What Are the Causes of Phenylketonuria?

Phenylketonuria (PKU) is a common amino acid metabolism disease, which is caused by enzyme defects in the phenylalanine (PA) metabolic pathway, making phenylalanine unable to be converted into tyrosine, resulting in phenylalanine and Its keto acid accumulates and is excreted in large quantities from the urine. This disease is more common in hereditary amino acid metabolic deficiency diseases, and its inheritance is autosomal recessive. The clinical manifestations are uneven, and the main clinical features are mental retardation, neuropsychiatric symptoms, eczema, skin scratch signs, pigment loss, and rat odor, and abnormal EEG. If early diagnosis and early treatment can be obtained, the aforementioned clinical manifestations may not occur, intelligence is normal, and EEG abnormalities can also be recovered.

Basic Information

English name: phenylketonuria
Visiting department: Pediatrics

Common causes: Phenylalanine and its ketoacid accumulation
Common symptoms: Mental retardation, neuropsychiatric symptoms, eczema, skin scratch signs, loss of pigment, rat odor, etc.

Causes of Phenylketonuria

Phenylalanine is one of the essential amino acids in the human body. The daily intake of normal people is about 200-500 mg, of which 1/3 is used for protein synthesis, and 2/3 is converted into tyrosine by phenylalanine hydroxylase (PAH) in liver cells. Synthesis of thyroxine, epinephrine and melanin. In the process of converting phenylalanine to tyrosine, in addition to PAH, tetrahydrobiopterin (BH4) must be involved as a coenzyme. Gene mutations may cause defects in the activity of related enzymes, resulting in abnormal accumulation of phenylalanine.

Clinical manifestations of phenylketonuria

Growth retardation

In addition to physical growth retardation, it is mainly manifested in mental retardation. It shows that the intelligence quotient is lower than normal children of the same age, and it can appear 4 to 9 months after birth. Severe people have an IQ of less than 50, and language development disorders are particularly obvious. These manifestations suggest brain development disorders.

2. Neuropsychiatric manifestations

Due to cerebral atrophy and cerebellar malformations, recurrent seizures, but alleviated with age. Increased muscle tone and hyperreflexia. Frequent excitement, hyperactivity, and abnormal behavior.

3. Skin hair performance

The skin is often dry and prone to eczema and skin scratches. Because tyrosinase is inhibited, melanin synthesis is reduced, so the child's hair is pale and brown.

4. Other

Due to the lack of phenylalanine hydroxylase, phenylalanine increases phenyllactic acid and phenylacetic acid from another pathway, and is excreted from sweat and urine with a musty smell (or rat odor).

Phenylketonuria test

Newborn screening

After 3 days of feeding the newborn, the blood from the heel is collected, absorbed on the regenerated thick filter paper, dried and mailed to the screening center. The Guthrie bacterial growth inhibition test is used for semi-quantitative determination. The principle is that phenylalanine can promote the inhibition of Bacillus subtilis was re-grown, and the content of phenylalanine in the blood was measured in the range of the growth circle. The colorimetric quantitative determination under the action of phenylalanine dehydrogenase was also used, and the false positive rate was low. When the phenylalanine content is> 0.24mmol / L (4mg / dl), which is twice the normal reference value, the phenylalanine and tyrosine should be re-examined or collected from venous blood. Normal humans have a phenylalanine concentration of 0.06 to 0.18 mmol / L (1 to 3 mg / dl) and children with plasma phenylalanine can reach 1.2 mmol / L (20 mg / dl) or more, and the blood tyrosine is normal or Slightly lower.

2.Urine ferric chloride test

Screening for older infants and children. When ferric chloride was dropped into the urine, if a green reaction occurred immediately, it was positive, indicating that the concentration of phenylalanine in the urine was increased. In addition, the dinitrophenylhydrazine test can also measure phenylalanine in urine, and the yellow precipitate is positive.

3. Plasma amino acid analysis and urine organic acid analysis

It can provide biochemical diagnosis basis for this disease, meanwhile, it can also identify other amino acid and organic acid metabolism diseases.

4. Uterine analysis

High-pressure liquid chromatography (HPLC) was used to determine the content of neopterin and biopterin in urine to identify various types of PKU. In children with typical PKU, total excretion of pterinate in urine is increased, and the ratio of neopterin to biopterin is normal. Children with DHPR deficiency have an increase in total tocopheryl excretion and a decrease in tetrahydrobiopterin. Children with 6-PTS deficiency have an increase in neopterin excretion. The ratio of biopterine to biopterin is increased. Children with GTP-CH deficiency Its total excretion of toxopterin is reduced.

5. Enzymatic diagnosis

PAH exists only in hepatocytes and needs liver biopsy. It is not suitable for clinical diagnosis. The activities of the other three enzymes can be determined using peripheral blood red, white blood cells or skin fibroblasts.

6. DNA analysis

In recent years, it has been widely used in the diagnosis of PKU and prenatal diagnosis of heterozygosity. However, due to genetic polymorphisms, analysis results must be cautious.

7. Other auxiliary inspections

(1) The electroencephalogram (EEG) is mainly slow spine waves, and occasionally high amplitude rhythm disorders. EEG follow-up studies show that with the increase of age, the abnormal manifestations of EEG gradually increase, and the EEG abnormalities gradually decrease after 12 years of age.

(2) Prenatal examination Because villus and amniotic fluid cells cannot detect phenylalanine hydroxylase activity, the problem of prenatal diagnosis cannot be solved for a long time. At present, 25 kinds of Chinese PKU pathogenic gene mutations have been identified in China, accounting for about 80% of the phenylalanine hydroxylase mutation genes in China, and have been successfully used for mutation detection and prenatal diagnosis of PKU patients.

(3) X-ray examination shows microcephaly, CT and MRI can find non-specific changes such as diffuse cerebral cortex atrophy.

Differential diagnosis of phenylketonuria

Classical and cofactor deficiency-induced PKU patients have hyperphenylalanineemia, but those with hyperphenylalanineemia do not necessarily cause PKU, so PKU should be distinguished from other hyperphenylalanineemia patients .

Phenylketonuria treatment

Once the diagnosis is clear, active treatment should be given as soon as possible, mainly diet therapy. The younger the age at which to begin treatment, the better the results.

Low phenylalanine diet

It is mainly suitable for patients with typical PKU and blood phenylalanine continuously higher than 1.22mmol / L (20mg / dl). Because phenylalanine is an essential amino acid for protein synthesis, it can also cause nervous system damage when it is completely lacking. Therefore, infants can be given a special low-phenylalanine milk powder. When supplementary food is added in early childhood, starch, vegetables, Low-protein foods, such as fruits, are predominant. The amount of phenylalanine required is about 50 to 70 mg / (kg · d) within two months, about 40 mg / (kg · d) within three to six months, and about 25 to 30 mg / (kg · d) at the age of two. For those over 4 years old, about 10-30 mg / (kg · d), it is better to maintain the concentration of phenylalanine in the blood at 0.12-0.6 mmol / L (2-10 mg / dl). Diet control needs to last at least after puberty.

The purpose of diet therapy is to keep phenylalanine in the blood at 0.24 to 0.6 mmol / L. Children can be fed with low phenylalanine foods, supplemented with breast milk and milk. Each 100 ml of breast milk contains about 40 mg of phenylalanine, and each 30 ml of milk contains 50 mg. Special foods that limit phenylalanine intake are expensive and difficult to handle. As for when the dietary treatment that restricts phenylalanine intake in the diet can be stopped, there is no unified opinion so far, and it is generally believed that it should be maintained for 10 years. While limiting phenylalanine intake to dietary treatment, supplement tyrosine or replace the diet with tyrosine supplementation. Dietary supplementation of tyrosine can restore hair pigment loss to normal, but has no effect on intellectual progress. During dietary treatment that restricts phenylalanine intake, children's growth and nutritional status, as well as blood phenylalanine levels and side effects should be closely observed. Side effects are mainly other nutritional deficiencies, such as diarrhea, anemia (large cell), hypoglycemia, hypoproteinemia, and niacin-like rash.

2.BH4, serotonin and L-DOPA

It is mainly used for BH4-deficient PKU. Such medications should be given in addition to diet control.

Phenylketonuria prevention

Avoid close relatives getting married. Carry out newborn screening to detect early and treat early. For pregnant women with a family history of this disease, prenatal diagnosis of their fetus must be performed by DNA analysis or detection of amniotic fluid.