phd89

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both MCAD and carnitice def present quite similar so how do you tell the difference?

Also is MCAD def the same thing as Fatty Acyl-coA dehydrogenase def?
 

withrye

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I don't know how questions typically differentiate between them, but theoretically patients would respond differently to long vs medium chain fatty acid challenges.

MCADD is a deficiency of the medium chain acyl-CoA dehydrogenase. There is a short chain enzyme as well, and that's not affected as far as I know.
 

thehundredthone

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MCAD deficiency presents with fasting hypoglycemia and vomiting.

CAT/CPT deficiency tends to present with muscle ache, weakness and hypotonia, often brought on by exertion. Myoglobinuria is possible. Biopsy reveals raised TGs in muscle.

I doubt they will ask you to differentiate between the two, if they do, the details will definitely tip the scales one way or the other.
 
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MCAD deficiency presents with fasting hypoglycemia and vomiting.

CAT/CPT deficiency tends to present with muscle ache, weakness and hypotonia, often brought on by exertion. Myoglobinuria is possible. Biopsy reveals raised TGs in muscle.

I doubt they will ask you to differentiate between the two, if they do, the details will definitely tip the scales one way or the other.

and in addition MCAD presents with increased dicarboxylic acids
 

Phloston

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With all of the practice questions I've done so far, I can say that the USMLE might frame this topic in a few different ways / here are some things you should know:

1) You'll get a question where they'll tell you the kid's got low blood glucose and is hypoketotic, and then they'll also tell you that muscle biopsy reveals intracellular fatty acyl-carnitines. If the latter is present, then that means carnitine can't be deficient, because if it were, then you'd only get fatty acyl-CoA derivatives, but not anything carnitine-related. Therefore, the answer here would be M- or LCAD deficiency.

2) MCAD deficiency is the most common beta-oxidation disorder.

3) Intestinal fatty acids that are 12 or more carbons in length are absorbed into lymph and bypass the liver. 12+ carbon FAs are termed long-chain. So if the question stem mentions the classic hypoketotic/hypoglycaemic vignette, and then tells you there's a build-up of 16C FAs (e.g. palmitate), for instance, the answer is LCAD, not MCAD, deficiency.

4) It is the decreased production of acetyl-CoA with carnitine, S-, M- or LCAD deficiencies that causes the hypoglycaemia. This is because acetyl-CoA is a cofactor for pyruvate carboxylase, the first step in gluconeogenesis.

5) Hyperammonaemia can occur with MCAD deficiency because decreased acetyl-CoA --> decreased TCA cycle activity --> decreased ATP --> decreased carbamoyl phosphate synthesis.

6) For MCAD deficiency, they might give you a scenario that's very similar to McArdle's, where muscle cramping + myoglobinuria occur following intense exercise, except the catch is that, rather than occurring within minutes, the Sx occur after prolonged exercise, and intramuscular lipid droplets will be seen on biopsy. (I got confused when I saw this question, because I believe they said there were clear droplets viewed on biopsy, and somehow I had thought they were referring to glycogen that is non-stained when used with PAS).

7) Know that carnitine acyl-transferase-I is in the cytosol; CAS-II is in the mitochondria.

8) Nausea, vomiting + seizures are the most common Sx of severe MCAD / carnitine deficiency.

9) Although most beta-oxidation is mitochondrial, super-long- and branched-chain FA beta-oxidation occurs in peroxisomes. Refsum and Zellweger syndromes are deficiencies of the peroxisomal system. Chlorophyll should be avoided in the diets of those with Refsum disease, because it liberates phytol intestinally, which is anabolized to phytanic acid, and it is phytanic acid that cannot be catabolized. Also, beta-oxidation in peroxisomes is used to generate H2O2.
 
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Amazing explanation above!

It's scary to note that I knew all of what he said, but had it been presented in a vignette I wouldn't have been able to pick it apart. I don't think I would have made some of those links when reading a Q and would likely end up stuck ARH!!:mad::(
 

Transposony

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@Phloston this is a great overview. You need to write a book man, I couldn't find concise explanation of these anywhere else. Thank you
I believe it's part of that process :thinking:

Also, defect in transport of VLCFAs across the peroxisomal membrane leads to accumulation of VLCFAs in the blood and tissues resulting in X-linked adrenoleukodystrophy. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex and the Leydig cells in the testes.
 
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With all of the practice questions I've done so far, I can say that the USMLE might frame this topic in a few different ways / here are some things you should know:

1) You'll get a question where they'll tell you the kid's got low blood glucose and is hypoketotic, and then they'll also tell you that muscle biopsy reveals intracellular fatty acyl-carnitines. If the latter is present, then that means carnitine can't be deficient, because if it were, then you'd only get fatty acyl-CoA derivatives, but not anything carnitine-related. Therefore, the answer here would be M- or LCAD deficiency.

2) MCAD deficiency is the most common beta-oxidation disorder.

3) Intestinal fatty acids that are 12 or more carbons in length are absorbed into lymph and bypass the liver. 12+ carbon FAs are termed long-chain. So if the question stem mentions the classic hypoketotic/hypoglycaemic vignette, and then tells you there's a build-up of 16C FAs (e.g. palmitate), for instance, the answer is LCAD, not MCAD, deficiency.

4) It is the decreased production of acetyl-CoA with carnitine, S-, M- or LCAD deficiencies that causes the hypoglycaemia. This is because acetyl-CoA is a cofactor for pyruvate carboxylase, the first step in gluconeogenesis.

5) Hyperammonaemia can occur with MCAD deficiency because decreased acetyl-CoA --> decreased TCA cycle activity --> decreased ATP --> decreased carbamoyl phosphate synthesis.

6) For MCAD deficiency, they might give you a scenario that's very similar to McArdle's, where muscle cramping + myoglobinuria occur following intense exercise, except the catch is that, rather than occurring within minutes, the Sx occur after prolonged exercise, and intramuscular lipid droplets will be seen on biopsy. (I got confused when I saw this question, because I believe they said there were clear droplets viewed on biopsy, and somehow I had thought they were referring to glycogen that is non-stained when used with PAS).

7) Know that carnitine acyl-transferase-I is in the cytosol; CAS-II is in the mitochondria.

8) Nausea, vomiting + seizures are the most common Sx of severe MCAD / carnitine deficiency.

9) Although most beta-oxidation is mitochondrial, super-long- and branched-chain FA beta-oxidation occurs in peroxisomes. Refsum and Zellweger syndromes are deficiencies of the peroxisomal system. Chlorophyll should be avoided in the diets of those with Refsum disease, because it liberates phytol intestinally, which is anabolized to phytanic acid, and it is phytanic acid that cannot be catabolized. Also, beta-oxidation in peroxisomes is used to generate H2O2.

Hey Phloston, I had a question regarding point 6. Isn't the presentation that you have described refers to Carnitine deficiency specifically myopathic Carnitine Acyl Transferase 2 rather than MCAD? Also, for point 1, if the mucle biopsy did not have Carnitine, would the diagnosis have been Carnitine deficiency?
 
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