What is Canavan Disease?
Canavan disease, also known as Canavan-Van Bogaert-Bertrand disease, is a rare, inherited condition that progressively worsens and can lead to death. This disease, which starts in infancy, is part of a group of genetic issues called leukodystrophies. It is caused due to the lack of a vital enzyme, resulting in diminishing white matter in the brain, which is crucial for transmitting nerve signals.
The most common form of this disease appears just after birth and usually has the most severe symptoms. Most newborns seem healthy initially but demonstrate clear signs of delayed physical development within 2 to 6 months. The baby might struggle with movements like turning over, controlling head movements, or supporting itself. Low muscle tone (also known as hypotonia) and an abnormally large head size (called macrocephaly) are typical features. Most infants with Canavan disease have feeding difficulties and may experience seizures.
What Causes Canavan Disease?
Canavan disease is a genetic disorder linked to a specific location on chromosome 17. The disease occurs when there’s a mutation or change in the ASPA gene, which is responsible for producing an enzyme called aspartoacylase. When this enzyme is missing or not functioning correctly due to the ASPA mutation, a substance called N-acetylaspartic acid (NAA) starts to build up in the brain.
Usually, NAA aids the normal functioning of brain cells, but excessive amounts can lead to problems. Specifically, it’s thought to impair cells called oligodendrocytes, which play a crucial role in supporting and insulating nerve fibers. This results in changes to the brain’s structure and the gradual breakdown of a protective coating around nerve fibers, known as myelin, housed in the outer layer of axons (the long, thin part of a nerve cell). This happens in a way similar to a sponge absorbing water, hence the term ‘spongiform changes’. This disruption can result in various neurological issues associated with Canavan disease.
Risk Factors and Frequency for Canavan Disease
Canavan disease is a very common brain disease in infants that often deteriorates over time. While it seems to affect Ashkenazi Jews more frequently, it can also occur in other community groups. It’s currently challenging to determine how common the disease is because there isn’t enough data. For Ashkenazi Jews, about 1 in every 37 to 57 people carry the disease which indicates that this disease affects about 1 in every 6,000 to 14,000 individuals in this group.
Signs and Symptoms of Canavan Disease
Aspartoacylase deficiency is a rare genetic condition that usually appears when a baby is about three months old. It is characterized by symptoms such as weariness, feeling uninterested in things around them, a weak cry and suck, lack of control over the head when it is moved from a lying to a sitting position, low muscle tone, poor or no ability to follow movement with their eyes, vomiting, and seizures. Some babies might also have difficulty feeding, show irritability, and lack visual attention.
By the time they reach three to six months, their heads may have grown larger than usual. In addition, the low muscle tone can shift into stiffness, overactive reflexes, uncontrolled movements, and spasms, especially in response to loud sounds.
When they reach six months, almost all babies with this condition show significant nervous system abnormalities and may stop developing motor skills.
Blindness due to damage to the optic nerve typically occurs around six to eighteen months. Also, around half the patients experience seizures similar to epilepsy. Contrary to most similar conditions, the protein level in the fluid around the brain and spinal cord is usually normal.
In the final stages of the disease, the patient will have difficulty swallowing, reflux, and signs of severe brain dysfunction.
- Less common forms of aspartoacylase deficiency show up later in life. A possible adolescent-onset form, appearing after age five, results in slightly delayed speech and motor skill development during childhood. It is often overlooked, mainly due to the mild nature of the delays.
- An adult-onset version of the disease clinically resembles multiple sclerosis.
Testing for Canavan Disease
If a baby shows certain symptoms like floppy muscles, inability to control their head, and an unusually large head, and a brain scan suggests they may have a deficiency in an enzyme called aspartoacylase, testing the baby’s urine could help confirm the diagnosis. This is because a high level of a substance called NAA in the urine could be an indicator of this deficiency. The most accurate way to confirm it would be to analyze skin cells grown in the lab for their aspartoacylase activity. If the urine and skin cell results suggest the deficiency, then a genetic test can be done, which can help in advising the family on genetic risks.
The amount of NAA in the urine can be up to 200 times higher than normal levels. To measure these levels, techniques such as gas chromatography or mass spectrometry are used.
Prenatal testing (testing while the baby is still in the womb) can be done by measuring NAA levels in the amniotic fluid, which surrounds the baby in the uterus. This testing also involves gas chromatography or mass spectrometry and a genetic analysis.
Brain scans can also help in diagnosing the deficiency. A CT scan may show low density in the white matter of the brain, due to degeneration and swelling. Ordinarily, there is no enhancement after a contrast dye is injected – a technique commonly used to make clearer images.
With an MRI, the brain might appear larger than normal (a condition called megalencephaly). Usually, there is extensive involvement of the white matter in both sides of the brain, which typically shows up as low signal on the T1 images and high signal on the T2 images. There is usually no enhancement after a contrast dye is used. An MRI scan can also show high levels of NAA, and a high ratio of NAA to creatine, another substance found in the body. The term “CaNAAvan” helps to remember this relationship.
Treatment Options for Canavan Disease
Currently, there isn’t a specific medication that can modify or cure Canavan disease. The management of this condition focuses on maintaining good hydration and nutrition, safeguarding the airways, managing seizures, reducing the risk of muscle shortening and stiffness (contractures), and treating infections. It’s usually recommended that the patient’s nutritional and developmental status be evaluated to guide the treatment plan.
If a person with Canavan disease has difficulty swallowing (dysphagia), a feeding gastrostomy tube, which is a tube inserted through the abdomen into the stomach, may be utilized. This can help maintain adequate nutrition and hydration and lower the risk of aspiration, which is when food or liquid enters the lungs, due to the patient’s weakened reflexes.
Seizures, or sudden overactivity of nerve cells in the brain, are managed with standard antiepileptic drugs, which are medications that can reduce the frequency and impact of seizures. Physical therapy and regular changes in body position can lessen the risk of contractures and ulcers and can help improve the patient’s seated posture. Injections of botulinum toxin, a type of toxin that can relax muscles, can be utilized to manage muscle stiffness or spasms (spasticity). Special education programs and other interventions can also be considered to support the patient’s development and quality of life.
What else can Canavan Disease be?
When looking into disorders that affect the protective covering of nerve fibers (also known as dysmyelinating diseases), the following should be considered:
- Adrenoleukodystrophy: This usually doesn’t affect the U-fibers in the subcortex. It typically has a noticeable pattern in the white matter of the occipitoparietal periventricular region.
- Alexander disease: This tends to affect the front part of the brain, and it becomes more widespread as time goes on. The levels of NAA (an important chemical in the brain) appear normal when conducting Magnetic Resonance Spectroscopy tests.
- Metachromatic leukodystrophy: This usually doesn’t affect U-fibers in the subcortex as well, and presents a unique ‘butterfly’ pattern.
- Pelizaeus-Merzbacher disease: This condition is often paired with cerebellar atrophy (loss of cells in the cerebellum, a region of the brain). A “tigroid” pattern of bright spots can be noticed, and like others, it typically doesn’t affect the subcortical U-fibers.
What to expect with Canavan Disease
For serious cases, the outlook can be quite severe, and it may not always be possible to live beyond the first ten years of life. For less severe cases, life expectancy can vary. Most patients are likely to live through their teenage years and may have a normal lifespan.
Possible Complications When Diagnosed with Canavan Disease
The following are some of the potential issues that may occur:
- Difficulty with cognitive activities
- Struggling with controlling body movements
- Difficulty in consuming food
- Lack of muscle strength
- Inability to move body parts
- Loss of vision
- Unexpected, uncontrolled body movements
- Possibility of life loss