Elevated N-acetylaspartic acid is due to the genetic disorder Carnavan’s disease, a potentially fatal disease causing spongy degeneration of the brain. 

What is Carnavan’s disease?

Canavan disease is a rare inherited disorder that damages the ability of nerve cells (neurons) in the brain to send and receive messages. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies disrupt the growth or maintenance of the myelin sheath, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses.

Mutations in the ASPA gene cause Canavan disease. The ASPA gene provides instructions for making an enzyme called aspartoacylase. This enzyme normally breaks down N-acetyl-L-aspartic acid, which is predominantly found in neurons in the brain. The function of N-Acetylaspartic is unclear. Researchers had suspected that it played a role in the production of the myelin sheath, but recent studies suggest that N-Acetylaspartic does not have this function. The enzyme may instead be involved in the transport of water molecules out of neurons.

Mutations in the ASPA gene reduce the function of aspartoacylase, which prevents the normal breakdown of NAA. The mutations that cause the neonatal/infantile form of Canavan disease severely impair the enzyme's activity, allowing N-Acetylaspartic to build up to high levels in the brain. The mutations that cause the mild/juvenile form of the disorder have milder effects on the enzyme's activity, leading to less accumulation of N-Acetylaspartic.

Synonyms of Canavan Disease:

The symptoms of the disease can vary greatly. 

Some of the most common symptoms are:

- larger-than-normal head circumference
- poor head and neck control
- reduced visual responsiveness and tracking
- unusual muscle tone, leading to stiffness or floppiness
- unusual posture, with legs often kept straight and arms flexed
- difficulty eating, with food sometimes flowing up into the nose
- difficulty sleeping
- seizures

The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally large head (macrocepahly), and severely diminished muscle tone (hypotonia) resulting in “floppiness.” Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.

Affected infants also show delays in reaching developmental milestones (e.g., sitting or standing unassisted) and most never walk independently. The progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression) and mental retardation also become apparent during infancy. Most affected infants do learn to smile, laugh, raise their heads and interact socially.

Additional symptoms that affect children with Canavan disease include seizures, sleep disorders, feeding difficulties, nasal regurgitation, backflow of acid from the stomach to the esophagus (reflux) sometimes associated with vomiting, and deterioration of the nerves of the eyes (optic nerves) that transmit impulses from the nerve-rich membrane lining the eyes (retina) to the brain (optic atrophy). Optic atrophy may cause reduced visual responsiveness. In most case, hearing is unaffected, but hearing loss can occur.

As affected infants age, hypotonia may eventually develop into spasticity, a condition characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Affected individuals may eventually exhibit uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or paralysis. Canavan disease eventually progresses to cause life-threatening complications; however, the severity and progression of the disease varies. Some individuals develop life-threatening complications in infancy; others live beyond their teen-age years.

In the last few years, a mild form of Canavan disease has been recognized, with characteristic mutations of the ASPA gene and only slightly increased NAA in the urine. These children may be only slightly delayed, can learn and go to school. The head may be somewhat enlarged, but the typical white matter changes associated with Canavan may be absent. The prognosis is certainly much better.

Potential treatment options:

The treatment of Canavan disease is directed toward the specific symptoms that are apparent in each individual. Supportive care may alleviate some discomfort. Physical therapy and early intervention may help to improve posture and communication skills, respectively. If swallowing difficulties occur, feeding tubes may be useful to ensure proper nutrition and hydration. Seizures may be treated with anti-seizure (anti-convulsant) medications.

Genetic counseling and carrier testing will benefit families in which this disease occurs.

References:

https://link.springer.com/chapter/10.1007%2F978-3-642-55878-8_14
https://medlineplus.gov/genetics/condition/canavan-disease/
https://rarediseases.org/rare-diseases/canavan-disease/