Galactosemia

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Galactosemia

• PHM226 Presentation
• 5 March 2008
• Anne Wilbur, Brenna Hanwell,
• Saeed Tavakoli and Sassha Orser

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What is Galactose?

• Galactose is a sugar that is found in many foods.
• Lactose is a sugar that is found in many foods.
  When lactose is broken down in the body, glucose
  and galactose are produced.
• Foods that contain galactose and lactose include
  fruits, vegetables, legumes, organ meats,
  processed meats and sandwich meats, milk and
  dairy products, coffee

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What is Galactose?
Glucose
Lactose
Galactose
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What is Galactosemia?

• Galactosemia is an inherited metabolic disorder
  that is caused by impaired metabolism of
  a-D-galactose in the body
• The most common form of galactosemia is caused by
  deficiency in GALT. The incidence of this form is
  1/30,000 to 1/60,000 live-births. This is also
  the most clinically severe form of the disease.

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Galactose Metabolism - Leloir
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Galactose Metabolism - Leloir

• a-D-galactose is metabolized in species ranging
  from E.coli to humans
• predominantly metabolized through the Leloir
  Pathway which involves three enzymes
• Galactokinase (GALK) phosphorylates
  a-D-galactose to produce gal-1-P
• Galactose-1-phosphate uridylyl transferase
  (GALT) transfers UMP from UDP-glucose to gal-1-P
  to release glucose 1-phosphate and produce
  UDP-galactose
• UDP-galactose 4-epimerase (GALE) interconverts
  UDP-galactose and UDP-glucose
• Deficiency of any one of these enzymes can lead
  to a form of galactosemia
• Classical galactosemia is caused by profound
  impairment of the GALT enzyme

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Galactose Metabolism - Alternate
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Galactose Metabolism - Alternate

• There are also three non-Leloir enzymes involved
  in the metabolism of galactose
• Conversion of galactose to UDP-glucose by the
  sequential activities of GALK, UDP-glucose/galacto
  se pyrophosphorlyase (UGP) and GALE
• Reduction of galactose to galactitol by aldose
  reductase
• Oxidation of galactose to galactonate by
  galactose dehydrogenase
• Under normal circumstances the non-Leloir enzymes
  metabolize minimal amounts of galactose but with
  failure of the Leloir pathway these alternative
  pathways may become more significant
• These alternative pathways may
• Limit accumulation of toxic intermediates
• Cause accumulation of other end products that are
  also problematic

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Pathophysiology

• Abnormal production and accumulation and/or
  depletion of specific metabolites leads to the
  characteristic symptoms of galactosemia
• Galactose
• Galactose-1-phosphate (gal-1-P)
• Galactitol (accumulation in lens cells leads to
  cataracts)
• Inositol
• Galactonate (does not accumulate in tissue due to
  excretion in urine)
• UDP-galactose (partially depleted in RBCs)

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Signs Symptoms

• At birth, galactosemia is usually asymptomatic.
• Escalating symptoms develop after exposure to a
  milk-based diet.
• Symptoms include vomiting, diarrhea, cataracts,
  hepatomegaly, and E. coli sepsis. Without
  treatment, these symptoms can lead to neonatal
  death.
• Even with treatment, long-term complications such
  as speech and cognitive disabilities in 30-50 of
  patients, primary or premature ovarian failure in
  85 of females, ataxic neurologic disease,
  delayed growth and decreased bone density can
  occur.

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Signs Symptoms
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Diagnosis

• Prenatal diagnosis by direct measurement of the
  enzyme galactose-1-phosphate uridylyl transferase
  
• The presence of "reducing substances" in the
  infant's urine with normal or low blood sugar
  while the infant is being fed breast milk or a
  formula containing lactose. A simple test on the
  urine indicates the presence of a reducing
  substance, and a specific enzymatic study on the
  urine can prove the substance to be galactose.
• Normal range for Galactose-1-phosphate uridylyl
  transferase is18.5 to 28.5 U/g Hb.
• Other methods for diagnosis include
• Galactose Tolerance
• Eryrthrocyte Assay for Gal-1-P Uridylyl
  Transferase
• White Blood Cell Assay for Gal -1-P Uridylyl
  Transferase
• Amniocentesis

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Screening

• Individuals with galactosemia must remain on a
  restricted diet and maintain low blood galactose
  levels throughout life.
• There is no treatment per se for galactosemia.
• However, lethal and toxic events of galactosemia
  can be prevented by dietary interventions.
• Therefore it is extremely important that early
  diagnosis is made.
• Genetic screening is done in utero (ex. if there
  is family history) or post-partem in many states
  and provinces

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Treatment

• The dietary intervention, technically sounds
  simple to avoid lactose and galactose.
• However, so many foods (and medications) contain
  lactose and galactose that it is hard to avoid
  it. Some common examples are
• ANYTHING with milk ingredients (milk, butter,
  cheese, yogurt, etc)
• Organ meat such as liver, heart, and pancreas.
• Margarine (some contain no milk products, so
  checking label is key however, any other product
  that has margarine as an ingredient is assumed to
  have lactose in it)
• MSG (some contain lactose extenders)
• Fermented soy sauce
• Hydrolized protein (i.e. canned tuna)
• Coffee
• Legumes, peas, tomatoes, hazelnuts
• Dried figs, grapes, papaya, pineapple,
  watermelon, blueberries.
• Goal is to keep blood gal-1-p level below 3 to 4
  mg/100 mL

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Pharmaceutical Applications

• Lactose is a common excipient used in oral
  medication dosage forms.
• Children with galactosemia often require
  medications to treat conditions associated with
  the disease, such as tremors, ovarian failure and
  sepsis.
• These children will also require treatment for
  other common childhood diseases.
• Lilac pages in the Clin-Info section of the CPS
  contain information regarding medications
  containing lactose.
• If this information is not in the CPS, can
  contact the manufacturer for more information.
• Calcium supplementation also a concern,
  especially since many supplements contain
  lactose.
• Suggestions for Calcium supplementation liquid
  calcium/magnesium combinations, Caltrate brand
  chewable calcium tablets.

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Pharmaceutical Applications
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Future Research

• Current treatment focuses on eliminating
  galactose from the diet and treating the
  conditions associated with disease.
• Continued focus on understanding all aspects of
  the disease including how the disease causes
  associated conditions, such as behavioural
  issues.
• Possible gene therapy.
• The alternative pathways, and the genes and
  enzymes that comprise them, are logical targets
  for small molecule therapeutic intervention and
  potential modifiers of patient outcomes

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Summary
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Summary

• Galactosemia is an inherited condition, where the
  affected individual cannot properly breakdown
  galactose.
• Galactose is a sugar that forms during the
  breakdown of lactose.
• Galactose is metabolized by three different
  enzymes GALT, GALK, GALE.
• There are three different forms of galactosemia,
  which affect different parts of the enzymes in
  galactose metabolic pathway. The most common form
  is caused by a deficiency in GALT.
• Inability to breakdown galactose leads to a
  build-up of toxic metabolites.
• The build-up of these toxic metabolites can lead
  to conditions in the body, such as tremors,
  ovarian failure, and behavioural abnormalities.
• There is not treatment for galactosemia, the
  associated conditions can be prevented, to a
  certain extent by adherence to strict dietary
  restrictions.
• Dietary restrictions include milk and milk
  products, organ meats, grapes among many other
  ingredients.
• Patients also must be aware of hidden sources of
  lactose, such as excipients in medications.
• The pharmacist can play a role in being aware of
  prescription medications containing lactose, and
  supplements that most suit the patients needs.

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References

• Yi-Hung Hsia, D. et. al. Galactosemia
  Northwestern Medical School Printing 1969
  Springfield Illinois
• Parents of Galactosemic Children
  www.galactosemia.org Last update 2007.
• Washington State Department of Health Newborn
  Screening http//www.doh.wa.gov/EHSPHL/PHL/Newbor
  n/galgo.htmq4 Last updated 11/20/2006
• Chemfinder www.chemfinder.com Cambridge Software
  Corporation
• United States Library of Medicine Genetics Home
  Reference http//ghr.nlm.nih.gov/conditiongalact
  osemia Last updated January 2008.
• BioCarta The Pathway of Glucose Metabolism
  http//kugi.kribb.re.kr/KUGI/Pathways/BioCarta/h_g
  1pPathway/h_g1pPathway.gif Last update June 2007
• National Academy of Science Earth and Life
  Sciences Pathway of Galactose Breakdown
  http//dels.nas.edu/ilar_n/ilarjournal/43_2/43_2_7
  3f4.gif Last Updated 2007
• Medline Plus www.urac.org Galactosemia Signs and
  Symptoms John Goldenring, MD, MPH, JD,
  Department of Pediatrics, Children's Hospital,
  San Diego, CA
• CPS
• Fridovich-Kiel, J. Galactosemia the Good, the
  Bad, and the Unknown Journal Of Cellular
  Physiology 209701705 (2006)

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