Phenylketonuria in children

Introduction to Pediatric Phenylketonuria Pediatric phenylketonuria is a more common autosomal recessive hereditary disease caused by enzyme defects in the phenylalanine metabolic pathway. Both parents have chromosomal defects, but they are asymptomatic, and the incidence of children with close relatives is high. The child is normal at birth, and after the milk is introduced, the symptoms usually appear at 3 to 6 months, and the symptoms are obvious at the age of 1 year. The disease has been used as one of the routine screening programs for obstetric newborns. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: Eczema Cerebral Palsy Epilepsy

Causes of phenylketonuria in children

(1) Causes of the disease

The disease is an autosomal recessive hereditary disease caused by a defect in the enzyme in the phenylalanine metabolic pathway.

(two) pathogenesis

Phenylalanine (Phe) is an essential amino acid in the body. Part of Phe that is eaten into the body is used for protein synthesis, and part of it is converted to tyrosine by phenylalanine hydroxylase. Only a small amount of Phe is secondary. The metabolic pathway is converted to phenylpyruvate by the action of a transaminase.

Phenylalanine hydroxylase

PKU is caused by a decrease or loss of PAH activity due to mutation of phenylalanine hydroxylase (PAH) gene, and a disorder of Phe metabolism in the liver. PKU patients lack phenylalanine hydroxylase, tyrosine and normal Reduced metabolites, increased blood Phe content, stimulated the development of transaminase, enhanced secondary metabolic pathways, produced phenylpyruvate, phenylacetic acid and phenyllactate, and discharged from the urine, so it is called phenylketonuria, phenyl lactic acid makes children urine The liquid has a special rat odor, high concentration of Phe and its abnormal metabolites inhibit tyrosinase, causing melanin synthesis disorder, Phe increase affects brain development, leading to mental retardation and microcephaly, convulsions and other nervous systems symptom.

Genetic characteristics

1 The parents of the children are carriers of the disease-causing gene (heterozygous); 2 children with 3 children with a mother may have a quarter of children with PKU; 4 the incidence of children who are close relatives is higher than that of the general population. The human PAH gene is located on chromosome 12 (12q22~12q24.1). The PAH gene is about 90 kb in length, with 13 exons and 12 introns. The exon is between 57 and 892 bp in length. About 2.4 kb, encoding 451 amino acids, intron length ranging from 1 to 23 kb. With the development of molecular biology techniques, single-strand configuration polymorphism analysis (SSCP) has been carried out in Beijing, Shanghai and other places. Gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), dot blot and DNA sequence analysis were used to analyze the genetic analysis of PKU patients. More than 30 gene mutations were found in the Chinese population, and exons 7 and The proportion of mutations in 12 is relatively high, and some of them are Chinese-specific mutants. These gene mutations lead to amino acid substitution, early termination of translation, abnormal mPNA cleavage, and reading frame shift.

Pediatric phenylketonuria prevention

Avoid kinship marriage, heterozygous should not be married. Newborn screening was conducted to detect PKU children early, and treatment was started early to prevent mental retardation. Every newborn should be tested in a diaper for early diagnosis and early treatment.

For couples with a family history of the disease, prenatal diagnosis of their fetus must be performed by DNA analysis or by detecting pteridophytes in amniotic fluid. To decide whether to make selective abortion.

At present, about 80% of the genetic mutations in children with PKU in China have been clarified, and about 20% of the genetic mutation mechanisms are unknown. There are two mutant genes in each PKU family, so genetic diagnosis can have three outcomes:

1. Both mutant genes can be diagnosed clearly.

2. A mutant gene is clearly diagnosed and another mutant gene is unclear.

3. Both mutant genes cannot be diagnosed clearly. The first two results provide prenatal diagnosis, and the third result can be used for prenatal diagnosis by indirect genetic diagnosis through linkage analysis on the premise of identifying non-classical PKU.

Since PKU is a hereditary disease, it is necessary for children and parents to take blood samples at the same time for genetic diagnosis. At the same time, due to the variety of mutant genes and complex analysis, genetic diagnosis should be carried out in advance of the first half year to one year before pregnancy. A targeted prenatal diagnosis based on genetic diagnosis can be performed during pregnancy.

Phenylketonuria can be tested from blood and urine several days after birth. Therefore, many countries have listed this disease as a disease in the neonatal period.

Pediatric phenylketonuria complications Complications eczema cerebral palsy epilepsy

Feeding difficulties, intelligence, sports development, often have eczema, increased muscle tone, hyperreflexia, severe cases may have cerebral palsy, seizures, depression, hyperactivity, inferiority, solitude and so on.

Pediatric phenylketonuria symptoms common symptoms melancholia irritability ketone urinary dysfunction convulsions sacral angulation reflexes sputum reflexes involuntary movement small head eczema

Most of the children were normal at birth, and there were no obvious special clinical symptoms in the neonatal period. Some children may have non-specific symptoms such as feeding difficulties, vomiting, irritability, and untreated children gradually manifested after 3 to 4 months. Out of intelligence, backward sports, hair from black to yellow, white skin, body and urine have a special rat smell, often with eczema.

With age, children's mental retardation becomes more and more obvious. About 60% of older children have severe mental retardation, and 2/3 have mild neurological signs, such as increased muscle tone, hyperreflexia, and microcephaly. Etc. Severe cases may have cerebral palsy, about 1/4 of children have seizures, often appear 18 months ago, can be manifested as infantile seizures, nodding or other forms, about 80% of children have brain The electrogram was abnormal, and the abnormal performance was mainly epileptiform discharge. After treatment, the blood Phe concentration decreased and the EEG was also improved. In addition to affecting the intelligent development, PKU patients may have some behaviors, personality abnormalities such as depression and hyperactivity. Inferiority, solitude and so on.

Depending on the clinical type, PKU can be divided into:

1. Classical PKU (classical PKU): sick children have typical clinical manifestations, with varying degrees of mental retardation, 60% are severely low (IQ is less than 50), about 1/4 of children have seizures, patients with hair The skin color is light, the urine smell in the urine and sweat is accompanied by abnormal mental behavior, the blood Phe concentration is >1200mol/L (20mg/dl), and the urine FeCl3 and DNPH tests are strongly positive.

2. Moderate PKU (moderate PKU): The clinical performance is relatively light, the laboratory test results are the same as the classic PKU, but the blood phenylalanine is in the range of 360 ~ 1200mol / L, the child responds better to the treatment, blood phenyl The concentration of amino acid is easier to control than the classic type of patient.

3. Light PKU (mild PKU): clinical manifestations are mild or asymptomatic, blood phenylalanine is less than 120 ~ 360mol / L, found in very few newborn or premature infants, or phenylalanine hydroxylase residual enzyme activity The taller.

4. Tetrahydrobiopterin (BH4): deficiency clinically all blood phenylalanine >120mol / L is called hyperphenylalaninemia, from the cause of high phenylalanineemia divided into two Class: phenylalanine hydroxylase deficiency and PAH coenzyme - tetrahydrobiopterin (BH4) deficiency, two different types of hyperphenylalaninemia treatment, early differential diagnosis is very important.

Examination of phenylketonuria in children

1. Newborn screening

In the neonatal period, children with PKU did not have any clinical manifestations, and the performance of PKU gradually appeared 3 months after birth. With the development of preventive medical science, newborn screening for phenylketonuria has gradually become a routine, newborn screening By measuring blood phenylalanine, each newborn is screened in the group, so that children with PKU can be diagnosed early before the clinical symptoms have not appeared, and their biochemical changes have been obvious. Early diagnosis Treatment, to avoid the occurrence of intelligent backwardness, 2. Urinary ferric chloride (FeCl3) and 2,4-dinitrophenylhydrazine test (DNPH)

(1) Ferric chloride (FeCl3) test: 0.5 ml of FeCl3 was added to 5 ml of fresh urine, and urine was positive in green.

(2) 2,4-Dinitrophenylhydrazine test: 1 ml of DNPH reagent was added to 1 ml of urine, and urine was positive for yellow fluorescence.

The positive reactions of these two tests can also be seen in maple glucosuria, cystineemia, so it is not a PKU-specific test. Further determination of blood phenylalanine is needed to confirm the diagnosis. Neonatal PKU is bypassed by phenylalanine metabolism. Not yet sound, the patient's urine is negative, this method can not be used for newborn screening.

3. There are two ways to determine blood phenylalanine:

(1) Guthrie bacterial inhibition method: normal concentration <120 mol/L (2 mg/dl), PKU>1200 mol/L.

(2) phenylalanine fluorescence quantification method: normal value and bacterial inhibition method.

4. Phenylalanine load test

For the concentration of blood phenylalanine greater than the normal concentration, <1200mol/L oral phenylalanine 100mg/kg, before the service, 1, 2, 3, 4h after the test, the blood phenylalanine concentration, blood phenylalanine The acid >1200 mol/L was diagnosed as PKU, <1200 mol/L, which was hyperphenylalaninemia.

5.HPLC urinary pterin mapping analysis

10ml morning urine added 0.2g vitamin C, acidified urine, soak 8cm × 10cm newborn screening filter paper, dry, send a conditional laboratory analysis of urinary pterin map, for tetrahydrobiopterin deficiency Diagnosis and differential diagnosis.

6. Oral tetrahydrobiopterin load test

In the case of blood Phe concentration >600mol/L, oral administration of BH4 tablets 20mg/kg, BH4 before taking, 2, 4,6,8,24h after taking blood were taken for Phe determination, for blood Phe concentration <600mol/L Phe + BH4 combined load test, that is, the patient should be given oral Phe (100mg / kg), oral administration of BH4 3h after serving, before Phe, 1, 2, 3h, after BH4 2, 4, 6 At 8 and 24 hours, Phe concentration was measured by blood. BH4 deficiency, when BH4 was given, its phenylalanine hydroxylase activity was restored, blood Phe decreased significantly, PTPS deficiency, blood Phe concentration was 4-6 h after taking BH4. Down to normal; DHPR deficiency, blood Phe concentration generally decreased to normal after 8h or after taking BH4; classic PKU patients due to phenylalanine hydroxylase deficiency, blood Phe concentration did not change significantly.

Auxiliary inspection

EEG

About 80% of sick children have EEG abnormalities, which can be manifested as peak rhythm disorder and focal spikes.

2. CT and MRI examination

Patients with head CT or magnetic resonance imaging (MRI) can be found without abnormalities, and can also be found to have varying degrees of brain dysplasia, manifested as cerebral cortical atrophy and white matter demyelinating lesions, the latter can show ventricles on MRI T1-weighted images A strip-shaped or patchy high-signal area of brain tissue around the triangle.

3. Intelligence measurement

Assess the level of intelligent development.

Diagnosis and diagnosis of phenylketonuria in children

diagnosis

BH4 deficiency, also known as non-classical PKU or malignant PKU, due to the lack of PAH cofactor BH4, in addition to the typical PKU performance, the nervous system is more prominent, such as decreased trunk muscle tone, increased limb muscle tone, involuntary Exercise, tremor, paroxysmal angle angulation, intractable seizures, etc., BH4 deficiency alone with low phenylalanine diet can reduce blood phenylalanine concentration, but the symptoms of the nervous system are still persistent Progress, the incidence of the disease accounts for about 10% of PKU, so all high phenylalanineemia should be routinely diagnosed, CT and MRI can be seen in progressive brain atrophy, the diagnosis mainly depends on HPLC to determine new butterfly in urine(N) and biopterin (B), such as BH4 deficiency caused by deficiency of 6-pyruvyltetrahydropterin synthase (PTPS), neopterin in urine increased significantly, N/B increased, B %<10%, if it is a deficiency of dihydropterin reductase (DHPR), N is normal, B is significantly increased, N/B is decreased, B% is increased, and guanosine triphosphate cyclase (GTPCH) is deficient. N and B in urine are very low, N/B is normal, because the determination of specific enzymes is more complicated and difficult to enter. Step BH4 loading test to help for diagnosis.

This disease is one of the few treatable hereditary metabolic diseases. It should be diagnosed and treated at an early stage to avoid irreversible damage of the nervous system. Since the child does not have symptoms at an early stage, the diagnosis must be based on laboratory tests, typical of PKU. After the onset of symptoms, the diagnosis is not difficult, but it is too late, because the time to prevent brain damage has been lost, it is necessary to emphasize the pre-symptomatic diagnosis, that is, diagnosed in the uterus or early neonatal, some cities in China are carrying out all newborns For PKU universal screening, all PKU infants were discovered at the same time.

Differential diagnosis

Classical PKU should be differentiated from various types of hyperphenylalaninemia, and different genetic mutations cause different hyperphenylalaninemia.

The main features of classical PKU and various types of hyperphenylalaninemia are as follows:

1. Classic PKU (classical PKU) as described above.

2. Persistent mild hyperphenylalaninemia (stained mild hyperphenylalaninemia) symptoms are mild, most of the sick children have no obvious mental retardation, blood PA is 0.244 ~ 1.22mmol / L.

3. Transient hyperphenylalaninemia (Transient hyperphenylalaninemia) found in neonates or premature infants, blood tyrosine is more obvious than PA, phenylpyruvate and phenylacetic acid in the urine, months after birth The tolerance to PA has improved, but it is still not normal.

4. PA transaminase deficiency After PA load, blood PA increased, and phenylpyruvate in urine only slightly increased.

5. Dihydropteridine reductase (DHPR): Defects in defective DHPR lead to deficiency of tetrahydrobiopterin (BH4), while BH4 is a cofactor for PAH, so DHPR deficiency can cause severe hyperphenylalaninemia. At the same time, BH4 is a cofactor for tyrosine and tryptophan metabolism enzymes. Its lack of synthesis can cause the synthesis of neurotransmitters such as dopamine, norepinephrine and serotonin. The clinical manifestations are severe brain dysfunction, such as development. Delayed, progressive mental retardation, abnormal muscle tone, involuntary movement, tremor, eye movement crisis, paroxysmal angle angulation, seizures, etc. CT and MRI can be seen in progressive brain atrophy, diagnosis based on blood PA increase, nerve Reduced transmitter, DHPR activity in skin fibroblasts decreased or disappeared, treatment should be supplemented with levodopa and 5-hydroxytryptophan and folic acid, this disease alone can limit PA intake can reduce PA levels, but the nervous system still For progressive symptoms, the DHPR enzyme gene is located at 4p15.3.

6. Dihydrobiopterin: The clinical manifestations of synthetase deficiency are the same as those of DHPR. The diagnosis is based on the increase of blood PA, the increase of neopterin in urine, the decrease of biopterin, and the treatment of DHPR deficiency.

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