Download - Inborn errors of metabolism
Phenylketonuria苯丙酮尿症
Xue Fan Gu, MD, PhD
Xinhua Hospital
Shanghai Jiao Tong University School of Medicine
Inborn errors of metabolismOverview
• Disorders in which defects of single gene cause clinically significant blocks in metabolic pathways
• Many kinds of disorders
• Lower incidence
• Clinical manifestations vary widely: mental retardation, seizure, hypotonia, failure to thrive, vomiting/anorexia, special odor, hypoglycemia, hyperammonemia, metabolic acidosis, elevated lactate/pyruvate etc.
An autosomal recessive disease
The incidence of PKU in China is about 1/11 800
The incidence of PKU in Shanghai is about 1/16 000
Phenylketonuria
Phenylalanine metabolic
pathway diet protein
phenylalanine hydroxylase(PAH)
phenylalanine tyrosine BH4
phenylpyruvic acid
phenyllactate phenylacetate
thyroxindopa
adrenaline
Biosynthesis and regeneration of tetrahydrobiopterin
Guanosine triphosphate ( GTP ) GTPch p35
Neopterin Dihydroneopterin triphosphate
(N) PTPS - +
6-Pyruvoyl-tetrahydropterin SR Phe Tyrosine Tryptophan tetrahydropterin(BH4)
DHPR PAH TH TPH
PCD
q-dihydrobiopterin(BH2) pterin- Try L-DOPA 5-OH-Tryptophan 4a-carbinolamine
biopterin (B) Dopamine serotonin
Clinical manifestations• to appear symptoms after 3 mont
hs of birth• fair hair, hypopigmentation in ski
n, eczema• special odor (mouse-like) dischar
ged from urine,sweat• mental retardation• nod-like seizure or infantile spas
m
Classical PKU PAH activity is about 0-4.4% of normal Persistent elevation of Phe or its metab
olites is neurotoxic, the result is profound intellectual handicap
Typical PKU symptoms Strong positive result of urinary FeCl3 a
nd DNPH test Blood Phe level is 1200mol/L ( 20
mg/dl)
Transient PKU
Delay in PAH maturityThe Phe level was 1200mol/L at neona
tal periodThe Phe level is gradually dropped to nor
mal even on free diet after 2-yearsDietary restriction is only temporary, if r
equired at all
Differential diagnosis Tetrahydrobiopterin deficiency ( BH4D )
• Deficiency of PAH cofactor -- BH4
• 6-Pyruvoyl-tetrahydropterin synthese (PTPS) deficiency is the most common of BH4D
• The incidence of BH4D is 10% among HPA patients in Chinese
• The blood Phe is slightly increased at early stage in most patients
• Some cases were missdiagnosed as having PAH deficiency
Neonatal Screening for PKUNo PKU symptoms in neonatal periodhigher Phe level in blood Neonatal screening program can make dia
gnosis, treatment earlier and prevent mental retardation
NS program has been carried out in China since 1981
Neonatal Screening method
Subject : • Newborns who should be breast-fed for 3 d
ays after birth
• Method of Phe determination on Guthrie cardby bacterial inhibition assay (semi-quantity) or fluorescence analysis, the positive cut off of Phe is 120umol/L
新生儿疾病筛查中心工作采血邮寄化验结果通知治疗
医 院
信 件
实 验 室
如 果
阳 性
通 知医 院和家 属
编号
姓名
出生日期
采血日期
地址
电话
姓名 :
出生日期:
电话 :
DAYS
治疗
Laboratory findings
Urine FeCl3 test and DNPH test used in clinical screening for PKU
Blood Phe measurement Urinary pterin analysis by HPLCBH4 loading test
PAH gene analysis, common PAH gene mutations are in exon 7 in Chinese PKUs
TreatmentLow or free Phe milk powder was develo
ped in 1953Low-Phe diet can not only provide prope
r protein, but also reduce the Phe taking
Phe restriction should be continued at least 18 years old or throughout life
Female patients must be treated before and whole pregnancy to avoid maternal PKU
The series products of low-Phe diet
Milk powder
• component: Protein 15%, Fat 8%,CHO 68%
• two kinds of:
free Phe formula
low-Phe formula
• Flour,Biscuitpure,aminoacid powder
Control range of blood Phe level in different a
ge for treated PKU/HPA
Age ( Y ) phe level ( mol/L ) _____________________________
0 ~ 3 120 ~ 240
3 ~ 8 180 ~ 360
8 ~ 13 180 ~ 480
13 ~ 18 180 ~ 600 >18 180 ~ 900 ______________________________
Treatment for BH4D
•To control Phe concentration <120 mol/L BH4 tablet 2 ~ 10mg.Kg-1.d-1
•to improve neurological symptoms L-DOPA/ Carbidopa 5-15mg.Kg-1.d-1
5-hydroxytryptophan 5-10mg.Kg-1.d-1
•Patient with DHPR deficiency should be treated with BH4(20mg.Kg-1.d-1) and given folic acid(10-20mg/d) as well as neurotransmitte precursors
PKU patients at the 2 years old untreated patient daignosed by NS and treated
M469 4-year old,diagnosed by NS and treated by local-made low-Phe diet