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NBME 24 Answers

nbme24/Block 4/Question#8
A 1-week-old newborn is brought to the ...
Organic acid metabolism disorder🔍

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 +29  upvote downvote
submitted by lsmarshall(314),

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.

lsmarshall  Summary of metabolic issues relating to hyperammonemia +5  
seagull  i'm leaning towards Ornithine transcarbamylase deficiency. +2  
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 +2  
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 +2  
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? +  
yb_26  1) hyperammonemia is seen in all urea cycle disorders except arginase deficiency 2) organic acids directly inhibit urea cycle => hyperammonemia (from UWorld) +1  
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. +7  

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:

  1. Organic acids inhibit gluconeogenesis, leading to fasting hypoglycemia which then causes ketoacidosis, causing a high AG metabolic acidosis

  2. Organic acids inhibit the urea cycle, leading to hyperammonemia

 +1  upvote downvote
submitted by sattanki(50),

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.

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 +3  

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).

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

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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