Phenylketonuria

First, the preamble:
1, disease name:
PKU (Phenylketonuria), referred to as PKU.
2, Origin:
Dr.Folling Norway in 1934 at familial mental retardation found in the urine of patients with special triteness Taste
, Was later learned the substances are phenylketonuria (phenylpyruvic acid), which has sugar and urine sugar
Urine disease is nothing to do officially named in 1937 for phenylketonuria (phenylketonuria; PKU).
Second, epidemiological studies:
Incidence:
Phenylketonuria is currently the most common congenital genetic metabolic diseases, PKU incidence in Europe and America
For the ten thousandth, 1/30000 about our country's statistics. Europe and the United States the vast majority of PKU patients for
Food-type patients, and patients with drug-based incidence is extremely rare, Taiwan District, one of phenylketonuria due to BH4
Caused by the lack of phenylketonuria is as high as 33% ~ 45%.
Three, pathogenesis:
Heterotypic phenylketonuria (BH4 deficiency) is an autosomal recessive genetic disease of amino acid metabolic disorders
Disease.
Phenylalanine (phenylalanine) amino acids for the human body must be the main metabolic reactions of amphetamine
Acid (PHE) by phenylalanine hydroxylation (PAH), BH4 Des substances such as the role of hydroxylation of tyrosine into
(Tyrosine). Heterotypic phenylketonuria because PAH hydroxylation are required for BH4 Des
(Tetrahydrobiopterin) plane of the metabolic process happen impaired, unable to generate sufficient BH4 supply PAH
Use, resulting in phenylalanine can not be successfully converted into tyrosine, and the substantial accumulation in the body, thereby producing
Health lot of toxic metabolites. Under normal circumstances, BH4 from GTP are a series of anti -
Should be, including the GTP-Cyclohydrolase and 6-Pyruvoyltetrahydropterin Synthase (6PTS)
Such as the role of enzyme synthesis. Involved in hydroxylation of phenylalanine after hydrolysis by
Dihydropteridine Reductase DHPR restore BH4 form a network for the application cycle. BH4
Not only involved in hydroxylation of phenylalanine into tyrosine, are also involved in hydroxylation of tyrosine into DOPA and tryptophan
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(Tryptophan) hydroxylation into 5-OH Tryptophan response. One of DOPA and 5-OH
Tryptophan conductive material for the central nervous system Dopamine and serotonin pioneer material. So
If the lack of BH4 Des , then the three reactions are blocked, this time not only of high phenylalanine disease
Symptoms, but also because of the lack of central nervous conduction material, and the emergence of many neurological symptoms.
Currently known to have the following five different enzymes will cause a lack of metabolism phenylketonuria Machine impaired:
● phenylalanine hydroxylation enzyme (PAH)
● guanine nucleoside triphosphate cyclohydrolase enzyme hydrolysis (GTPCHI)
● C dione tetrahydro biopterin synthase (PTPS)
● HD-acridine Dihydroartemisinin reductase (DHPR)
● amine methanol dehydration neopterin enzyme (PCD)
Domestic common phenylketonuria has three types are as follows:
1. Phenylalanine hydroxylase (referred to as PAH) lack of phenylketonuria:
Phenylketonuria mostly belong to this type, so called "classic PKU", such a disease
Child is low-phenylalanine diet to treat, so called "diet therapy type phenylketonuria."
2. Tetrahydro neopterin Health (hereinafter referred to BH4) synthesis of a lack of coenzyme type phenylketonuria:
The lack of BH4 synthesis may be known by three different enzymes caused by a lack of domestic this type
Most of the children are 6-PTPS enzyme caused by the lack of the lack of BH4 synthesis. This type of domestic benzene
Ketone urine disease accounts for about 20% of all PKU to 30%. This type untreated phenylketonuria, the often
Severe neurological symptoms (Example: pumping bear), are given to BH4 treatment and nerve conduction to more complex
Quality (Example: L - Dopa, 5 - HTP), such as drugs, so it was commonly known as "drug therapy type benzene ketone
Urine disease. "
3. Dihydroartemisinin neopterin reductase (the DHPR) lack of phenylketonuria:
BH4 metabolism DHPR plays an important role, DHPR makes BH4 recycling not
Scarce. DHPR resulted in the lack of BH4 can not be recycled, resulting in the lack of BH4. Therefore DHPR
Lack of "BH4 synthesis of a lack of coenzyme phenylketonuria type" of a type. Treatment methods are "drink
Fresh control "and" drug "(Example: BH4 and nerve conduction to more material) a two-pronged approach, adding
Flinic acid.
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Four clinical symptoms:
1, the lack of hydroxylation enzyme alanine (PAH):
Resulted in typical phenylketonuria. Their clinical symptoms showed a yellow hair, pale skin dry and intelligent residual
Impaired sequelae.
2, the lack of guanine nucleoside triphosphate cyclohydrolase enzyme hydrolysis (Gtp cyclohydrolase I; GTPCHI), C
Dione tetrahydro biopterin synthase (6-pyruvoyl tetrahydropterin synthase; PTPS), dihydrotestosterone
HD-acridine reductase (dihydropteridine reductase; DHPR):
The lack of these three enzymes would cause either lack of BH4. Its typical clinical symptoms apart from phenylketonuria
Some of the symptoms, there are serious neurological symptoms (such as convulsions), growth retardation, easy infection.
3, chronic lack of congenital hemolytic anemia:
Although BH4 deficiencies may also result, but the clinical symptoms of mild, may not need treatment. PKU in China
Patients with about 20% ~ 30% for lack of tetrahydro Health neopterin type, with results to differ materially from those in Western countries,
The special needs of differential diagnosis in order to adopt the correct method of treatment.
Friday, diagnosis:
• PKU identified projects should include:
1, receive specialist training, as there is a pediatrician in clinical evaluation.
2, blood amino acid analysis.
3, urine organic acids by gas chromatography mass spectrometry (GC / Mass)
4, urine by high performance liquid chromatography (HPLC) quantitative neopterin (neopterin; N) and biopterin (biopterin;
B) the content, and calculate the percentage of Health neopterin ratio B% = [B / (B + N)] × 100%.
5, erythrocyte DHPR activity quantitatively.
6, BH4 oral loading test (BH4 loading test): the blood concentration of phenylalanine in the oral
BH4 (7.5 mg / kg) 4-6 hours later, down to the following 2mg/dl that case the taking of BH4
There is reaction (responsive); if no reduced phenylalanine phenomenon, namely the express cases of BH4
Taking non-response (nonresponsive).
• PKU differential diagnosis
Through the above assessment and testing, if blood phenylalanine increased, but normal or low tyrosine and urine
Medium has phenylpropanoid metabolite abnormalities ketones can be inferred by reason of PKU patients. And further identification
Cases for what type of phenylketonuria. Methods of identification are as follows:
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1, the typical PKU: B% of normal (or high), BH4 oral loading test without reaction, DHPR activity
Normal.
2, GTPCHI lack of type PKU: B% normal, but the content of N and B is very low, BH4 oral
Load test response has, DHPR activity normal.
3, PTPS or SR-type lack of PKU: B% <5%, BH4 oral loading test has reaction, DHPR
Normal activity.
4, DHPR type lack of PKU: B%> 80%, BH4 oral loading test partial response, DHPR
Activity is very low.
5, PCD type lack of PKU: high-performance liquid chromatography in the urine, there are a large number of 7 - biopterin
(7-biopterin) material.
6, treatment:
To prevent the occurrence of sequelae of PKU, except to be the right remedy, and the sooner the better therapeutic effect. Root
According to foreign literature, the treatment of patients at one month, the average IQ of 95, one to two months
Patients before treatment, the average IQ of 85; and advanced medical treatment or treatment, the average IQ
For 53-45. According to the experience of domestic and foreign literature, BH4 treatment type lack of a good prognosis, especially
Their neurological symptoms are the control and the growth and development, if that is during the neonatal period for treatment, their IQ can be
Achieve the normal standard.
PKU patients with various types of treatment are as follows:
1, the typical PKU: given the low phenylalanine diet control, so that the blood phenylalanine concentration remained at
4-8mg/dl, but we must also consider the protein, calories, such as balanced nutrition to maintain the patient's normal growth.
The longer the better diet control, at least to maintain the six-year-old. Female cases of child-bearing age should be continued until after
In order to avoid future occurrence of maternal phenylketonuria (maternal PKU), congenital disabilities caused by the next generation of middle class children
Health.
2, Des tetrahydro Health Synthesis neopterin lack of type (guanine nucleoside triphosphate cyclohydrolase enzyme hydrolysis, C HD-tetrahydro dione
Methotrexate synthetic enzyme): given BH4 (1-5 mg / kg / day), so that the blood phenylalanine concentration of at least maintained at
4mg/dL following. Because patients have neurological symptoms, have to add a pioneer in the central nervous conduction material,
L-dopa (5-15 mg / kg / day) and 5-hydroxy tryptophan (4-10 mg / kg / day),
carbidopa (1-2mg/kg/day), nerve conduction drugs are advised to add low-dose slowly up to meet the patients
Maximum tolerated volume.
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3, Dihydroartemisinin lack of HD-acridine reductase type: diet control such as "typical phenylketonuria", BH4, and the central nervous
Conduction pioneer supplementary material such as "Des tetrahydro Health neopterin synthesis lack of type", adding folinic acid.
Seven, prevention and screening:
At present, BH4 Des gene sequencing has been out of the use of molecular biology (gene mutation analysis) of
Ways, for one child up for phenylketonuria heterotypic parents and patients, its detection of defective genes,
To identify and confirm point mutations, and then in antenatal mothers (after 16 weeks of pregnancy) for amniocentesis samples
Fetal amniotic fluid cells for the detection of DNA analysis, would be effective for prenatal diagnosis, was informed that the fetus
Whether the patients.
PKU neonatal screening is to provide the best method for early diagnosis. The most effective screening methods are measured filter
Paper blood spot samples of amphetamine acid, when the concentration is higher than 2mg/dL blood should be further rehabilitation
Search. Phenylalanine concentrations continue to rise if the phenomenon, that is, there should be recognition and differential diagnosis. In the new
Period of screening babies amino acid metabolic disorders such diseases, it should be noted whether the cases had a sufficient intake
Enough protein (breast-feeding for more than 48 hours), in order to avoid the emergence of false-negative.