Phenylketonuria

1
Phenylketonuria

• Presented by
• Katherine Inouye (katherine.inouye_at_utoronto.ca)
• Luke Kawka (luke.kawka_at_utoronto.ca)
• Alan Li (alan.li_at_utoronto.ca)
• Diana Shin (diana.shin_at_utoronto.ca)

April 8, 2009
2
Introduction

• Single gene defect cause clinically significant
  blocks in metabolic pathways (inborn errors of
  metabolism)
• Classic form caused
• by decreased activity
• of hepatic
• phenylalanine
• hydroxylase (PAH)

http//www.bio.davidson.edu/courses/MolBio/MolStu
dents/spring2003/Kogoy/favorite.html
3
Introduction

• Autosomal recessive trait
• Incidence in Caucasians
• of 110,000 live births
• Rare variants can be due to deficiency of
  dihydropteridine reductase or defects in
  biopterine synthesis

http//www.actionbioscience.org/genomic/siegal.htm
l
4
Diagnosis

• On normal diet, affected patients develop
  hyperphenylalaninemia
• Untreated, PKU exhibits severe mental
  retardation, hyperactivity, seizures, light
  complexion, and eczema
• Newborn determine serum phenylalanine
  tyrosine levels on normal diet and by examining
  pterins in blood and urine
• Urine has mouse-like odour

5
Classic PKU

• Prenatal diagnosis of PKU possible using
  molecular methods
• Elevated serum levels of phenylalanine (gt20 mg/dL
  on regular diet)
• Normal or low serum levels of tyrosine pterins

http//commons.wikimedia.org/wiki/FileL-phenylala
nine-3D-balls.png
6
Phenylalanine Metabolism

• Human PAH gene expressed in liver
• and kidney as a monomer of 452
• amino acids
• Monomers assemble to form functional
• dimers and tetramers
• PAH normally converts phenylalanine into tyrosine
• Occurs in presence of molecular oxygen and
  catalytic amounts of tetrahydrobiopterin (BH4)

http//www.ncbi.nlm.nih.gov/books/bookres.fcgi/gnd
/PAH.gif
7
Inborn Error of Metabolism

• Over 500 mutations in the PAH gene identified
• Classical PKU associated with null alleles (gene
  deletions)
• Leads to complete or near-complete deficiency in
  PAH
• Most severe form of the disease
• Missense mutations lead to misfolding of the
  protein, producing other hyperphenylalaninemia
  phenotypes

8
Disease Presentation

• Profound retardation, microcephaly, epilepsy, and
  other neurological symptoms
• Psychiatric problems including depression,
  anxiety, and phobias
• Musty urine/body odour, eczema,
• decreased skin and hair pigmentation
• Exaggerated deep tendon reflexes,
• tremour, paraplegia/hemiplegia
• High incidence of osteopenia

http//www.dshs.state.tx.us/newborn/images/PKU_unt
reated.jpg
9
Mechanism of Pathology

• Precise pathophysiological mechanism not yet
  understood
• PAH deficiency leads to high levels of
  phenylalanine in the blood and tissues
• Tyrosine concentrations are low to normal
• High phenylalanine concentration impairs
  transport of other large neutral amino acids
  across the blood brain barrier

10
Mechanism of Pathology

• Elevated phenylalanine in the brain has a direct
  effect on several enzyme systems
• Also leads to decreased synthesis of serotonin,
  dopamine, norepinephrine

http//biochemistryquestions.wordpress.com/categor
y/amino-acid-metabolism-a/
11
Mechanism of Pathology

• Studies in PKU mice models show decreased
  cerebral protein synthesis
• Pathological studies in deceased PKU patients
  show decreased brain weight, impaired
  myelination, early myelin degradation, and lack
  of neuronal maturation
• Correlation found between high plasma
  phenylalanine levels and decreased performance on
  neuropsychologic tests of higher integrative
  functioning
• Early treatment decreases extent of pathology

12
Treatment for PKU

• Low protein diet to avoid excessive amount of
  phenylalanine (meat, chicken, fish, nuts, cheese,
  legume and dairy)
• Avoid Aspartame sweeteners with phenylalanine
  and aspartic acid
• Infants should switch to low phenylalanine baby
  formula such as Lofenalac(stay on breast milk,
  but monitor amount taken)

13
Treatment for PKU

• Use of Sapropterin (tetrahydrobiopterin BH4)
  have been shown to be useful in some patient
• Cofactor for phenylalanine hydroxylase
• Have to first determine if the patient is
  responsive to the treatment
• Use genotype or responsiveness test (initial load
  and check blood Phe level)
• Not for pregnancy and breastfeeding

14
Summary

• PKU is an inborn error of metabolism, caused by a
  defect in the gene encoding phenylalanine
  hydroxylase (PAH)
• PAH is responsible for the conversion of
  phenylalanine into tyrosine
• It is an autosomal recessive disorder causing
  hyperphenylalaninemia
• Classical PKU is caused by a complete or
  near-complete deficiency of phenylalanine
  hydroxylase activity
• Classical PKU usually associated with null
  alleles (gene deletions)
• High phenylalanine concentration impairs
  transport of other large neutral amino acids
  across the blood brain barrier
• Untreated, PKU exhibits severe mental
  retardation, hyperactivity, seizures, light
  complexion, and eczema
• Affected individuals also have decreased myelin
  formation and dopamine, norepinephrine, and
  serotonin production.
• Newborn determine serum phenylalanine
  tyrosine levels on normal diet and by examining
  pterins in blood and urine
• Avoid phenylalanine in diet (low protein and
  aspartame)
• Sapropterin might be useful for BH4 responsive
  patients

15
References

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  (BH4) in the management of phenylketonuria.
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  15863.
• Channon S et al. Effects of dietary management of
  phenylketonuria on long-term cognitive outcome.
  Arch Dis Child. 2007 92 213.
• Fiege B et al. Extended tetrahydrobiopterin
  loading test in the diagnosis of
  cofactor-responsive phenylketonuria A pilot
  study. Mol Genet Metab. 2005 86 (Suppl 1) S91.
• Gassio R et al. Cognitive functions in classic
  phenylketonuria and mild hyperphenylalaninaemia
  Experience in a paediatric population. Dev Med
  Child Neurol. 2005 47 443.
• Hoeksma M et al. Phenylketonuria High plasma
  phenylalanine decreases cerebral protein
  synthesis. Mol Genet Metab. 2009 96(4) 177-82.
• Leuzzi V et al. The pathogenesis of the white
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  spectroscopy (1H MRS) study. J Inherit Metab Dis.
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• National Institutes of Health. Phenylketonuria
  (PKU) Screening and Management. NIH Consensus
  Statement 2000.
• Pietz et al. Neurological outcome in adult
  patients with early-treated phenylketonuria. Eur
  J Pediatr. 1998 157 824-30.
• Pietz et al. Large neutral amino acids block
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• Scriver CR. The PAH gene, phenylktonuria, and
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• Weglage et al. Neurological deterioration in
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• Zeman et al. Bone mineral density in patients
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