NBME 24 Organic acid metabolism disorder (NBME Answers)

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A 1-week-old newborn is brought to the ...
Organic acid metabolism disorder 🔍 / 📺 / 🌳 / 📖
tags: biochem artist90

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submitted by ∗lsmarshall(465)

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Urea Cycle Disorders > Isolated severe hyperammonemia (> 1000; i.e., no other severe metabolic disturbances

Ornithine transcarbamylase deficiency > (most common urea cycle dis.) orotic acidemia/aciduria, hyperammonemia

Organic Acidemias > Hyperammonemia, anion-gap acidosis, ketosis (from hypoglycemia)

Medium-chain acyl-CoA dehydrogenase deficiency > Hyperammonemia, hypoketotic hypoglycemia (seen in β-oxidation disorders, EXCEPT adrenoleukodystrophy)

Liver dysfunction > Hyperammonemia, LFTs messed up, older pt.

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lsmarshall Summary of metabolic issues relating to hyperammonemia +9

seagull i'm leaning towards Ornithine transcarbamylase deficiency. +3

notadoctor Not sure why this isn't considered a mitochondrial disorder since the issue is Ornithine transcarbamylase deficiency in the mitochondria? +2

charcot_bouchard if it was mitochondrial disorder no one would escape +3

wowo figure in OTC deficiency, they might have to explicitly mention the orotic aciduria AND typically presents earlier, around 24-48hrs of life after they've fed (at least per BB) + also per BB, propionic acidemia and MM acidemia have an onset of weeks to months and lead to build up of organic acids --> acidemia in addition to hyperammonemia (not sure why, but several aa enter the TCA cycle via propionyl CoA --> methylmalonyl CoA --> succinyl CoA, but now this is defunct d/t enzyme deficiencies...?). Anywho, propionic acidemia described on FA2019 p85, but doesn't list hyperammonemia +2

artist90 i think it cannot be Ornithine transcarbamylase deficiency bc it is XR disease. this pt has a healthy 2yr old brother which rules out X-linked recessive disease correct me if i m wrong +7

artist90 it is 100% Propionic acidemia Uworld Q-id: 1340. it is an exact copy question of uworld. i got it wrong bc i forgot these are organic acids. But i am still confused on 2 things 1-how does acidosis cause Hypoglycemia and Ketosis. 2-why is Ammonia elevated in these pts bc urea cycle will be fine? +2

yb_26 1) hyperammonemia is seen in all urea cycle disorders except arginase deficiency 2) organic acids directly inhibit urea cycle => hyperammonemia (from UWorld) +2

yex According to UW, there is another question # 1341. This one refers to methylmalonic acidemia (ORGANIC ACIDEMIA). HYPOGLYCEMIA results from overall increased metabolic rate leading to increased glucose utilization and direct toxic (-) of gluconeogenesis by organic acids. The presence of hypoglycemia leads to increased free fatty acid metabolism that produces KETONES, resulting in a further anion gap met acidocis. Finally, organic acids also directly (-) the urea cycle, leading to HYPERAMMONEMIA. +19

ih8payingfordis I think there has been some confusions because FA does a poor job integrating these concepts together but here are some references: FA 2019 pg 85: Propionic Acidemia (this is one example of organic acid metabolism disorder) In the summary figure on Pg 74, look at the protein metabolism (located bottom right). Basically, you can have disorders where you have Propionyl-CoA buildup alone OR Proionyl-CoA and Methylmalonyl-CoA buildup. And these organic acidemias are autosomal recessive in their inheritance pattersn, which fit with the stem we're given (ie XX individuals can be affected) One thing that UW state that I do not have an explanation for: the buildup of organic acids inhibit the urea cycle hence the increase in ammonia (anyone knows how this happens?) +

aaftabsethi1 Can someone tell me why not MELAS ? +1

jaramaiha @aaftabsethi because all of the siblings would show some symptoms if it were to be a mitochondrial disease. Which his brother is healthy, and sister was full-term but died due to unspecified causes. +

utap2001 Why acidosis cause Hypoglycemia and Ketosis and hyperammonia? In acidosis(such lactic acidosis)-> indicate body energy crisis -> inc. glycolysis, Hypoglycemia-> inc. protein breakdown, Hyperammonia -> dec. TCA cycle, Ketosis +

forkyeaa https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282273/figure/Fig1/ +

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submitted by ∗powerfulgarbage(17)

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Just to add to what some others have said, this is in First Aid as well. FA 2020 page 85:

Organic acidemias most commonly present in infancy with poor feeding, vomiting, hypotonia, a high anion gap metabolic acidosis, hepatomegaly, and seizures.

The organic acid accumulation does 2 things:

Organic acids inhibit gluconeogenesis, leading to fasting hypoglycemia which then causes ketoacidosis, causing a high AG metabolic acidosis
Organic acids inhibit the urea cycle, leading to hyperammonemia

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forkyeaa this ncbi flowchart shows how the cycles are inhibited. might help. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282273/figure/Fig1/ +

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submitted by ∗sattanki(82)

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Can’t help much on the exact reasoning why, but there are a few UWorld questions on this where if a neonate has hypoglycemia, ketosis and hyperammonemia, a organic acid disorder should be suspected (propionic acid or methylmalonic acid). Less suspicious of an RTA cause hypoglycemia is not characteristic of that.

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sweetmed Im assuming because N-acetylglutatmate is an allosteric activator of CPS I needed in urea cycle. and N-AG is made of glutamate and acetyl coA. So in organic acidemias, all the acetyl CoA is being used to make ketones for energy since gluconeogenesis is messed up. So Urea cycle doesnt work as well and NH3 accumulates +4

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submitted by passispass(1)

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My reasoning on this questions was simpler - I think they wanted us to pick an autosomal recessive disease based on pattern of kids affected (both females are affected - can't be anything X-linked); boy was healthy - rule out mitochondrial. With rest - rule out because of increased ammonia and infantile presentation. Only organic acid metabolism disorder left

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submitted by ∗forkyeaa(1)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282273/figure/Fig1/

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submitted by ∗abhishek021196(119)

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Ornithine transcarbamylase deficiency. Most common urea cycle disorder. X-linked recessive (vs other urea cycle enzyme deficiencies, which are autosomal recessive).

Interferes with the body’s ability to eliminate ammonia.

Often evident in the first few days of life, but may present later. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).

Findings: Increased orotic acid in blood and urine, Decreased BUN, symptoms of hyperammonemia. No megaloblastic anemia (vs orotic aciduria).

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passispass Can it be an X-linked disease if both females are affected and boy is not? I think unlikely +

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