Phenylketonuria

1934 Norway Dr.Folling in the urine of patients with familial mental retardation were found to have a special taste stale, and later learned that the substance is phenylketonuria (phenylpyruvic acid), which and urine sugar diabetes is irrelevant, in 1937 was officially named as PKU (phenylketonuria; PKU).

Pathogenesis: Shaped phenylketonuria (BH4 deficiency) is an autosomal recessive amino acid metabolic disorders. Phenylalanine (phenylalanine) is the body's essential amino acids, the main metabolic reactions of phenylalanine (PHE) by the enzyme phenylalanine hydroxylase (PAH), BH4 cofactor role of substances such as tyrosine hydroxylase (Tyrosine). Shaped Phenylketonuria is necessary because PAH hydroxylation BH4 cofactor (Tetrahydrobiopterin) metabolic process occurs machine fails, the supply can not produce enough BH4 PAH use, resulting in phenylalanine can not be successfully converted into tyrosine, and in vivo large accumulation, and produce many toxic metabolites. In normal circumstances, BH4 is GTP through a series of reactions, including the GTP-Cyclohydrolase and 6-Pyruvoyltetrahydropterin Synthase (6PTS) the action of enzymes such as synthetic. Participation in phenylalanine hydroxylation reaction after hydrolysis by Dihydropteridine Reductase DHPR must restore BH4 form a network loop applications. BH4 only involved in phenylalanine into tyrosine hydroxylase, is also involved in tyrosine and tryptophan hydroxylation into Dopa (Tryptophan) into the 5-OH Tryptophan hydroxylation reaction. Where Dopa and 5-OH Tryptophan central nervous neurotransmitters Dopamine and Serotonin pioneer substances. Therefore, if the lack of BH4 cofactor, then the three reactions are blocked, this time there will be not only the symptoms of high phenylalanine, but also because of the lack of central nervous system neurotransmitters, and the emergence of many neurological symptoms. Now known to have the following five different enzyme deficiency causes phenylketonuria metabolic mechanisms:1 enzyme phenylalanine hydroxylase (PAH)2 guanine nucleoside triphosphate cyclization hydrolase (GTPCHI)3 propanedione tetrahydro neopterin synthase (PTPS)4 dihydrotestosterone pteridine reductase (DHPR)5 neopterin methanolamine dehydration enzyme (PCD)

Domestic common phenylketonuria There are three types as follows:1 phenylalanine hydroxylase (abbreviated PAH) lack of phenylketonuria:Phenylketonuria is mostly belong to this type, so called "classical PKU," such sick children at a low phenylalanine diet to treat, so called "therapeutic diet phenylketonuria."2 tetrahydro Health neopterin (referred BH4) deficiency type phenylketonuria coenzyme synthesis: Synthesis of BH4 deficiency may be known by three different enzyme deficiency caused by the domestic children with this type mostly 6-PTPS enzyme deficiency caused by BH4 synthesis deficiency. This type of domestic accounting for all PKU Phenylketonuria 20% to 30%. When this type of untreated phenylketonuria, often severe neurological symptoms (Example: pumping 'A'), the treatment is given to the first BH4 and nerve conduction chemotactic substance (Example: L - Dopa, 5 - HTP) and other drugs, thus It was commonly known as "drug therapy type phenylketonuria."3 dihydrotestosterone neopterin reductase (referred DHPR) deficiency phenylketonuria: BH4 metabolism DHPR play an important role, DHPR makes BH4 recycling are not scarce. BH4 deficiency causes DHPR not recycled, resulting in BH4 deficiency. Therefore, lack of DHPR "BH4-deficient synthesis of coenzyme phenylketonuria" in one type. Treatment is "diet" and "drugs" (Example: BH4 and nerve conduction first chemotactic substances) two-pronged approach, and added Folinic acid.


Clinical symptoms:
A lack of hydroxylation enzyme alanine (PAH): cause typical phenylketonuria. Show clinical symptoms of yellow hair, pale skin dryness and intelligent disability sequelae.
2, the lack of guanine nucleoside triphosphate cyclization hydrolase (Gtp cyclohydrolase I; GTPCHI), propanedione tetrahydro neopterin synthase (6-pyruvoyl tetrahydropterin synthase; PTPS), dihydrotestosterone pteridine reductase (dihydropteridine reductase; DHPR): the lack of any one of these three enzymes will cause BH4 deficiency. The clinical symptoms in addition to some of the typical symptoms of phenylketonuria, there are serious neurological symptoms (such as convulsions), growth retardation, easy to infection.
3, chronic congenital hemolytic anemia deficiency: although also cause BH4 deficiency, but clinical symptoms are mild, you may not need treatment. China's PKU patients about 20% to 30% of the students neopterin tetrahydro-deficient, and results to differ materially Western countries, the differential diagnosis of special needs in order to take proper treatment.



Diagnosis:PKU identified projects should include:1, the acceptance of the pediatrician with specialist training clinical assessment.2, blood amino acid analysis.3, the urine organic acid analysis 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 share of raw neopterin B% = [B / (B + N)] × 100%.5, erythrocyte DHPR activity quantification.6, BH4 oral loading test (BH4 loading test): the concentration of phenylalanine in the blood oral BH4 (7.5 mg / kg) 4-6 hours, the reduced 2mg/dl Hereinafter, taking the case of BH4 react ( responsive); phenylalanine completely reduced if the phenomenon, that means taking the case on BH4 no response (nonresponsive).



Differential diagnosis of PKUVia the above assessment and inspection, if elevated blood phenylalanine, tyrosine, but normal or low, and urine ketones abnormal metabolites styrene, it can be inferred for the PKU patients. And further to identify what type of case as phenylketonuria. Identification method is as follows:

1, a typical PKU: B% normal (or high), BH4 oral loading test no reaction, DHPR activity is normal.2, GTPCHI deficient PKU: B% normal, but the content is very low N and B, BH4 oral loading test responders, DHPR activity is normal.3, PTPS or SR-deficient PKU: B% <5 activity="" bh4="" br="" dhpr="" is="" loading="" normal.="" oral="" responders="" test="">4, DHPR deficient PKU: B%> 80%, BH4 loading test oral part of the reaction, DHPR activity is very low.5, PCD-deficient PKU: HPLC chromatogram in the urine, there are a lot of 7 - Biopterin (7-biopterin) substances.

Various types of treatment for PKU patients is as follows:1, a typical PKU: given a low phenylalanine diet control, so that the blood phenylalanine levels maintained at 4-8mg/dl, but also consider the protein, calories and other nutritional balance, in order to maintain the patient's normal growth. Diet as long as possible, to maintain at least six years old. Women continue to be the case even after childbearing age to avoid future occurrence of maternal phenylketonuria (maternal PKU), resulting in the generation born disabled children produce.2, auxiliary tetrahydro born neopterin synthesis deficient (guanine nucleoside triphosphate hydrolase cyclization, propanedione tetrahydro neopterin synthetase): to give BH4 (1-5 mg / kg / day), so that the blood The amphetamine acid content of at least maintained at 4mg/dL less. Because patients have neurological symptoms, should 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 should add up to a small dose slowly, in order to achieve the maximum tolerable amount of patients.
3, hydrochlorothiazide pteridine reductase deficiency type: diet control, such as a "typical phenylketonuria", BH4 and central nervous conduction pioneer supplemental materials such as "secondary raw neopterin synthesis of tetrahydro-deficient," and added folinic acid.


Talk so much, but being a pharmacist BH4 looks do you recognize?
BH4: Tetrahydrobiopterin
He has two, one is 10mg, the other one is 50mg
BH4
Special reminder, this drug is to ice Oh, and -20 degrees, otherwise it will lose activity.