Phenylketonuria (PKU) is a common disease of amino acid metabolism. It is due to the enzyme defect in the phenylalanine (PA) metabolic pathway that phenylalanine cannot be converted into tyrosine, leading to the accumulation of phenylalanine and its ketoacid, which are largely discharged from the urine.This disease is common in hereditary amino acid metabolic defects, and its inheritance mode is autosomal recessive inheritance.The clinical manifestations were uneven, and the main clinical features were mental retardation, psychoneurological symptoms, eczema, skin scratch sign, depigmentation, rat odor, and abnormal EEG.If early diagnosis and treatment can be obtained, the above clinical manifestations may not occur, intelligence may be normal, and EEG abnormalities may also be recovered.
On May 11, 2018, the National Health Commission and other five departments jointly formulated the First Batch of Rare Diseases Catalogue, which included phenylketonuria.[1]
Phenylalanine is one of the essential amino acids for human body.The daily intake of normal people is about 200~500 mg, of which 1/3 is for protein synthesis, and 2/3 is converted into tyrosine through phenylalanine hydroxylase (PAH) in liver cells to synthesize thyroxine, adrenaline, melanin, etc.In addition to PAH, tetrahydrobiopterin (BH4) must be involved as a coenzyme in the conversion of phenylalanine to tyrosine.Gene mutation may cause the activity defect of related enzymes, resulting in abnormal accumulation of phenylalanine.
clinical manifestation
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1. Growth retardation
In addition to physical growth and development retardation, it is mainly manifested in mental retardation.It can be seen in children whose IQ is lower than that of normal children of the same age, and it can appear 4 to 9 months after birth.The IQ of severe patients is lower than 50, and the language development disorder is particularly obvious, which indicates the brain development disorder.
2. Neuropsychiatric performance
There are cerebellar malformations due to brain atrophy, and recurrent convulsions, but they decrease with age.Muscle tension increases, hyperreflexia.There are often excitement, restlessness, hyperactivity and abnormal behavior.
3. Appearance of skin and hair
The skin is often dry and prone to eczema and skin scratch.Because tyrosinase is inhibited, melanin synthesis is reduced, so the hair color of children is light and brown.
4. Others
Due to the lack of phenylalanine hydroxylase, phenylalanine produces more phenyllactic acid and phenylacetic acid from another pathway, which is discharged from sweat and urine with a musty odor (or rat odor).
inspect
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1. Neonatal screening
Three days after feeding the newborn, collect the heel tip blood, absorb and regenerate the thick filter paper, dry it in the air and mail it to the screening center for semi quantitative determination by Guthrie bacterial growth inhibition test. The principle is that phenylalanine can promote the growth of inhibited Bacillus subtilis again, and determine the content of phenylephrine in blood according to the range of growth circle,It can also be quantitatively determined by colorimetry under the action of phenylalanine dehydrogenase, and its false positive rate is low.When the content of phenylalanine is more than 0.24 mmol/L (4 mg/dl), which is twice the normal reference value, recheck or take venous blood for quantitative determination of phenylalanine and tyrosine.The concentration of phenylalanine in normal people is 0.06~0.18 mmol/L (1~3 mg/dl), while the plasma phenylalanine in children can reach more than 1.2 mmol/L (20 mg/dl), and the serum tyrosine is normal or slightly low.
2. Urine ferric chloride test
It is used for screening older infants and children.If ferric chloride is dropped into the urine and a green reaction occurs immediately, it is positive, indicating that the concentration of phenylalanine in the urine is increased.In addition, Dinitrophenylhydrazine test can also measure phenylalanine in urine, and yellow precipitate is positive.
3. Plasma amino acid analysis and urine organic acid analysis
It can provide biochemical diagnosis basis for this disease, and can also identify other amino acid and organic acid metabolic diseases.
4. Urinary pterin analysis
The contents of neopterin and biopterin in urine were determined by high pressure liquid chromatography to identify various types of PKU.The total urinary excretion of neopterin in children with typical PKU was increased, and the ratio of neopterin to biopterin was normal.The total excretion of pterin in children with DHPR deficiency increased, and tetrahydrobiopterin decreased. The excretion of neopterin in children with 6-PTS deficiency increased, and its ratio to biopterin increased. The total excretion of pterin in children with GTP-CH deficiency decreased.
5. Enzymatic diagnosis
PAH only exists in hepatocytes and needs to be determined by liver biopsy, which is not suitable for clinical diagnosis.The activity of the other three enzymes can be measured by red blood cells, white blood cells or skin fibroblasts in the peripheral blood.
6. DNA analysis
In recent years, it is widely used for PKU diagnosis and prenatal diagnosis of heterozygote detection.However, due to the polymorphism of genes, the analysis results must be cautious.
7. Other auxiliary inspection
(1) Electroencephalogram (EEG)It is mainly spike slow wave, and occasionally high amplitude rhythm disorder.The EEG follow-up study showed that the EEG abnormalities gradually increased with age, and gradually decreased after 12 years of age.
(2) Antenatal examinationThe problem of prenatal diagnosis cannot be solved for a long time because phenylalanine hydroxylase activity cannot be measured in villi and amniotic fluid cells.At present, 25 Chinese PKU pathogenic gene mutations have been identified in China, accounting for about 80% of the phenylalanine hydroxylase mutant gene in China, which has been successfully used in the family mutation detection and prenatal diagnosis of PKU patients.
(3) X-ray examinationSmall head malformation can be seen. Non specific changes such as diffuse cortical atrophy can be found on CT and MRI.
differential diagnosis
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Both classic and cofactor deficiency PKU patients have hyperphenylalaninemia, but those with hyperphenylalaninemia may not cause PKU, so PKU should be differentiated from other hyperphenylalaninemia patients.
treatment
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Once the diagnosis is clear, active treatment should be given as soon as possible, mainly diet therapy.The younger the age of starting treatment, the better the effect.
1. Low phenylalanine diet
It is mainly applicable to patients with typical PKU and blood phenylalanine continuously higher than 1.22mmol/L (20mg/dl).Since phenylalanine is an essential amino acid for protein synthesis, complete deficiency can also cause damage to the nervous system. Therefore, infants can be fed special low phenylalanine milk powder. When complementary food is added in infancy, it should be mainly low protein food such as starch, vegetables, fruits, etc.The phenylalanine requirement is about 50-70mg/(kg · d) within two months, about 40mg/(kg · d) within 3-6 months, about 25-30mg/(kg · d) at the age of 2, and about 10-30mg/(kg · d) above the age of 4. It is appropriate to maintain the blood phenylalanine concentration at 0.12-0.6mmol/L (2-10mg/dl).Dietary control should last at least until after puberty.
The purpose of diet treatment is to keep phenylalanine in blood at 0.24-0.6mmol/L, and children can be fed with low phenylalanine food supplemented with breast milk and milk.Each 100ml of human milk contains about 40mg of phenylalanine, and each 30ml of cow milk contains 50mg.The special food limiting phenylalanine intake is expensive and difficult to operate.As for the dietary treatment limiting phenylalanine intake in diet, there is no consensus on when to stop it, and it is generally believed that it should be persisted for 10 years.At the same time of dietary treatment to limit phenylalanine intake, supplement tyrosine or replace diet with tyrosine supplement.Tyrosine supplementation in diet can make hair pigment loss return to normal, but has no effect on intellectual progress.In the course of dietary treatment to limit the intake of phenylalanine, the growth, development and nutritional status of children, as well as the level of phenylalanine in blood and side effects should be closely observed.The side effects are mainly other nutritional deficiencies, such as diarrhea, anemia (large cell), hypoglycemia, hypoproteinemia and niacin deficiency like rash.
2. BH4, 5-hydroxytryptamine and L-DOPA
It is mainly used for BH4 deficient PKU. In addition to diet control, such drugs should be given.
prevention
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1. Genetic counseling: The disease is autosomal recessive inheritance.According to the genetic law, it can be inferred that the parents of the children are heterozygotes (i.e. disease gene carriers), and the children are homozygotes, with an incidence of 25%.If the spouse of the patient is also the patient, then 100% of the offspring will be the patient;If one party is a patient and the other party is a carrier, 50% of the offspring are patients;If one party is a patient or a heterozygote, and the other party is normal, then it represents normal phenotype, but 100% or 50% are disease gene carriers.Therefore, genetic counseling of this disease is extremely important.
2. Prenatal diagnosis: refers to the technology that can diagnose the disease before the birth of the fetus.In China, recombinant DNA technology has been used for prenatal diagnosis of phenylketonuria.
3. Early diagnosis: A simple method to diagnose this disease is to observe whether the urine of children born 5~8 days after being treated with ferric chloride reagent turns green, so as to make a preliminary diagnosis;The disease can also be diagnosed by measuring the serum phenylalanine concentration, such as more than 15mg~20mg, combined with clinical manifestations.It is better to recheck and combine with family investigation to achieve accurate diagnosis.
4. Heterozygote examination: the diagnosis of asymptomatic disease causing gene carriers is not only conducive to taking preventive measures, but also conducive to carrying out genetic counseling, which is also of great significance for marriage and family planning guidance.However, it is believed that the method of heterozygote detection is more accurate to determine the ratio of phenylalanine to tyrosine after phenylalanine load test.
5. Screening measures: Since this disease is a disease with a high incidence among congenital metabolic defects, eleven provinces and cities across the country have carried out screening work for this disease, generally using bacterial inhibition analysis or ferric chloride reagent method.[2]
