Phenylketonuria ????? Xue Fan Gu, MD, PhD Xinhua Hospital Shanghai Jiao Tong University School of Medicine - PowerPoint PPT Presentation

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Phenylketonuria ????? Xue Fan Gu, MD, PhD Xinhua Hospital Shanghai Jiao Tong University School of Medicine

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Title: Phenylketonuria ????? Xue Fan Gu, MD, PhD Xinhua Hospital Shanghai Jiao Tong University School of Medicine


1
Phenylketonuria????? Xue Fan Gu, MD, PhD
Xinhua Hospital Shanghai Jiao Tong University
School of Medicine

2
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.

3

Phenylketonuria
  • 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

4
Phenylalanine metabolic pathway
  • diet protein
  • phenylalanine
    hydroxylase(PAH)
  • phenylalanine
    tyrosine

  • BH4

  • phenylpyruvic acid

  • phenyllactate phenylacetate

thyroxin
dopa
adrenaline
5
  • 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

6
  • 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

7
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8
  • 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)

9
  • 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

10
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

11

12
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

13
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

14
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15
  • 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

16
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

17
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

18
  • Control range of blood Phe level in different
    age for treated PKU/HPA
  • Age(Y) phe level(?mol/L)
  • _____________________________
  • 03 120240
  • 38 180360
  • 813 180480
  • 1318 180600
  • gt18 180900
  • ______________________________

19
Treatment for BH4D
  • To control Phe concentration lt120 ?mol/L
  • BH4 tablet 210mg.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

20

PKU patients at the 2 years old
untreated patient daignosed by NS and
treated
21
M469 4-year old,diagnosed by NS and treated by
local-made low-Phe diet
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