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