U01.01.114 Organic acidemias

Organic acidemias are a group of inborn errors of metabolism that are primarily present in infancy. These conditions involve the accumulation of organic acids in the body, leading to significant metabolic disturbances. Understanding their clinical presentation, pathophysiology, and treatment is crucial for USMLE Step 1.

Clinical Presentation

Organic acidemias typically present in infancy with the following symptoms:

Poor feeding
Vomiting
Hypotonia
Hepatomegaly
Seizures

Additionally, metabolic disturbances are common, including:

High anion gap metabolic acidosis
Hypoglycemia (low fasting blood glucose levels)
Ketoacidosis

Pathophysiology

The accumulation of organic acids in the body leads to the following metabolic issues:

Inhibition of gluconeogenesis:
- This results in hypoglycemia (low fasting blood glucose levels).
- Contributes to ketoacidosis and high anion gap metabolic acidosis.
Inhibition of the urea cycle:
- This causes hyperammonemia due to the impaired conversion of ammonia into urea.

Specific Organic Acidemias

1. Propionic Acidemia

Cause: Deficiency of propionyl-CoA carboxylase.
Biochemical Consequences:
- Decreased propionyl-CoA.
- Increased methylmalonic acid.
Treatment:
- Low-protein diet.
- Avoid substances that metabolize into propionyl-CoA, represented by the acronym VOMIT:
  - V: Valine
  - O: Odd-chain fatty acids
  - M: Methionine
  - I: Isoleucine
  - T: Threonine

2. Methylmalonic Acidemia

Cause: Deficiency of methylmalonyl-CoA mutase or vitamin B12 deficiency.
Biochemical Consequences:
- Impaired conversion of methylmalonyl-CoA to succinyl-CoA, resulting in the accumulation of methylmalonic acid.

Points to Remember

Organic acidemias are most commonly diagnosed in infancy with symptoms like vomiting, poor feeding, and hypotonia.
High anion gap metabolic acidosis is a key feature of organic acid accumulation.
Treatment for propionic acidemia focuses on dietary restrictions (VOMIT) to prevent the buildup of harmful metabolites.
Methylmalonic acidemia is due to deficiencies in either methylmalonyl-CoA mutase or vitamin B12.

Summary Table: Organic Acidemias

Condition	Deficiency	Metabolic Abnormalities	Treatment
Propionic Acidemia	Propionyl-CoA carboxylase	Decreased propionyl-CoA, increased methylmalonic acid	Low-protein diet, avoid VOMIT substances (Valine, Odd-chain fatty acids, Methionine, Isoleucine, Threonine)
Methylmalonic Acidemia	Methylmalonyl-CoA mutase or Vitamin B12	Methylmalonic acid accumulation	Vitamin B12 supplementation

By understanding the pathophysiology, clinical signs, and management of these conditions, you can better prepare for questions related to organic acidemias on the USMLE Step 1 exam.

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