Clinical and laboratory presentation of MCADD in kids?
Episodic hypoketotic hypoglycemia, infections and comatose (from FFAs in blood) after 12 hours of fasting. Labs: FA intermediates in urine (dicarboxylic acids, medium chain FAs and conjugates w/carnitine and glycine)
What hormonal changes occur in the fasted state?
1) Blood glucose and insulin go down. Glucagon increases 2) Glucagon releases glucose into the blood from glycogen 3) Glucagon to adipose tissue and stimulates release of FAs and glycerol into the blood. 4) Muscle takes up FAs and oxidizes them for energy, breaks down amino acids. Glycerol, Ala and lactate go to liver for gluconeogenesis. Nitrogen is routed to urea cycle and is excreted in urine. 5) Fatty acid enters liver and makes acetyl-CoA, extra acetyl-CoA goes to ketone bodies. 6) Heart and muscle use ketone bodies. 7)
Why are kids in bad shape if they cannot produce a sufficient amount of ketone bodies?
Their bodies cannot produce enough glucose to fuel the brain and the brain relies upon ketone bodies much more heavily than an adult brain does.
Why do you end up producing less amounts of urea when you are fasting for 3 days as opposed to 1 day?
By 3 days, most other tissues turn off ketone body usage except for the brain, which ramps it up. This has a protein sparing effect and glycerol becomes the main source of fuel for ketogenesis instead of Ala. Glycerol does not have a nitrogen to dispose of and less urea is formed.
What conditions will really promote a crisis in kids with MCADD?
Combination of fasting and infection (stress response).
How are the ketone bodies synthesized?
Beta oxidation produces acetyl CoA. Acetyl CoA -> acetoacetate which can further go to beta-hydroxybutyrate.
How do fatty acids get into the mitochondrial matrix?
Fatty acid goes to mitochondrial membrane -> converted to fatty acyl CoA by fatty acyl CoA synthase + 2ATP -> converted to fatty acyl carnitine by CPTI -> shuttled into mitochondrial matrix -> goes back to fatty acyl CoA by CPTII -> beta oxidation
Metabolism of what fatty acids is affected in kids with MCADD?
C4-C12 medium chain fatty acids
Which enzyme is deficient in MCADD?
Acyl CoA dehydrogenase, the 1st enzyme in beta-oxidation
Steps of beta oxidation
1) Acyl CoA DH + FAD converts fatty acyl CoA to fatty enoyl CoA and produces FADH2, which is carries to CoQ by ETF (electron transfer flavoprotein). 2) Water is added across the double bond in trans-delta2-fatty enoyl CoA by enoyl CoA hydratase to form L-beta-hydroxy acyl CoA 3) beta-hydroxy acyl CoA dehydrogenase + NAD oxidizes the hydroxyl group of L-beta-hydroxy acyl CoA to form beta-ketoacyl CoA and NADH 4) Beta-keto thiolase and another CoASH cleaves the beta-keto acyl CoA to form acetyl CoA and fatty acyl CoA. ***As the fatty acyl chain gets shorter the LCFA enzymes don’t work as well and the baton gets passed to MCFA enzymes, this is when MCADD causes trouble***
Pathognomonic lab findings in MCADD
Unsaturated fatty acid oxidation
After several rounds of beta oxidation you end up with a cis double bond between 3 and 4 that prevents formation of the double bond between 2 and 3. Enoyl CoA isomerase can move the cis 3,4 to a trans 2,3 double bond and proceed with normal beta oxidation. Eventually you will end up with a trans 2,3 and cis 4,5 conjugated double bond. 2,4 dienoyl CoA reductase combines the conjugated double bonds to a trans 3,4 double bond. Then enoyl CoA isomerase moves it to 2,3 and beta oxidation can continue.
What happens when you are oxidizing polyunsaturated fatty acids and you get to 4-cis decanoyl CoA intermediate?
MCAD is required to convert to the next intermediate: 2-trans-4-cis-decanoyl CoA; however, normal MCAD activity here is low and with MCADD 4-cis decanoic acid accumulates and is thought to be neurotoxic.
Alternative routes for fatty acid oxidation
Peroxisomes work on long chain fatty acids and stall at medium chain fatty acids, so they can’t compensate for MCADD. Microsomal (omega-oxidation) in the smooth ER of the liver.
When is omega oxidation used?
Metabolism of hydrophobic xenobiotics for excretion and metabolism of normal fatty acids when beta-oxidation is defective (removing 1C at a time). It will produce C6-C8 dicarboxylic acids for excretion, which are good indicators of metabolic disorder in fatty acid oxidation.
How does omega oxidation work?
1) MFO (P450) hydroxylates the omega carbon 2) Further oxidation occurs in cytosol with NAD+ by dehydrogenases 3) Short dicarboxylic acid excreted in urine