PKU (Phenylketonuria, PKU) FAQ

Prenatal diagnosisQ * Will phenylketonuria at check-check it out when you can do?A * due to congenital anomalies are many reasons, there is not no family history of the disease for all congenital fetal anomaly detection, unless you already know someone in phenylketonuria patients and found mutations on the gene location, is it possible to provide for your baby prenatal check phenylketonuria. We recommend that you can be close to genetic counseling centers for further consultation.
 Newborn ScreeningQ * as told by hospitals to report suspected suffering from phenylketonuria newborn screening is required again to re-examination. I ask you:1 to the current screening devices or whether the process will be errors or mistakes?(2) the domestic positive initial screening out the false positive probability is about how much?3 again after re-examination to determine the probability of positive or what percentage?4, such as whether poor neonatal liver can also cause metabolic initial inspection is positive?5 Because twenty-three days before breastfeeding posture, resulting in baby milk supply is very limited indeed absorbed (Unknown inspection required before breast-feeding full 48 hours), whether this will result in an initial inspection of the results of this generation?A * newborn screening for phenylketonuria positive cases may be due to liver dysfunction caused by a temporary increase in the concentration of phenylalanine, or because of congenital metabolic enzyme phenylalanine deficiency leads to high amphetamine acidosis (Hyperphenylalaninemia) and therefore need further referral. National Taiwan University Hospital, 93-94 years of experience, into the re-examination work (to be taken a second blood films) of every hundred, about 42 people identified as high amphetamine acidosis, as to enter the confirmation operation (subject to the hospital do confirm the diagnosis) of eight people, eight were identified as high amphetamine acidosis. We understand the concerns of parents, suggests that parents work with the re-examination, re-examination report on the results the first patient is appropriate.Q * I am a patient suspected positive phenylketonuria families, children born in March after screening three values ​​are 2.0 times, to the hospital after re-examination, in May back to hospital that blood is normal, but the urine for drug type. Will Since normal blood, which means that phenylketonuria insufficient concentration, why urine value will be high? Typical phenylketonuria do this count? Newborn blood screening that they represent what? Altogether in order to judge the urine like, why 2.0 or less normal blood, it is determined as abnormal?A * Since we do not see your child's urine test results, so no way of knowing the exact situation. In general, newborn screening is to look at the value of phenylalanine in the blood is increased, if the rising phenomenon, which means that phenylalanine metabolism pathway hinder it. But phenylalanine metabolic pathway obstruction causes, there may be metabolic enzyme phenylalanine itself wrong, or this enzyme cofactor manufacturing problems, also, or the child's liver enzymes metabolize the amino acids in the neonatal period not yet mature due. Urine test is usually producing coenzyme order to identify whether there is a problem in the differential diagnosis of which is an important examination. Fortunately, your child amphetamine acid is not high, may represent your child if coenzyme metabolic pathway is not very smooth, but for kids the body's metabolism of phenylalanine, pretty enough, but when in poor physical condition, such as illness cold time, will have to check whether there is a rising phenylalanine phenomenon. Recommend that you check again urine, and confirm the status of coenzyme metabolic pathways, if you have additional questions, please communicate with your physician for further discussion.
 TreatmentQ * Will be judged if the newborn is typical PKU, whether it may be false positive? Do they need to re-examine? May heal you grow up? Do a liver transplant can cure? Way to cure the current classic PKU What?A * If the newborn screening found to have abnormal increase in phenylalanine will then notify the confirmation and differential diagnosis to receive specialist clinical assessment, and blood and urine tests and analysis related to the content of amino acids, and will then conducted a number of inspections to step into a distinction is typical (PAH deficiency) or drug type (BH4 deficiency) in patients with phenylketonuria. PKU is autosomal recessive congenital metabolic disorders, growth will not be healed, if recognized as patients receiving early dietary protein restriction therapy, can have good results. Current clinical liver transplantation as a treatment is not the way, if the examination and treatment of the doubt, and then discussed with the attending physician.
 Disease CareQ * Can I ask, what factors will cause PKU disease in children speaking and walking road barriers, as well as lighter hair color and a musty causes it?A * You mentioned symptoms associated with PKU is associated with in vivo phenylalanine (phenylalanine; Phe) value is too high for, but if the amount of this amino acid in the body control is good, there will not be mentioned in your Symptoms produced, Thank you for your letter.Q * Will the current prognosis of PKU in Taiwan?A * PKU patients by the lack of an enzyme can be divided into PAH deficiency (treatment depends mainly on diet control), and BH4 deficiency (treatment comprising administering BH4, may need to be controlled with diet to achieve the desired concentration of phenylalanine in the blood). At present, due to the implementation of newborn screening, and PKU patients can get early diagnosis and treatment, so most of them can have good growth and development and academic performance.

Phenylketonuria, PKU

Phenylketonuria (PKU) is an autosomal recessive genetic disease, mainly due to the body phenylalanine (phenylalanine; Phe) hydroxylation (hydroxylation) into tyrosine (tyrosine; Tyr) machines impaired metabolic pathway caused congenital metabolic disorders . There are five different enzymes are known to be the cause of such a lack of metabolic machine failure; these include: phenylalanine hydroxylase enzyme (phenylalanine
hydroxylase; PAH), guanine nucleoside triphosphate cyclization hydrolase (Gtp cyclohydrolase I; GTPCHI), propanedione tetrahydro neopterin synthase (6-pyruvoyl tetrahydropterin synthase; PTPS), dihydrotestosterone pteridine reductase (dihydropteridine reductase; DHPR) and neopterin methanol amine dewatering enzyme (pterin-4 -carbinolamine dehydratase; PCD). Different according to their deficiency, have different clinical symptoms and diagnostic methods, the treatment method is not the same.
Because aspartame contains phenylalanine, so containing this sweetener (E950 and E951) drinks (example: Coca-Cola zero) are not suitable for patients with phenylketonuria drinking.
Patients with liver phenylalanine hydroxylase deficiency, making dietary phenylalanine can not be converted to tyrosine, phenylalanine, resulting in accumulation within the brain, the role of transaminase into phenylketonuria, thus affecting the patient brain development, causing mental retardation and epilepsy, and to patients with skin bleaching, hair yellow, smell a rat urine and other symptoms.

Phenylketonuria,PKU

Etiology:High amphetamine acidosis (Hyperphenylalaninemia), also known as PKU (phenylketonuria), is an autosomal recessive genetic disease, mainly due to the body phenylalanine (phenylalanine; Phe) hydroxylation (hydroxylation) into tyrosine (tyrosine ; Tyr) metabolic pathways of local failure caused by congenital metabolic disorders. There are five different enzymes are known to be the cause of such a lack of metabolic barrier according to their lack of different machines, different clinical symptoms and diagnosis, the treatment methods are not the same.
Five different enzymesPhenylalanine hydroxylase enzyme Phenylalanine hydroxylase / PAH PAH deficiencyGuanine nucleoside triphosphate hydrolase cyclization Gtp cyclohydrolase I / GTPCHI BH4 deficiencyPropanedione tetrahydro neopterin synthesis enzyme 6-pyruvoyl tetrahydropterin synthase / PTPS BH4 deficiencyHydrochlorothiazide pteridine reductase dihydropteridine reductase / DHPR BH4 deficiencyNeopterin methanolamine dehydrated enzyme pterin-4-carbinolamine dehydratase / PCD BH4 deficiencyIncidence:Europe and the United States occur in approximately ten thousandth, eight hundred and seventy thousand domestic newborn screening results show that the incidence is about 1/34000.
Genetic model:Is an autosomal recessive genetic disease, the parents each with a mutated gene, but no clinical symptoms were due to be called with. Patients themselves must be the same time with two mutant genes (by the parents each get a mutated gene) before onset; as long as both parents are carriers, then each tire gender birth disease probability is 1/4 .
Clinical features:Patients because they can not metabolize food protein contains phenylalanine, resulting in the accumulation of phenylalanine in the blood, and thus the infant or child's brain and central nervous system, causing permanent damage, resulting in mental retardation. If diagnosed early, giving last a lifetime diet, can effectively prevent mental retardation issue. According to foreign reports in the literature of patients treated within one month, the average IQ of 95, one to two months before the treatment of the patients, with an average IQ of 85; rather late treated or untreated, their average IQ of 53-45 . The first enzyme phenylalanine hydroxylase (PAH) deficiency: The most common cause typical phenylketonuriaShow clinical symptoms of yellow hair, pale skin dryness and intelligent disability sequelae. PKU patients in Europe and America about 98 ~ 99% for this type of domestic PKU patients only about 70 to 80% of patients with this type.The second to the fifth cause lack of phenylalanine into tyrosine hydroxylase coenzyme necessary when methotrexate tetrahydro Health (tetrahydrobiopterin; BH4) deficiencyThe clinical symptoms in addition to some of the typical symptoms of phenylketonuria, there are strict kind of neurological symptoms (such as convulsions), growth retardation, easy to infection. China's PKU patients about 20% to 30% of the students neopterin tetrahydro-deficient, the special needs of the differential diagnosis in order to take proper treatment.
Diagnosis:Newborn screening filter paper blood spots were measured specimen phenylalanine levels, when the concentration is higher than 120 mM blood should further review, phenylalanine concentrations continue to rise if the phenomenon, which should be recognized and differential diagnosis. Also screening in the neonatal period such amino acid metabolism, the need to pay attention to whether the case has been getting enough protein (feeding more than 48 hours), in order to avoid the generation of false negatives.Positive cases may be due to liver dysfunction caused by a temporary increase in the concentration of phenylalanine, or because of congenital metabolic enzyme phenylalanine deficiency leads to high amphetamine acidosis (Hyperphenylalaninemia), thus further confirm the diagnosis. Confirm the diagnosis in addition to the clinical assessment of pediatric specialist outside laboratory confirmation method for the analysis of blood and urine related to the content of amino acids, and the need to tie in with other related analysis to confirm the diagnosis.Distinguish between patients with PAH deficiency or lack of BH4 methods include oral BH4 loading test (BH4 loading test), neopterin urine (urine pterin) analysis neurotransmitters cerebrospinal fluid (CSF neurotransmitter) analysis, quantification of erythrocyte DHPR activity. Oral BH4 loading test was monitored after oral BH4 concentration of phenylalanine in the blood is decreased, and if more than 30% decline, it means taking the case on BH4 responsive (responsive), may consider the use of oral BH4 treatment. However, this test need blood once every two hours, so be patient way to detect better.
Treatment:Without early treatment will result in severe mental retardation, so the damage to the brain disease is progressive in nature, and therefore more asymptomatic newborn babies, about 3 to 4 months or so symptoms will slowly appear. The sooner the better therapeutic effect, according to foreign reports in the literature that patients treated within a month, the average IQ of 95,1 ~ 2 months before treatment of patients with an average IQ of 85; while receiving treatment or therapy of advanced , their average IQ of 53-45. PAH-deficient patients in the neonatal period begins when a good diet, then IQ is different from normal people, and the growth is completely unaffected. BH4-deficient patients also suggested to be added in the neonatal period began to accept the treatment of central nervous conduction precursor substances.Patients received dietary or drug treatment, requiring regular ISR growth and development, intellectual development, blood and other essential amino acids phenylalanine concentration to confirm whether diet or medication appropriate. If caught and treated early, you can avoid the complications of mental retardation.

PAH deficiency / classic phenylketonuria (food type)Treatment depends mainly on diet control, and strictly limit the intake of phenylalanine, therefore need under the direction of a physician or nutritionist, eating a small amount of baby milk formula or a general after the age of a low-protein diet, and with a special formula milk (milk without phenylalanine ) replenish amino acids necessary to maintain normal growth and physiological functions.
Need to last a lifetime diet, female patients of childbearing age should be more strictly controlled to avoid maternal phenylketonuria (maternal PKU), resulting in the generation born disabled children produce. Some cases can be helped by medication, a slight relaxation diet, has reached more humane treatment goals and better prognosis.
BH4 deficiency (medication type)Treatment includes giving BH4 (1-5 mg / kg / day), may need to be controlled with diet has achieved the desired concentration of phenylalanine in the blood and central nervous conduction pioneer supplementary substances, including L-dopa and 5-hydroxy tryptophan. For DHPR deficient patients required additional supplementary Folinic acid.

Prognosis:Precautions everyday lifeIf the value of the U.S. youth revolt of the patient, often different from many people wanting his peers, so give diet therapy and companions started eating the same food, the cause of many behavioral deviations, even if during this period some patients pregnancy, will produce very serious deformity children.So we need to help these suffering children, to understand and to give them timely encouragement and support to assist them survive; Because patients can eat extremely limited, and special milk tastes really hard to swallow. This disease has now developed a number of low-phenylalanine foods for patients with this disease, but few domestic manufacturers are willing to import these foods, because the patient is small and low profits, while the vast majority of families also can not afford these expensive costs, hope that these patients can take control of their diet, it is a bit reluctant.

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.