Why can symptoms of inherited metabolic diseases appear only after fasting or illness?

In individuals with inherited metabolic diseases, symptoms often remain latent until the body is subjected to metabolic stress, such as prolonged fasting or severe illness.1

These disorders typically involve a deficiency or dysfunction of a specific enzyme required for a metabolic pathway. Under normal conditions, the body may maintain sufficient function; however, during fasting, the body must shift its energy production to alternative sources, such as breaking down stored fats or utilizing glycogen stores. If the enzymes necessary for these specific energy-producing pathways are defective, the pathway becomes blocked.123

This blockage leads to two primary issues:
* Deficiency: The body fails to produce essential end products, such as glucose, leading to conditions like hypoglycemia.31
* Toxicity: The accumulation of intermediate substrates or the activation of minor, dormant pathways can produce atypical, toxic substances that cause organ damage, lethargy, or seizures.31

Metabolically stressful events, such as viral infections, increase the body's energy demands, further straining these compromised pathways and triggering the clinical manifestation of the disease.1