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

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

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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.

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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

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Phenylalanine metabolic pathway

• diet protein
• phenylalanine
  hydroxylase(PAH)
• phenylalanine
  tyrosine
• 
  BH4
• 
  
• phenylpyruvic acid
• 
  
• phenyllactate phenylacetate

thyroxin
dopa
adrenaline
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• 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

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• 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

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• 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)

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• 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

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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

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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

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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

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• 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

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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

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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

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• 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
• ______________________________

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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

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