1、Phenylketonuria(PKU)Dr.Xiaoping Luo Professor and Chairman Department of Pediatrics Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyBackgroundThe most common inborn errors of amino acid metabolismCharacterized by a deficiency in the enzyme phenylalanine hydroxylase(
2、PAH)Deficiency of PAH leads to accumulation of phenylalanine(Phe)in the plasma and to excretion of phenylpyruvic acid and phenylacetic acid in the urine.Low frequencyAfrican Americans 1:50000FrequencyGeneral 4:100000 High frequency Turkey1:2600Scotland 1:5300China1:11700Finland Japan1:1000001:125000
3、(higher in northern)no gender differencePathophysiologyPathophysiologyAtypical PKUclassicalcoenzyme1BH4dopamineNAphenylalaninePAHThe metabolic pathway of phenylalanineGTP GTPCHdihydroneopterin triphosphate PTPS6-pyruvoyl-tetrahydropterin Phenylpyruvic acidadnephrinReduced coenzyme1pterin-4a-carbinol
4、amine tyrosine DOPA DOPA Quinoneq-dihydrobiopterinp-OH-phenylpyruvicindole quinonehomogentisic acidmelaninPAH:phenylalanine hydroxylase1Autosomal recessive inherited diseaseChromosome 12(12q2212q24)Length 90kb Extron 13Intron 12 Code 451AAMilestone1934 Flling discovered PKU 1947 Jervis the metabolic
5、deficiency1953 Dickel therapy with low phenylalanine milk1963 Guthrie newborn screening of PKU1983 Woo clone PKU geneClinical FeaturesNerve systemMental retardationMuscle spasm irritability,seizures Abnormal EEGActive muscle tendon reflexesClinical FeaturesNerve systemAppearanceBlue eyesFairer hair
6、and skin Seborrheic skin Lesion microcephalyInitial symptoms may include:A musty or mousy odor of the body and urineMovement disordersSlower than normal growth rateDevelopmental delays in sitting,crawling,and standingMicrocephaly(small head size)If patients remain untreated they may develop:Decrease
7、d skin and hair pigmentation(due to lack of tyrosine)EczemaHeart defects and other heart problemsBehavior problemsSeizuresProfound mental retardation2Laboratory studiesGuthrie assay(newborn screening)Ferric chloride assay(not all PKU have a positive test)Dinitrophenylhydrazine assayBlood amino acid
8、assayUrine organic acid assayUrine pterin(HPLCclassification of PKU)PAH Gene detectionay be indicated in older indivi deficits in motor or cognitiveelination are commonImaging StudiesMRICranial MRI mdualsexperiencing functionAreas of demyMRSPreliminary indications suggest that brain phenylalanine le
9、velsSome controversy surrounds whether state-of-the-art technology makes it a useful clinical tool.Diagnosisclinical features+lab studiesTypical PKU(99%)-PHA deficiency Plasma phenylalanine 20 mg/dl(1200mmol/L),Plasma tryosine level normalMetabolites of phenylalanine in urine increased Oral challeng
10、e of phenylalanineAtypical PKU(1%),up to 1015%in HPBH4 deficiency,PTS/PPH4S,DHPRTherapyThe earlier the betterPrevent or minimize brain damageMaintain the blood level of phenylalanineAge(y)Phe(mmol/L)0312024039180360912180480121618060016180900Chicken Fish Nuts CheeseStarchy foodSoft drinks that conta
11、in theoided.DietCaution:Meatartificial sweetener aspartame must be avLow phenylalanine dietAspartame contains phenylalanine and aspartic acidDrug TherapySapropterin(Kuvan),a commercial form of the biopterin cofactor 10mg/kg.d(4y)Large neutral amino acids(PreKunil or NeoPhe).(15y,refuse Low phenylala
12、nine diet)Atypical PKU:Kuvan,L-DOPA,5-HTP ContinueGene Therapy?3Investigational Treatments of PKUGene Therapy was tested out on mice.Gene therapy involves inserting genes into the non coding region of the genome so to ensure that there is no danger of interfering with other genes.Once the gene is in
13、serted,it will remain a permanent part of the cells genome.PrognosisThe outcome is good if the diet is closely followed,starting shortly after the childs birth.Severe mental retardation occurs if the disorder is untreated.Genetic counseling is recommended for prospective parents.The carrier state fo
14、r PKU can be detected by enzyme assays,and PKU can be diagnosed prenatally.It is very important that women with PKU closely follow a strict low-phe diet both before and throughout the pregnancy.2-year-old daughterIrene,PKUhusband,healthyUntreated sisterThis photo was taken at my wedding a few years
15、ago.I have PKU.I was diagnosed on the 3rd day of my life when treatment with the diet began.I stayed on the diet for 16 years.After I married and when my husband and I decided we would like to have a child,I went back on the diet before conception and I stayed on it throughout the pregnancy.Our daug
16、hter Stephanie was born without any evidence of maternal PKU effects.She is now in her second year and passing all her developmental milestones in style.The other woman in the picture is my older sister.She also has PKU but when she was born there was no newborn screening program for PKU.The diagnos
17、is of her disease was made late in her first year of life when she developed convulsions.It was too late for treatment and she has never known the benefits of early diagnosis and treatment as I know them.Our picture is on this web site so that parents of newly-diagnosed infants with PKU will have so
18、me evidence of good news.(Irene,May 1998)The girl in this picture is Stephanie,age 2 years,daughter of Irene (the bride in the wedding photo).Irene and her husband planned the pregnancy;dietary control was excellent from conception to delivery.The hazards of maternal hyperphenylalaninemia were avoid
19、ed.Stephanie has passed all developmental milestones with distinction.Maternal PKUFetal Alcohol Syndrome,XX,2007Pathophysiology of maternal PKU-SyndromeEmbryo:high phenylalanine interferes with organogenesis especially the heartNeural crest cells more vulnerable to high phe or amino acid imbalance?F
20、etus:high phenylalanine impairs brain developmentAlterations in neurotransmiter synthesis?MPKU Mouse model,Embury et al.,2005Most critical time period:8-12 weeks:peak of blood phenylalanine4IQ in Adult PKU Patients Grouped by Age at Diet Discontinuation120100806040200Adult FS IQParentsFS IQTreatment
21、 6.5 Years,n=356.5-12.5Years n=1412.5-20Years,n=12Never off Diet,n=9Koch et al.,2002ConclusionsUntreated PKU usually results in severely retarded patients with behavioral problems,dietary treatment may be beneficialLate(6 years)treated patients improve under dietary treatmentSuccess of early treatment is dependent from blood phenylalanine concentrations over timeLifelong dietary treatment is recommended even final data are not yet availableBest Outcome inEarly and Continous Good TreatmentThank You!5
