I. What is phenylketonuria Phenylketonuria (PKU) is a genetic metabolic disorder that is caused by a decrease in phenylalanine hydroxylase activity in the body or a lack of its coenzyme tetrahydrobiopterin, resulting in impaired metabolism of phenylalanine to tyrosine, increased phenylalanine concentration in blood and tissues, and a significant increase in urinary phenyl pyruvate, phenylacetic acid and phenyl lactate, hence the name “phenylketonuria”. Although this disease is a genetic metabolic disease, it is not uncommon. The prevalence of PKU is about 1:10,000 in China, about 1:14,000 in the United States, about 1/4,400 in Northern Ireland, about 1:7,000 in Germany, and about 1:78,400 in Japan. II. How is phenylketonuria caused Phenylketonuria is caused by abnormal phenylalanine metabolism in the body. Phenylalanine is an essential amino acid for human growth and metabolism. Part of the phenylalanine consumed in the body is used for protein synthesis, and part of it is transformed into tyrosine through the action of phenylalanine hydroxylase, which functions. Phenylalanine hydroxylase requires tetrahydrobiopterin as a coenzyme to function better. Reduced phenylalanine hydroxylase activity or tetrahydrobiopterin deficiency can lead to a failure to convert phenylalanine to tyrosine, resulting in a significant increase in phenylalanine and its bypass metabolites, phenyl pyruvate, phenylacetic acid and phenyl lactate, causing brain damage and morbidity. The production of phenylalanine hydroxylase and tetrahydrobiopterin is genetically determined. If a parent has an abnormal gene related to phenylalanine hydroxylase or tetrahydrobiopterin metabolism, both parents are heterozygous for the abnormal gene related to phenylalanine hydroxylase or tetrahydrobiopterin metabolism, but do not develop the disease because they have only 1 abnormal gene. The fetus has two abnormal genes, which are pure congeners and can cause the disease, so it is a recessive metabolic disease.
What are the abnormal manifestations of phenylketonuria? Most of the PKU children are born with normal performance, and there are no obvious special clinical symptoms in the neonatal period. Untreated children gradually show intellectual and motor development after 3 to 4 months, their hair turns from black to yellow, their skin turns white, their whole body and urine have a special rat odor, and they often have eczema. As the child grows older, the mental retardation becomes more and more obvious, and about 60% of the older children have severe mental retardation. 2/3 of the children have mild neurological signs, such as increased muscle tone, hyperactive tendon reflexes, microcephaly, etc. Severe cases may have cerebral palsy. About 1/4 of the children have seizures, often before 18 months of age, which may manifest as infantile spasmodic seizures, nodding-like seizures, or other forms. About 80% of children have EEG abnormalities, which are predominantly epileptiform discharges, with a few abnormal background activity. After treatment, the blood phenylalanine concentration decreases and the EEG improves significantly.
If the child has the above abnormal manifestations, the following tests should be done for diagnosis.
(A) Blood phenylalanine measurement Since phenylketonuria is first manifested by an increase in blood phenylalanine concentration, the detection of blood phenylalanine concentration is the preferred method to diagnose PKU, and generally blood phenylalanine 3120 mmol/L is judged as positive for further diagnosis. At present, tandem mass spectrometry can rapidly detect phenylalanine and tyrosine concentrations and automatically calculate their ratios, which can reduce the false-positive rate or false-negative rate.
(b) Urine pterin profile analysis Since the lack of tetrahydrobiopterin can be reflected in the urine pterin profile, the detection of urine pterin profile can help PKU typing.
（Since some children with tetrahydrobiopterin deficiency are caused by the deficiency of dihydrobiopterin reductase activity, the measurement of dihydrobiopterin reductase activity of blood erythrocytes is helpful for the diagnosis of dihydrobiopterin reductase deficiency.
(iv) MRI of the head The children diagnosed by neonatal screening generally do not need to do MRI of the head because they do not have clinical symptoms before the onset of the disease. The main brain imaging changes in PKU patients are delayed myelination and scattered patchy high signal foci in the white matter of the brain on T2-weighted images, mostly involving the periventricular white matter and the frontal, parietal and occipital lobes. Some children also have cerebral gray-white matter hypoplasia, corpus callosum hypoplasia, hyaline septal defects, and diffuse and focal brain atrophy.
The diagnosis of phenylketonuria is based on the symptoms of mental retardation, yellow hair, white complexion, motor and language development, and increased blood phenylalanine. However, at present, in some places, doctors are not sufficiently aware of this disease, and when they encounter such patients, they fail to think of this disease and do not do relevant tests, which often leads to missed diagnosis or misdiagnosis, so this disease needs the attention of the majority of doctors. The screening of neonatal diseases currently carried out enables PKU to be diagnosed before the onset of the disease and early treatment is provided, so the onset of PKU children is less common than before.
(B) Typing of phenylketonuria Diagnosis of phenylketonuria is only a partial diagnosis. There are different types of phenylketonuria due to the pathogenesis of the disease and different treatment methods for different types, so once PKU is diagnosed, early typing is needed.