screening Practice Considerations
The phenylalanine level of affected infants rises gradually after birth with little, if any, effect of the amount of protein ingested by the infant. Screening at 72 hours is recommended to maximize detection. The practice of early discharge from the nursery may lead to a falsely negative screening result. Calculations based upon the rate of rise of phenylalanine levels in affected infants shows a screening test sensitivity of 84% before 2 hours, 97.8% at or before 48 hours, and 99.7% after 48 hours. Another reference suggests a false negative rate of 30% in babies tested in the first 12 hours of life. If an infant is tested before 48 hours of age, a repeat test is recommended. Dialysis or transfusion may also temporarily lower phenylalanine levels. Children who develop retardation before one year of age should undergo testing for PKU even if a negative screening test is documented.
Prompt confirmatory testing is required even if there is evidence to suggest that one of the situations associated with false positive screens is present (these include early specimen collection, prematurity, heat-damaged specimen, hyperalimentation, or antibiotic therapy). The presence of any of these does not exclude the possibility of disease.
Maternal PKU
Pregnancy presents a special problem with PKU and hyperphenylalaninemia; high blood levels of phenylalanine are teratogenic to the fetus. This is important in the context of newborn screening because early testing of an infant born to a mother with PKU or hyperphenylalaninemia can reflect the mother's phenylalanine levels. A positive test on a newborn who then has a normal repeat test, especially if the baby has growth retardation, microcephaly, or malformations, should raise the possibility of maternal PKU. If maternal PKU is suspected, the mother should be appropriately tested and counseled. Treatment in future pregnancies may prevent similar effects on future offspring.
The purpose of newborn screening is to identify infants at risk and in need of more definitive testing. As with any laboratory test, both false negative and false positive results are possible. Screening test results are insufficient information on which to base diagnoses or treatment.
|
|
|
|
Latest Posts
| |
|
|
Latest Articles
| |
|
Home Page