Inborn errors of metabolism are a group of diseases where a genetic defect blocks a metabolic pathway, resulting in a single enzyme dysfunction. When metabolic pathways are blocked the consequences can in some cases lead to disease. The downstream effects of a missing enzyme can affect many parts of the body. These effects lead to the clinical presentation of a disease.
Soon after birth, newborns are tested for these inborn errors of metabolism. It is very helpful to identify some of the very serious and very treatable IEMs before they cause significant damage. Phenylketonuria (PKU) is an excellent example. In this disorder, there is a deficiency or absence of the enzyme phenylalanine hydroxylase (PAH), which processes the amino acid into another amino acid, tyrosine. Amino acids are the building blocks of proteins but when they are not fully converted into their requisite proteins, they accumulate in tissues, like the brain, causing intellectual disability and seizures. The treatments for PKU can prevent this tragedy and the affected person can have a normal lifespan. They must follow a diet that is low in phenylalanine and follow that diet for life. For other IEM, the results are less successful. Tay-Sachs disease is another such disorder where a mutation in the HEXA gene leads to the buildup of GM2 ganglioside within the neurons that leads to loss of motor function and death within a few years.
When my son showed up at the emergency room experiencing metabolic acidosis with high ketones. He was 8 years old. We had experienced ongoing episodes of vomiting and lethargy and weight loss and doctors could never explain it.
The differential diagnosis for metabolic acidosis with high ketones are typically metabolic disorders.
- Fatty Acid Oxidation disorder
- Ketone body utilitzation disorder
- Interference in the mitochondrial respiratory chain
- Organic Acidurias
Finding the Zebra 