Secondary Energy Deficiencies in Organic Acidemias. Kimberly A Chapman MD PhD Children s National July 26, 2014

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2 Secondary Energy Deficiencies in Organic Acidemias Kimberly A Chapman MD PhD Children s National July 26,

3 Goals of this talk Describe the secondary energy deficiencies seen in organic acidemias Identify the systems involved Explore therapeutic options 3

4 What is Energy? Energy is the currency that drive all biological processes. We think of is as ATP or CPK. Created from catabolism of protein (amino acids), carbohydrates (CHOs), and fatty acids Made in the mitochondrion. 4

5 Where do we need the most energy? Eye (retinas) Growth Brain: Structure and function 20-25% Heart: 9% Kidneys Muscles Wajner

6 What does Secondary Energy Deficiency Mean? Most energy is produced by the oxidative phosphorylation system with reducing substances from catabolism Secondary energy problems are problems with producing reducing substances 6

7 Secondary Energy deficiencies Lysine & Tryptophan FA Glucose Acetyl CoA Citrate Aconitase Oxaloacetate Isocitrate Glutamate VOMIT Propionyl CoA Malate Fumarate Succinate α-ketoglutarate Succinyl CoA Methylmalonyl CoA 7

8 Basically the system breaks down 8

9 Why does it break down? The diseases themselves prevents enzymes from working (toxins) There are not enough intermediates to function (i.e. Acetyl CoA or succinyl CoA) There is an inhibition in movement of the correct substrates into the correct place. 9

10 Organic acidemias: which ones are we going to talk about? Glutaric aciduria 1 Propionate pathway (MMA, PA) 10

11 Basic Biochemical Disease Typical Reactions A + B C Biochemical Disorder A + B C F E 11

12 Glutaric Aciduria 1 Glutaryl CoA cannot be converted to Crotonyl Co A by glutaryl CoA dehydrogenase Macrocephaly, fronto-temporal atrophy, mitochondrial-stroke like episodes (resulting in dystonia) Lysine and tryptophan Glutaric acid Glutaryl CoA GCDH Crotonyl CoA Acetyl CoA Aggressive therapy and a little luck can prevent the complications TCA 12

13 GA1 example Inhibit enzyme working Transport inhibited Transport failure Glutamate/Glutamine cycle inhibition Small decrease in substrate 13 Kolker et al JIMD 2013; used with permission.

14 Secondary Energy problems in GA1 Especially brain sensitive because of the importance glutamine/glutamate During illness or stress: become catabolic If brain is in need of more energy, any level of inhibition like seen in GA1 -> problems 14

15 Propionate Pathway Metabolic acidosis, hyperammonemia, developmental delay, myopathies, metabolic stroke like episodes, cardiomyopathies and arrhythmias, optic atrophy, and renal failure (MMA) Propionic acidemia Dysfunction of Propionyl CoA Carboxylase Accumulation of methylcitrate, 3-hydroxypropionate, propionylglycine Decreased production of methylmalonyl CoA (and subsequently succinyl CoA) Methylmalonic Acidemia Dysfunction of methylmalonyl CoA mutase (Cobalamin A or Cobalamin B) Accumulation of methylmalonic acid, methylcitrate, 3-hydroxypropionate, propionylglycine Decreased production of succinyl CoA 15

16 Propionate pathway Acetyl CoA Citrate Aconitase VOMIT Oxaloacetate Isocitrate Propionyl CoA Malate Fumarate Succinate α-ketoglutarate Succinyl CoA Methylmalonyl CoA 16

17 Acute events INFECTION: Catabolic and inflammation Problem is that we need to increase energy We have preliminary studies that indicate OAA can t do this 17

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19 Long term problems Cardiomyopathy and Arrhythmias Myopathies Developmental Delay/Intellectual disabilities Renal dysfunction (predominately MMA) Optic Neuropathy 19

20 Why not as significant at Birth? Other systems to make energy (multiple generators) Cells may compensate with time (changing normal balances of other things to make up) More responsibilities as get older 20

21 As we age More demand Functional New Construction Energy for repair 21

22 Overtime we think this happens MMAA: CS, SS, SDH, FH Activities normal 1 SS, SDH, FH Normal in muscle and liver (MMA& PA) 3 Acetyl CoA Oxaloacetate C. Elegans with PA accumulate citrate and deficient in oxaloacetate 4 Citrate Aconitase Isocitrate CS low in kidney (1 MMA) CS normal in PA hearts (2) 3 VOMIT Oxidation of pyruvate, malate and succinate Down in PA patients 2 Malate α-ketoglutarate Succinyl CoA Propionyl CoA Methylmalonyl CoA Fumarate Succinate PDH and OGDH inhibited by propionyl CoA 2 1 Valayannopoulos 2009, 2 Schwab De Keyzer Chapman et al.

23 Now what? 23

24 What can I as a caregiver do to make things better? Maximize nutrition Wash Hands Immunize Learn as much as you can about the disorder 24

25 There is this thing called the mitochondrial cocktail? Vitamin E and C CoEnzyme Q Thiamine (B vitamins) Gamma-glutamyl-cysteine N-acetylcysteine L-carnitine Others 25

26 Should I do it? Carnitine in OAA has been proven to help remove the acid The others: there is NO data Clinical trials are really important We don t know if any of these things will help We need good markers if they are working (like RMR and other ways) Trial designs are in preparation 26

27 Questions and Discussions 27

28 Acknowledgements Section of Genetics and Metabolism at Children s National Matthew Rasberry Sandra Yang Marshall Summar Gary Cunningham Ariel Badger Lynn Hakki NIH collaborators: Chuck Venditti Jennifer Sloan Peter McGuire Funding NICHD (CHRCDA) program (05K12-HD ) Research studies funded in part by PA foundation. Research studies funded in part by the Board of Visitors at Children s National 28