Inborn Errors of Metabolism
Inborn Errors of Metabolism
This domain covers the clinical presentation and pathophysiology of specific metabolic disorders. You must know the major categories: aminoacidopathies, organic acidemias, fatty acid oxidation defects, urea cycle disorders, lysosomal storage diseases, peroxisomal disorders, and mitochondrial disorders. For each, understand the typical age of onset, presenting symptoms (e.g., encephalopathy, hypoglycemia, cardiomyopathy, hepatosplenomegaly), and key laboratory findings (e.g., elevated ammonia, anion gap, specific metabolites).
Questions often present a clinical vignette and ask for the most likely diagnosis or the next best test. Traps include overlapping presentations (e.g., urea cycle disorder vs organic acidemia both cause hyperammonemia) and atypical or mild forms that present later. Be cautious with disorders that can present acutely in neonates (e.g., MSUD, propionic acidemia) versus those with chronic progressive courses (e.g., lysosomal storage diseases). Remember that some disorders have specific triggers (e.g., fasting in fatty acid oxidation defects, illness in urea cycle disorders).
A worked example: a neonate with poor feeding, vomiting, tachypnea, and lethargy, with respiratory alkalosis and hyperammonemia, should raise suspicion for a urea cycle disorder (e.g., OTC deficiency). The absence of acidosis and the presence of respiratory alkalosis help distinguish it from organic acidemias, which typically cause metabolic acidosis. However, OTC deficiency may have normal or low citrulline and elevated urine orotic acid. This pattern recognition is key.
Key Points
- Urea cycle disorders: hyperammonemia, respiratory alkalosis, no acidosis; OTC deficiency has elevated urine orotic acid.
- Organic acidemias: metabolic acidosis, anion gap, often hyperammonemia secondary to inhibition of urea cycle.
- Fatty acid oxidation defects: hypoketotic hypoglycemia, triggered by fasting or illness.
- Lysosomal storage diseases: progressive organomegaly, neurodegeneration, dysmorphism; enzyme assay or genetic testing for diagnosis.
- Mitochondrial disorders: multiorgan involvement, lactic acidosis, often triggered by stress.