Acyl CoA Dehydrogenase Deficiency

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Acyl CoA Dehydrogenase Deficiency

• Gigi Wong gigiyc.wong_at_utoronto.ca
• Ying Ying Zeng yingying.zeng_at_utoronto.ca
• Sign-up date March 26th, 2008
• Presentation date Mar 25, 2008

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What is Acyl CoA Dehydrogenase Deficiency?

• Normally, fat broken down into energy by enzymes.
• Disease due to deficiency in one of these
  enyzmes
• acyl CoA dehydrogenase
• It is a fatty acid metabolism disorder
• Patient with this deficiency has problem when run
  out of glucose b/c can not break down fat
• Is inborn disorder of neonates
• Homozygous mutation

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Some types of ADD

• Very long chain ADD
• Long chain ADD (gt 12 carbons)
• Medium chain ADD (6-12 carbons) ? most common
• Short chain ADD (lt6 carbons)
• Long chain hydroxyl ADD
• Short chain hydroxyl ADD

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Some statistics

• For Medium Chain ADD (MCADD)
• Mortality due to metabolic decomposition is 20
  25
• Even for these survivors, 37 have
  neurodevelopmental problems
• This illustrate important early diagnosis of
  neonates to minimize severe health damaging
  effects
• Prevalence of disease varies depending on
  geography
• Finland 18000 versus Spain 150 000.

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A look at the metabolic pathway
Fatty acid acyl-CoA synthase

• Fatty acid

Acyl CoA
CPT1
Acyl CoA carnitine
CPT II
Inside mitochondria
Acyl CoA
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Further down the pathway(beta-oxidation)

• Acyl CoA

Acyl CoA Dehydrogenase
e-
FADH2
Cellular respiration Use energy Make ATP
Enoyl CoA
NAD/H
e-
Hydroxylacyl CoA dehydrogenase
Krebs cycle
3-keto acyl-CoA
Acetyl-CoA
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What are the common SSx?

• Hypoglycemic - low blood sugar
• Vomiting
• Lack of energy
• Some are asymptomatic, but can result in
  significant mortality or morbidity
• Notice that these are non-specific symptoms and
  illustrate importance of screening.

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What are the consequences of ADD?

• Frequent episodes of hypoglycemia (low blood
  sugar) ? increase risk of CNS damage
• Severe complications can result in
• Seizures
• Breathing difficulties
• Liver problems
• Brain damage
• Coma
• DEATH

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How do we screen for the disease?

• Tandem Mass Spectrometry (MS/MS)

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About Tandem Mass Spec (MS/MS)

• Able to detect MCADD easily
• Detects MCADD with gt99 specificity and gt 99
  sensitivity
• Is cost-effective, quicker, can detect 25 inborn
  errors of metabolism at once
• Take sample on dry blood paper filter
• Is 1st sample positive, take 2nd sample for
  confirmation
• Meanwhile parents feed child every 6 hrs to keep
  child in anabolic state.

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How does Tandem Mass Spec (MS/MS) work?

• Imagine the each type of coin is a different
  molecules

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• MS/MS will sort the coins into loonies, quarters,
  dimes, nickels and pennies

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• Then molecules of similar weight can be sorted
  into on slightly different structureslooking
  for specific carnitine spectrum.

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Timing is critical

• Screening results should be obtained
• within 72 hrs.
• In Australia babies from 1994 to 2004
• Found 4 in 81 babies with MCADD die within 72 hrs
• Equates to 5 babies die within this time
• The challenge is to have an efficient diagnosis
• Because need at least 24 hrs to obtain a sample
• Then 1st lab test
• 2nd sample for confirmation
• Includes sending samples, screening sample,
  receive results, find baby, provide treatment.

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• How do you treat it?

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• There is NO CURATIVE treatment...
• simply because its a genetic disorder.

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BUT we can always treat the symptoms

• Good News cheap and easy to prevent
  manifestations of MCADD effects
• Diet modification is key
• Provide patients with greater caloric diet with
• Lots of proteins
• Lots of carbohydrates
• And minimize lipids, because they can not utilize
  them
• Avoid fasting longer than 4 to 5 hours
• Provide L-carnitine supplements
• patients with MCADD have more toxics wastes,
  helps carry wastes out of cells to urine

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What should the patient know?

• If a first degree relative have ADD, then parents
  should seek genetic counseling
• Tight medical supervision in the 1st few years of
  life
• Newborn screening essential to allow rapid
  introduction therapy
• This can prevent metabolic complications and
  support normal development
• Minimizes neurological handicap and cardiac
  problems
• Know that support groups are available.

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Any questions?
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Summary of ADD

• Acyl CoA Dehydrogenase Deficiency (ADD) is an
  inborn metabolic disorder where the body is
  unable to utilize fatty acids for energy.
• There are many types based on chains of various
  fatty acid lengths, the most common type is
  medium chain ADD.
• Early screening important because can result in
  major health consequences in newborns including
  neurological handicap, cardiac problems, prevent
  healthy development.
• Tandem Mass Spectrometry is most cost-effective,
  efficient way of screening because it can screen
  for other inborn errors of metabolism, although
  efficient diagnosis within 72 hours is highly
  recommended.
• There is no curative treatment, because it is due
  to genetic mutation.
• Prevention of symptom manifestation involves
  modification of diet to one high in
  carbohydrates, high in protein, low in lipids and
  no fasting.
• L-carnitine can be given to patients to help
  eliminate toxics wastes accumulated in the body

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References

• 1. Ontario Ministry of Health and Long-Term Care.
  Neonatal Screening of Inborn Errors of
  Metabolism using Tandem Mass Spectrometry.
  Health Technology Literature Review. September
  2002.
•  
• 2. Stefanie Sander, Nils Janzen, Bernd Janetzky,
  Sabine Scholl, Ulrike Steuerwald, Jochen Schäfer,
  Johannes Sander . Neonatal screening for medium
  chain acyl-CoA deficiency high incidence in
  Lower Saxony (northern Germany)
• European Journal of Pediatrics. 2001
  May160(5)318-9.
•           
• 3. Chisholm, C A Vavelidis, F Lovell, M A
  Sweetman, L Roe, C R Roe, D S Frerman, F E
  Wilson, W G Prenatal diagnosis of multiple
  acyl-CoA dehydrogenase deficiency association
  with elevated alpha-fetoprotein and cystic renal
  changes. Prenatal diagnosis, 2001 Oct,
  21(10)856-9
•  
• 4. Han, Lian-shu Ye, Jun Qiu, Wen-juan Gao,
  Xiao-lan Wang, Yu Zhang, Yong-jun Gu, Xue-fan.
  Application of tandem mass spectrometry on the
  diagnosis of fatty acid oxidation disorders.
  Chinese journal of medical genetics, 2007 Dec,
  24(6)692-5
•  
• 5. Wilcken, Bridget. More on Medium-Chain
  Acyl-Coenzyme A Dehydrogenase Deficiency in a
  Neonate. The New England journal of medicine,
  2008 Feb 7, 358(6)647 author reply 647
•  
• 6. Rice G, Brazelton T III, Maginot K, Srinivasan
  S, Hollman G, Wolff JA. Medium chain
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  neonate. N Engl J Med 20073571781-1781. 
•  
• 7. O'Leary, Niall D. O'Connor, Kevin E. Ward,
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  2005.
•  
• 8. Bauer, Matthias F. Gempel, Klaus Hofmann,
  Sabine Jaksch, Michaela Philbrook, Christine
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• 10. Roth KS. Medium- Chain Acyl- CoA
  Dehydrogenase. Emedicine from WebMD. Accessed
  from World Wide Web on 2008Mar19.
  http//www.emedicine.com/ped/topic1392.htm
• 11. Roe CR. MCAD Medium Chain acyl CoA
  Dehydrogenase- Information for Families. FOD
  Family Support Group. Accessed from World Wide
  Web on 2008Mar19. www.fodsupport.org/mcad_fam.htm
  

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Thanks!
Gigi
Ying Ying