Neonatal Screening from Molecules to Ethics

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Neonatal Screening from Molecules to Ethics

• Janel Hanmer
• MD/PhD Candidate
• April 11, 2006

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Guthrie Test

• Phenylketonuria

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Guthrie Test

• Phenylketonuria
• 1962, Robert Guthrie

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Basic Ethical Principles of Screening

• The genetic disorder is serious
• The test is accurate
• There is available therapy
• The cost is proportional to the benefit
• No unreasonable burden was to fall on those
  falsely identified as ill or on those individuals
  who were screened but were found not to be
  affected

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Possible screening tests

• Glucose-6-phosphate dehydrogenase deficiency
  (G6PD)
• Sickle cell anemia (Hb SS) gt 1 in 5,000 among
  African-Americans 1 in 400
• Sickle-cell disease (Hb S/C) gt 1 in 25,000
• Hb S/Beta-Thalassemia (Hb S/Th) gt 1 in 50,000
• Tyrosinemia I (TYR I) lt 1 in 100,000
• Tyrosinemia II
• Argininemia
• Argininosuccinic aciduria (ASA) lt 1 in 100,000
• Citrullinemia (CIT) lt 1 in 100,000
• Phenylketonuria (PKU) gt 1 in 25,000
• Maple syrup urine disease (MSUD) lt 1 in 100,000
• Homocystinuria (HCY) lt 1 in 100,000
• Glutaric acidemia type I (GA I) gt 1 in 75,000
• Glutaric acidemia type II
• HHH syndrome (Hyperammonemia, hyperornithinemia,
  homocitrullinuria syndrome)
• Hydroxymethylglutaryl lyase deficiency (HMG) lt 1
  in 100,000
• Isovaleric acidemia (IVA) lt 1 in 100,000

• Beta-ketothiolase deficiency (BKT) lt 1 in 100,000
• Propionic acidemia (PROP) gt 1 in 75,000
• Adenosylcobalamin synthesis defects
• Multiple-CoA carboxylase deficiency (MCD) lt 1 in
  100,000
• Carnitine palmityl transferase deficiency type 2
  (CPT)
• Long-chain acyl-CoA dehydrogenase deficiency
  (LCAD)
• Long-chain hydroxyacyl-CoA dehydrogenase
  deficiency (LCHAD) gt 1 in 75,000
• Short-chain acyl-CoA dehydrogenase deficiency
  (SCAD)
• Short-chain hydroxy Acyl-CoA dehydrogenase
  deficiency (SCHAD)
• Medium-chain acyl-CoA dehydrogenase deficiency
  (MCAD) gt 1 in 25,000
• Very-long-chain acyl-CoA dehydrogenase deficiency
  (VLCAD) gt 1 in 75,000
• Carnitine/acylcarnitine Translocase Deficiency
  (Translocase)
• Multiple acyl-CoA dehydrogenase deficiency (MADD)
• Trifunctional protein deficiency (TFP) lt 1 in
  100,000
• Carnitine uptake defect (CUD) lt 1 in 100,000
• Congenital toxoplasmosis
• HIV

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Current National Neonatal Screening

• Congenital hypothyroidism
• Phenylketonuria/hyperphenylalaninemia
• Transferase deficient galactosemia
• Hearing

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Sickle Cell Anemia Origins
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Population Genetics

• A recessive condition
• In African-Americans, 1 in 11 is a carrier and1
  in 500 has sickle cell disease

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Molecular Basis
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Normal Hemoglobin Structure
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Change in Hemoglobin Structure
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Normal Red Blood Cell Development (Erythropoiesis
)
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What goes wrong?
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Physiological consequences of sickled red blood
cells

• Anemia
• Pain
• Swollen hands and feet
• Jaundice
• Frequent infections
• Stunted growth
• Vision problems
• Organ failure

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Was this a good choice for screening?

• There is neonatal sickle cell screening in 41
  states.
• We now have prophylactic treatment for sickle
  cell anemia.

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What went wrong

• Indirect paternity testing
• Limited benefit and other pressing needs
• Poor public education trait vs. disease
• Discrimination in jobs
• Discrimination in insurance
• Compare to Thalassemia in Cyprus.

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Revisiting the Ethics of Screening
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The genetic disorder is serious

• How should we define disease?
• What about a serious late-onset disorder?
• Polycystic kidney disease
• p53 mutations
• Huntingtons disease

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The test is accurate

• How accurate is accurate?
• Cystic fibrosis
• Will DNA chips resolve this issue?

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A therapy is available

• How will we ever develop therapies if we do not
  identify individuals with disorders?

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The cost is proportional to the benefit

• Screening may become very, very cheap.
• There are psychological as well as economic costs
  associated with screening.
• Anxiety
• Bonding with children

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No unreasonable burden

• Discrimination in insurance
• Discrimination in employment
• Eugenics
• Sense of determinism
• What about relatives?
• How can we educate the public?

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Thank you!

• I look forward to you questions.