Phenylketonuria
苯丙酮尿症
Xue Fan Gu,MD,PhD
Xinhua Hospital
Shanghai Jiao Tong University School of Medicine
Inborn errors of metabolism
Overview
? 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
thyroxin
dopa
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
months of birth
? fair hair,hypopigmentation in
skin,eczema
? special odor (mouse-like)
discharged from urine,sweat
? mental retardation
? nod-like seizure or infantile
spasm
Classical PKU
? PAH activity is about 0-4.4% of normal
? Persistent elevation of Phe or its
metabolites is neurotoxic,the result is
profound intellectual handicap
? Typical PKU symptoms
? Strong positive result of urinary FeCl3
and DNPH test
? Blood Phe level is ? 1200?mol/L (?
20mg/dl)
Transient PKU
? Delay in PAH maturity
? The Phe level was ?1200?mol/L at
neonatal period
? The Phe level is gradually dropped to
normal even on free diet after 2-years
? Dietary restriction is only temporary,if
required 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 PKU
? No PKU symptoms in neonatal period
? higher Phe level in blood
? Neonatal screening program can make
diagnosis,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
days 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
D? éú ?ù ?2 2? é· 2é ?D D? ?¤3÷
2é ?a ? óê ?? ? oˉ ?é ? ?μ ?? í¨ ?a ? ?? á?
ò? ?1
D? ?t
êμ ?é êò
è? ??
?? D?
í¨ ?a
ò? ?1
1í
?ò ê?
±′ 1?
D? ??
3? éú è? ?ú
2é ?a è? ?ú
μ× ?2
μ? o°
D? ??,
3? éú è? ?ú,
μ? o°,
1 ? ? DAYS
?? á?
Laboratory findings
? Urine FeCl3 test and DNPH test used in
clinical screening for PKU
? Blood Phe measurement
? Urinary pterin analysis by HPLC
? BH4 loading test
? PAH gene analysis,common PAH gene
mutations are in exon 7 in Chinese PKUs
Treatment
? Low or free Phe milk powder was
developed in 1953
? Low-Phe diet can not only provide
proper 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
age 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,diagnose
d by NS and
treated by
local-made
low-Phe diet
苯丙酮尿症
Xue Fan Gu,MD,PhD
Xinhua Hospital
Shanghai Jiao Tong University School of Medicine
Inborn errors of metabolism
Overview
? 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
thyroxin
dopa
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
months of birth
? fair hair,hypopigmentation in
skin,eczema
? special odor (mouse-like)
discharged from urine,sweat
? mental retardation
? nod-like seizure or infantile
spasm
Classical PKU
? PAH activity is about 0-4.4% of normal
? Persistent elevation of Phe or its
metabolites is neurotoxic,the result is
profound intellectual handicap
? Typical PKU symptoms
? Strong positive result of urinary FeCl3
and DNPH test
? Blood Phe level is ? 1200?mol/L (?
20mg/dl)
Transient PKU
? Delay in PAH maturity
? The Phe level was ?1200?mol/L at
neonatal period
? The Phe level is gradually dropped to
normal even on free diet after 2-years
? Dietary restriction is only temporary,if
required 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 PKU
? No PKU symptoms in neonatal period
? higher Phe level in blood
? Neonatal screening program can make
diagnosis,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
days 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
D? éú ?ù ?2 2? é· 2é ?D D? ?¤3÷
2é ?a ? óê ?? ? oˉ ?é ? ?μ ?? í¨ ?a ? ?? á?
ò? ?1
D? ?t
êμ ?é êò
è? ??
?? D?
í¨ ?a
ò? ?1
1í
?ò ê?
±′ 1?
D? ??
3? éú è? ?ú
2é ?a è? ?ú
μ× ?2
μ? o°
D? ??,
3? éú è? ?ú,
μ? o°,
1 ? ? DAYS
?? á?
Laboratory findings
? Urine FeCl3 test and DNPH test used in
clinical screening for PKU
? Blood Phe measurement
? Urinary pterin analysis by HPLC
? BH4 loading test
? PAH gene analysis,common PAH gene
mutations are in exon 7 in Chinese PKUs
Treatment
? Low or free Phe milk powder was
developed in 1953
? Low-Phe diet can not only provide
proper 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
age 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,diagnose
d by NS and
treated by
local-made
low-Phe diet
