Canavan disease is caused by mutations in a specific gene called ASPA, which leads to a deficiency of an important enzyme known as aspartoacylase. This enzyme normally breaks down a molecule called N-acetylaspartate (NAA) in the brain. When aspartoacylase is deficient or nonfunctional due to these genetic mutations, NAA accumulates to abnormally high levels in the brain. This buildup disrupts the normal development and maintenance of the brain’s white matter, which is essential for proper nerve signal transmission.
The disease is inherited in an autosomal recessive pattern, meaning a child must inherit two defective copies of the ASPA gene—one from each parent—to develop Canavan disease. Parents who carry only one mutated copy typically do not show symptoms but can pass the mutation to their offspring.
The excessive accumulation of NAA caused by the lack of aspartoacylase leads to the destruction of the myelin sheath, the protective covering around nerve fibers in the central nervous system. This demyelination impairs communication between nerve cells, resulting in the progressive neurological symptoms characteristic of Canavan disease, such as developmental delays, loss of motor skills, and muscle weakness.
At the cellular level, the failure to break down NAA affects the brain’s ability to regulate osmotic balance and myelin synthesis. NAA is normally synthesized in neurons and plays a role in brain metabolism, but when it cannot be properly metabolized due to the enzyme deficiency, it causes swelling and damage to the brain’s white matter.
Because Canavan disease is a genetic disorder, it is present from birth, although symptoms often appear in early infancy. The severity and progression can vary depending on the specific mutations in the ASPA gene and how much enzyme activity remains.
In recent years, advances in gene therapy have targeted the root cause by attempting to deliver functional copies of the ASPA gene to brain cells, aiming to restore aspartoacylase activity and reduce NAA accumulation. This approach holds promise for altering the course of the disease but is still under clinical investigation.
In summary, Canavan disease arises from inherited mutations in the ASPA gene that cause a deficiency of the aspartoacylase enzyme, leading to toxic buildup of N-acetylaspartate in the brain, which damages the white matter and disrupts normal neurological function.
