Introduction

Canavan disease is an uncommon degenerative disease that affects the brain which is inherited and causes damage to nerve cells and ultimately causes loss of white matter in the brain. It is classed as one of the leukodystrophy (loo-kuh-dih-struh-fee) disorders, meaning that it affects the myelin sheaths, which is the section of the nerves that forms a protecting cover around the nerves and helps the transfer of impulses along nerves. Most cases happen during infancy, with noticeable symptoms affecting development being displayed during this period, however there is also a juvenile form which happens during teenage years.

This article will go more into depth about what N-Acetylaspartic acid (NAA) is and what role it has in the development and progression of Canavan disease and in turn, the effects of that on the brain.

Symptoms of Canavan Disease

Symptoms of Canavan disease are differentiated into either Infantile or Juvenile form, with the infantile form generally having more severe symptoms. One of the most important and life-changing symptoms of the infantile form is developmental delays. Individuals affected would have trouble with basic tasks such as walking, sitting, eating, drinking and even being able to control their head properly. This is also accompanied by macrocephaly, meaning a larger than normal head that can appear floppy along with other muscles in the body, which is associated with a reduced muscle tone. Other symptoms include difficulty sleeping or constantly waking up, causing irritability. Less common symptoms include problems with eyesight and movement, with the individual having problems with visual tracking and possibly even blindness with severe cases. Life expectancy is greatly varied, with those with severe cases not making it out of infancy, while others with weaker symptoms can proceed into their teens and others even living out their full lives.

Unlike infantile form, individuals with juvenile form have less severe symptoms. Life expectancy is generally unaffected with people being able to live their lives, albeit with difficulty. There are still developmental delays and issues, however it might only be limited to speech and motor issues. Seizures can also be present, although they are less common compared to infantile form of Canavan disease.¹

What is N-Acetylaspartic Acid (NAA)

N-Acetylaspartic acid is a metabolite that is found abundantly in the central nervous system of mammals, especially the brain, and particularly the neurons. Although its primary function is still under debate, it has been documented to be involved in tasks such as myelin synthesis, neural metabolism, and osmoregulation.² NAA is derived from Aspartic acid, which is one of the 22 proteinogenic amino acids, which are the molecules that build proteins. A change in how this metabolite functions will have a drastic effect on the development of the brain and its activity, causing disorders such as Canavan disease. In that regard, NAA can be considered as a useful biomarker in such disorders as the quantity change can be examined and measured.

There have been a lot of trials and research done to find the biological function of NAA; however, it has been a difficult task since the molecule has a strange and unusual metabolic structure. The enzyme that produces NAA is found in the mitochondria of nerve cells, while the enzyme that breaks it down (aspartoacylase), is often found in the brain’s white matter, which contain myelin, this means that aspartoacylase is an important part of the myelin sheath in the white matter regions of the brain.³

Nerve cells or neurons are responsible for the transfer of electrical impulses. Without them, messages cannot be sent across the body and thus they are crucial. Myelin sheaths surround the neurons, providing them with a protein covering to insulate them and increase the speed of the impulse travelling through them. This speed increase is due to the gaps between the myelin sheaths, which makes the impulse jump across each neuron rather than travelling continuously along the axon. 

Although NAA doesn’t directly form the myelin sheath, it is taken to oligodendrocytes, which break down NAA to acetate and form lipids that eventually build the myelin sheaths. One of the roles of NAA is as an osmolyte. Osmolytes are molecules that help regulate fluid balance in the brain.

ASPA is a gene that essentially creates an enzyme called aspartoacylase. In a normal brain, aspartoacylase breaks down N-Acetylaspartic acid to produce the lipids that are necessary to build the myelin sheath. In certain individuals, a mutation happens in this gene which forms a deficiency in aspartoacylase. This deficiency essentially allows the uncontrolled buildup of NAA that disrupts brain activity since it is not broken down into the lipids required for myelin formation. Being unable to efficiently transfer electrical impulses leads to problems such as macrocephaly and reduced control of the head, reduced muscle tone that can cause a floppiness in the body and produce developmental delays in basic tasks such as walking.

Diagnosis and detection

Canavan disease is often diagnosed as a combination of several tests: biochemical, molecular genetic and clinical testing. The easiest way to diagnose it would be on a visual clinical test, such as witnessing the abnormal head size, developmental delays in speech and motor activities and hypotonia, which is the reduced muscle tone. These could be done with a simple consultation and examination with a medical professional.

Biochemical testing focuses on NAA levels and can be done primarily on urine analysis using gas chromatography-mass spectrometry and scans on the brain done with proton magnetic resonance spectroscopy. Both tests detect the excessive levels of NAA in the body and can be a positive identifier of Canavan disease.⁴

Molecular genetic testing is done by performing genetic testing on an individual, otherwise known as a proband, to identify two pathogenic variants or mutations in the ASPA gene, which is normally one from each parent.⁵

The final testing method performed can be a CT or MRI scan, which is used to view and identify the degeneration of white matter in the brain. On an MRI scan for example, damage and degeneration of white matter shows up as lesions, which are picked up as bright spots on the scan. As Canavan disease progresses, there may be more bright spots as the nerve fibres are damaged.

Treatment and research

Canavan disease is untreatable as of this moment. Most of the treatment options available focus on managing and controlling symptoms while also focusing on quality of life. Providing support during feeding, walking and other motor tasks such as vision tracking can be given to help the individual with daily activities. Regular doctor examinations with tests and scans can make sure the symptoms are not worsening and any changes can be immediately picked up. Those suffering from seizures can be put on anticonvulsant medication to help keep their seizures under control.

Gene therapy in the form of the replacement of the ASPA gene could be a potential treatment option.⁶ Replacing the mutated ASPA gene with a functioning normal gene may possibly prevent the excessive buildup of NAA from being formed, which can be a suitable cure. In vivo, gene editing might make it possible to fix ASPA mutations in vivo, however that requires more time, research and effort to make it feasible and effective.⁷

Conclusion

To summarise, Canavan disease is a debilitating and impactful degenerative illness that affects mostly infants but also toddlers and teens by the degeneration of white matter in the brain. This greatly affects the individual’s life by not only preventing them from being able to do simple tasks such as eating, walking or sitting, but also affecting their life expectancy. By a mutation in the ASPA gene, N-Acetylaspartic acid is allowed to build up uninhibited, preventing it from being broken down to form myelin. This slows down and alters how electrical impulses travel along the neurons as the myelin sheath is damaged, which is why individuals suffering are unable to effectively perform tasks that require motor function.

Early diagnosis is crucial since there is no cure at this current stage of time. Detecting the symptoms can at least help manage the condition slightly better and provide support to the individual and allow them to have a slightly better quality of life. With more research and time spent on treatment options and remedies, it may be possible to perform operations such as gene therapy to replace the mutated ASPA gene and hopefully be able to prevent the degeneration of white matter and myelin sheaths. Although it is too early to guarantee if this will be a cure, researchers and scientists are optimistic on this course of action.