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1、Phenylketonuria PKU Dr Xiaoping Luo Professor and Chairman Department of Pediatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Background The most common inborn errors of amino acid metabolism Characterized by a deficiency in the enzyme phenylalanine hydroxy
2、lase 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 frequency African Americans 1 50000 Frequency General 4 10 0000 High frequency Turkey1 2600 Scotland 1 5300 China1 11700 Finland Japan 1 1
3、00000 1 125000 higher in northern no gender difference Pathophysiology Pathophysiology Atypical PKU classical coenzyme1BH4dopamineNA phenylalanine PAH The metabolic pathway of phenylalanine GTP GTPCH dihydroneopterin triphosphate PTPS 6 pyruvoyl tetrahydropterin Phenylpyruvic acidadnephrin Reduced c
4、oenzyme1 pterin 4a carbinolamine tyrosine DOPA DOPA Quinone q dihydrobiopterinp OH phenylpyruvicindole quinone homogentisic acidmelanin PAH phenylalanine hydroxylase 1 Autosomal recessive inherited disease Chromosome 12 12q22 12q24 Length 90kb Extron 13 Intron 12 Code 451AA Milestone 1934 F lling di
5、scovered PKU 1947 Jervis the metabolic deficiency 1953 Dickel therapy with low phenylalanine milk 1963 Guthrie newborn screening of PKU 1983 Woo clone PKU gene Clinical Features Nerve system Mental retardation Muscle spasm irritability seizures Abnormal EEG Active muscle tendon reflexes Clinical Fea
6、tures Nerve system Appearance Blue eyes Fairer hair and skin Seborrheic skin Lesion microcephaly Initial symptoms may include A musty or mousy odor of the body and urine Movement disorders Slower than normal growth rate Developmental delays in sitting crawling and standing Microcephaly small head si
7、ze If patients remain untreated they may develop Decreased skin and hair pigmentation due to lack of tyrosine Eczema Heart defects and other heart problems Behavior problems Seizures Profound mental retardation 1 Laboratory studies Guthrie assay newborn screening Ferric chloride assay not all PKU ha
8、ve a positive test Dinitrophenylhydrazine assay Blood amino acid assay Urine organic acid assay Urine pterin HPLC classification of PKU PAH Gene detection ay be indicated in older indivi deficits in motor or cognitive elination are common Imaging Studies MRI Cranial MRI mduals experiencing function
9、Areas of demy MRS Preliminary indications suggest that brain phenylalanine levels Some controversy surrounds whether state of the art technology makes it a useful clinical tool Diagnosis clinical features lab studies Typical PKU 99 PHA deficiency Plasma phenylalanine 20 mg dl 1200mmol L Plasma tryos
10、ine level normal Metabolites of phenylalanine in urine increased Oral challenge of phenylalanine Atypical PKU 1 up to 10 15 in HP BH4 deficiency PTS PPH4S DHPR Therapy The earlier the better Prevent or minimize brain damage Maintain the blood level of phenylalanine Age y Phe mmol L 0 3120 240 3 9180
11、 360 9 12180 480 12 16180 600 16180 900 Chicken Fish Nuts Cheese Starchy food Soft drinks that cont ain the oided Diet Caution Meat artificial sweetener aspartame must be av Low phenylalanine diet Aspartame contains phenylalanine and aspartic acid Drug Therapy Sapropterin Kuvan a commercial form of
12、the biopterin cofactor 10mg kg d 4y Large neutral amino acids PreKunil or NeoPhe 15y refuse Low phenylalanine diet Atypical PKU Kuvan L DOPA 5 HTP Continue Gene Therapy 1 Investigational Treatments of PKU Gene Therapy was tested out on mice Gene therapy involves inserting genes into the non coding r
13、egion of the genome so to ensure that there is no danger of interfering with other genes Once the gene is inserted it will remain a permanent part of the cell s genome Prognosis The outcome is good if the diet is closely followed starting shortly after the child s birth Severe mental retardation occ
14、urs if the disorder is untreated Genetic counseling is recommended for prospective parents The carrier state for 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 pregn
15、ancy 2 year old daughter Irene PKUhusband healthyUntreated sister This photo was taken at my wedding a few years 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 li
16、ke to have a child I went back on the diet before conception and I stayed on it throughout the pregnancy Our daughter 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 diagnosis of her disease was made late in her first year of life when she developed convulsion
