Phenylketonuria (Tetrahydrobiopterin deficiency)

Biochemical principles of:
Phenylalanine (phenylalanine) amino acids for the human body must be the main metabolic reactions of phenylalanine (PHE) by oxygen, phenylalanine hydroxylation (PAH), BH4 Des , and other substances into the role of tyrosine hydroxylation (Tyrosine). Heterotypic phenylketonuria because PAH hydroxylation are required for BH4 Des (Tetrahydrobiopterin) plane of the metabolic process happen impaired, unable to generate sufficient supply of PAH using BH4, resulting in phenylalanine can not be smoothly converted into tyrosine, and in vivo with substantial accumulation, which lead to many toxic metabolites, can cause serious long-term intelligence on obstacles.

Under normal circumstances, BH4 from GTP are a series of reactions, 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 back to BH4 cycle of the application to form a network. BH4 not only involved in hydroxylation of phenylalanine into tyrosine, are also involved in hydroxylation of tyrosine into DOPA and Tryptophan (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, there will be high at this time not only the symptoms of phenylalanine, but also because of the lack of central nervous conduction material, and the emergence of many neurological symptoms.


Genetic mechanisms and prenatal diagnosis:



Heterotypic phenylketonuria (BH4 deficiency) is an autosomal recessive genetic disorders of amino acid metabolism, both parents are carriers of the recessive (the Parent with a defective gene, but no clinical symptoms ), the patient must at the same time with two defective genes (by the parents each have a) only the incidence, so as long as both parents are carriers, then the next pair subtidal fetal chance for phenylketonuria patients are up to a quarter of patients with no chance of suffering from gender-neutral.

At present, BH4 Des gene sequencing has been out of the use of molecular biology (gene mutation analysis) method, for one child up for phenylketonuria heterotypic parents and patients, its detection of defective genes, to identify and confirmed gene mutation point, and then in antenatal mothers (after 16 weeks of pregnancy) for amniocentesis samples of amniotic fluid fetal cells for DNA detection analysis, would be effective for prenatal diagnosis, for patients to know whether the fetus.



Incidence:
According to literature reports, the average incidence of PKU is about one ten thousandth, but there is a lot of regional and racial differences, which were caused by the lack of BH4 phenylketonuria only 1 ~ 3%. At present, the Taiwan region is about the incidence of phenylketonuria 1/40000, which were caused by the lack of BH4 phenylketonuria is as high as 33% ~ 45%, with the western countries results to differ materially.



Confirm the diagnosis:


(A) set up a correct early diagnosis: Neonatal Screening

Clinically, the baby was born because many asymptomatic at birth of about three, four months later, the accumulation of excessive blood product of phenylalanine metabolism of toxic symptoms only slowly, has often resulted in irreversible damage. Therefore, prior to the onset of how to obtain the correct diagnosis and appropriate treatment, neonatal screening for early detection are the best way. At birth 48 hours over 24 hours after feeding, from the heel to take a small amount of blood, determination of the rate of bleeding in the amphetamine-chip samples of the acid content, when the concentration is higher than 2mg/dLblood should be further reviewed, and the concentration of phenylalanine if the phenomenon continued to rise, (higher than 4mg/dLblood) that should be carried out to confirm the diagnosis.

(B) confirmation and differential diagnosis of the Project:

1. Accepted by the specialist training there is the clinical assessment of a pediatrician.

2. Laboratory confirmation for the sub-Ways:

(1) Does the blood amino acid analysis of blood to detect blood phenylalanine and tyrosine concentrations

(2) urine analysis of organic acids by gas chromatography mass spectrometry (GC / Mass)

(3) high performance liquid chromatography quantitative urine neopterin (Neopterin) and biopterin (Biopterin), and calculate the% B = B / N + BX 100%

(4) quantitative determination of erythrocyte DHPR activity

(5) When the blood PHE> 10mg/dl, can carry out the Des BH4 loading test (BH4 loading test). Fasting given BH4 7.5mg/kg ~ 20mg/kg, 30 minutes after feeding, at 2hr, 4hr, 8hr, 24hr, 48hr were measured in blood phenylalanine concentration and proportion of urine analysis Pterins, if the value at BH4 taking PHE 4-6 hours after the resumption of normal PHE <2mg/dl, for BH4 has reactive, if not lower, compared with BH4 not reactive.

(6) BH4 deficiency Des classification:

a, if the% B of normal, and Neopterin and Biopterin content were very low, BH4 Des have the load test for the reaction, they belong to the lack of GTP-cyclohydrolase type.

b, if the% B <5, the Neopterin and high content of, BH4 Des have the load test for responders, it may belong to the absence of 6-PTS-type.

C, if the% B> 80, or normal, and high-Biopterin content, BH4 Des the load test for the partial or no response, they belong to the absence of DHPR Restore type, determination of enzyme can be used to determine the red blood cells.




Clinical symptoms:


If the substantial accumulation of phenylalanine in the body, metabolism in the human body have a lot of amphetamine after acid-related metabolites, can cause the patient's brain injury, early treatment will not have a serious mental retardation. Since the disease of the brain caused by injury are progressive in nature, so many babies born asymptomatic, at about 3-4 months after the symptoms occur only slowly. The symptoms of vomiting, skin and hair color , eczema, growth retardation, urine and body odor Khan has mycophenolate draw bear, tremor and abnormal movements. If the wait time before beginning treatment, often the brain nerve has resulted in irreparable damage to the.

Against the lack of BH4 Des type of patients, apart from the above-mentioned symptoms, but also because of the lack of BH4 to merge the central nervous system conduction material and the lack of Dopamine and serotonin, and the conduct of serious central nervous system symptoms such as muscle tension reduction, beyond the control of convulsions , severe growth retardation, infection symptoms such as easy.




Treatment and prognosis:


(1) For the lack of BH4-type patients, the restriction of dietary phenylalanine method of treatment, and can not effectively prevent the central nervous system symptoms. Single use in patients with BH4 treatment can control blood phenylalanine concentration, but not easy BH4 itself through the brain barrier and can not reach the brain for brain conduction, so that caused the lack of Dopamine and serotonin can cause intellectual and spiritual obstacles Therefore, in patients with phenylketonuria need to be complemented by special-shaped above-mentioned neurotransmitter precursors for treatment, such as: dopa (L-Dopa), HTP (5-hydroxytryptophan), etc.

(B) The principle of treatment

1, BH4 (10mg BH4 2HCl, 50mg ascorbic acid, 25mg N-acetyl-L-cysteine):

Oral BH4 (10mg/tab) to 1-5mg/kg/day dose of treatment, so that the concentration of blood phenylalanine control in the long term <2mg/dl. Medication should be an empty stomach 30 minutes before eating, not the child could be crushed after the drug dissolved in cold water mixing within 30 minutes of taking finished because of BH4 on the temperature-sensitive, is strictly prohibited when taking a hot brew Moreover due to BH4 easily and with oxygen absorption effect, it should be stored in frozen state (-20. c), the BH4 in unopened -20. Under C can be stored for more than two years, placed in sealed BH4 months at room temperature, the color will become Lunatia, but still more than 99% of the activity, but when BH4 into a dark yellow color when it no longer edible.

2,5-OH tryptophan (5-OHTP: 100mg/Oxitriptan):

After meals, oral 5-OHTP to 4-10mg/kg/day dose of treatment, to add low-dose slowly up the volume, the largest not more than the use of 10mg/kg/day, in order to avoid excessive blood pressure may be a momentary instability, gastrointestinal discomfort, such as nausea, vomiting or diarrhea and other side effects. Has the above-mentioned symptoms need arises to reduce or disable the serious symptoms when treated with steroids can be used. And shall as soon as possible contact with the specialist physician.
3, Sinemet (250mg Levodopa, 50mg Carbidopa / tab):

After meals, oral Sinemet to L-dopa 5-15mg/kg/day, Carbidopa 1-2mg/kg/day dose of treatment to low-dose slowly add up the amount of time, therefore the role of medicine quickly, so dose adjustment period should be to observe the patient's response to the efficacy and side effects, if we find that patients have cramps, trembling, restlessness of the phenomenon, it may be excessive doses, or add the results of drug too fast, if the patient has weakness, or muscle stiffness and other symptoms may arise for the amount of drugs is not enough when there is the above symptoms should contact a doctor as soon as possible with the specialist.

(C) set up the ideal blood PHE control objectives

1, BH4 synthesis lack of type (GTP cylohydrolase and 6-PTS): phe <2mg/dl

2, DHPR restore lack type: phe at 2-6mg/dl between the growth period: phe at between 2-4mg/dl