Phenylketonuria PKU

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Phenylketonuria (PKU)

• Winnie Kuo
• ROP Biotechnology B
• Period 2

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Definition

• A genetic disorder characterized by an inability
  of the body to metabolize the essential amino
  acid, phenylalanine.
• Essential amino acid can only be obtained from
  food we consume, not synthesized by the body.
• Phenylalanine amino acid normally found in the
  brain.

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Causes

• A tiny mutation in a single gene on chromosome
  12.
• This gene, called PAH, contains instructions for
  making the PAH enzyme, a.k.a. phenylalanine
  hydroxylase.
• ONE single mutation in the PAH gene changes the
  shape of the enzyme.

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• Different mutations have different effects. Some
  mutations change the shape of the enzyme so that
  it doesnt recognize phenylalanine any more, thus
  no transformation to tyrosine.

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Classic PKU

• The enzyme that breaks down phenylalanine,
  phenylalanine hydroxylase, is completely or
  nearly completely deficient.

(Enzyme normally converts phenylalanine to
another amino acid, tyrosine.)
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• Normal blood phenylalanine level 1 mg/dl.
• Classic PKU blood phenylalanine level 6
  80mg/dl
• High concentration of phenylalanine can be toxic
  (or lethal) . scientists are still not sure why
  it is so.

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Hyperphenylalaninemia

• Use to describe a group of disorders other than
  classic, less common than classic.
• Disorders may be caused by a partial deficiency
  of the phenylalanine breakdown enzyme or the lack
  of another enzyme important to the processing of
  this amino acid.
• Phenylalanine levels somewhat lower than classic.

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Inheritance

• Affects about 1 out of every 10,000 to 20,000
  Caucasian or Oriental births. Very rare in
  African Americans.
• Equally frequent in both males and females.
• Recessive gene must be inherited from both
  parents.

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Symptoms

• Carriers (heterozygous) have no symptoms.
• Infants with PKU appear normal at birth.
• 50 of untreated infants have early symptoms.
• Child with undetected PKU may have a smaller than
  normal head, epilepsy, and mental retardation.
• Excess phenylalanine in skin creates musty odor,
  and a deficiency in tyrosine leads to lighter
  skin (fair skin) and hair.

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Testing Screening

• Symptoms of untreated PKU are avoided, in
  developed countries, by newborn screening, early
  identification, and management.
• Newborn babies are screened for high levels of
  phenylalanine in their blood at about 3 days of
  age.
• Since the same symptoms appear for the deficiency
  of another protein, BH4, further blood tests must
  be conducted to determine the cause of the high
  level.

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Treatment

• Children with PKU must adhere to low-protein diet
  as soon as the disease is diagnosed, and stay on
  the diet for as long as possible.
• To readjust to the PKU diet after a period of
  'relaxation' (regular diet) is difficult.
• Therefore, experts recommend patients to diet
  for life.
• Periodic phenylalanine blood level measurement
  and consult with a nutritionist will help to
  maintain the level of phenylalanine in a
  desirable range.

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Special Condition - Pregancy

• Women with PKU of child bearing age should adhere
  closely to the low-phenylalanine diet and monitor
  phenylalanine levels before conception and
  throughout pregnancy.
• The risk of spontaneous abortion, mental
  retardation, microcephaly (small head), and/or
  congenital heart disease in the child is high if
  Mother's blood phenylalanine is poorly
  controlled.

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Special Expenses

• Patients need to follow special formulas
  hundreds of dollars per month.
• Regular clinic visits.
• Recent government policy requires the insurance
  coverage of PKU, including cost of special diet
  for up to 2,500/yr.

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Limitations

• Adherence to special formula is sufficient for
  leading a normal life.

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Common foods to avoid

• All foods with high-protein content (meat, eggs,
  chicken, fish, milk and cheese)
• Aspartame (NutraSweet)
• Saccharin

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New Hopes

• A plant enzyme, phenylalanine ammonialyase has
  been found to survive in the gut of the patient
  long enough to deplete the phenylalanine derived
  from food protein and so reduce the rise in blood
  phenylalanine that would otherwise occur after a
  protein rich meal.
• Gene Therapy Two out of three basic steps
  accomplished 1) a cDNA clone expressing human
  phenylalanine hydroxylase and, 2) a phenylalanine
  hydroxylase-deficient animal model have been
  developed. However, vectors for efficient gene
  transfer in vivo have yet to be developed.

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Further explanation

• PKU News (http//www.pkunews.org/)
• Compiled list of drugs to be avoided, foods with
  low proteins, and news about the disease.
• Your Genes, Your Health (http//vector.cshl.org/yg
  yh/mason/ygyh.html?syndromepku)
• Video clips, interviews, animations.