What is Canavan Disease?

A progressive fatal neurological disorder

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Canavan disease is a progressive, fatal neurological disorder. Symptoms become apparent during infancy (3-5 months) and affected children are rarely able to walk or talk, with death usually occurring by age 10. This disorder is due to an abnormal accumulation of a compound in the brain that destroys the insulating sheath of the brain cells.

What are the Symptoms of Canavan Disease?

Canavan disease is caused by decreased levels of the aspartoacylase enzyme which is essential to prevent the build up of N-acetylaspartic acid (NAA) in the brain. It is the accumulation of NAA that damages the brain cells and causes the symptoms associated with Canavan disease. Some affected children only suffer from mild symptoms (mildly delayed speech or motor development), as they still produce enough aspartoacylase to prevent excessive NAA accumulation.

However, most patients diagnosed with Canavan disease have the neonatal/infantile form, which is the severe form of Canavan disease. Affected infants appear normal at birth, but by 3-5 months, NAA has accumulated to high enough levels that the typical disease symptoms become apparent. Symptoms include macrocephaly (an abnormally large head), lack of head control, developmental delays, delayed motor skills and an inability to sit, stand, walk or talk. Some children develop paralysis, blindness and/or hearing loss.

Optic atrophy, the deterioration of the optic nerve, is present in many children with severe Canavan disease, although these children can usually still visually track objects. As they get older individuals with Canavan disease develop spasticity, which is when certain muscles keep contracting continuously, because they have low muscle tone (hypotonia). Older children with severe Canavan disease may experience sleep disturbance, seizures and feeding difficulties. The life expectancy of children with severe Canavan disease is variable, with some children dying in the first few years and others surviving into their teens or beyond.

What Causes Canavan Disease?

Mutations in the ASPA gene are responsible for Canavan disease. ASPA encodes an enzyme called aspartoacylase, which is required for breaking down a compound called N-acetyl-L-aspartic acid (NAA). Mutations in the ASPA gene reduce the level and function of aspartoacylase and the resulting high levels of NAA damage the myelin sheaths that surround the brain cells (neurons). This prevents the neurons from communicating and functioning correctly.

How is Canavan Disease Diagnosed?

Diagnosis of Canavan disease can be achieved by measuring NAA levels in urine, aspartoacylase activity in cultured cells, neuroimaging and genetic analyses to identify mutations in the ASPA gene.

The concentration of NAA is measured using gas chromatography-mass spectrometry. Individuals with severe Canavan disease have more than 10-fold (up to 100-fold) increased levels of NAA in their urine. It is possible to test the NAA levels in amniotic fluids using the same techniques and the NAA concentration will increase from 0.33-2.55 μmol/L in unaffected pregnancies to 8.68 μmol/L in affected pregnancies. People affected by mild forms of Canavan disease, may not show significantly elevated NAA levels.

Aspartoacylase enzyme activity can be measured from cultured cells, commonly skin fibroblasts. Individuals with severe Canavan disease will have no measurable enzyme activity, whereas carriers of the disease (one defective ASPA gene) will have about half the normal enzyme activity. However, enzyme activity cannot be relied upon for prenatal testing and also is not reliable on its own, as enzyme activity can vary with culture conditions.

Neuroimaging (CT and MRI) is performed when severe Canavan disease is suspected, as it will show general degradation of white matter in the brain.

Genetic testing can be used to diagnose affected patients (pre- or post-birth) and identify carriers of the disease who do not show any symptoms. The Jewish disease panel offered here analyzes four different mutations in the ASPA gene that cause Canavan disease. Two common mutations, E285A and Y231X, and a rare mutation IVS2-2A>G account for 98% of the Ashkenazi Jewish individuals with Canavan disease and about 3% of the non-Jewish Canavan patients. The fourth mutation A305E is found in 40%-60% of non-Jewish patients and in about 1% of Ashkenazi Jewish patients with Canavan disease. These four mutations may also be referred to by the following nucleotide changes – c.854A>C (E285A), c.693C>A (Y231X), c.433-2A>G (IVS2-2A>G) and c.914C>A (A305E).

How is Canavan Disease Treated?

There is no cure or standard treatments for Canavan disease and current treatment options involve managing symptoms. After diagnosis, a brain MRI, a developmental assessment and a nutritional assessment will be performed to establish the severity of the disease. In the case of severe or neonatal/infantile Canavan disease, treatment is supportive and is directed towards providing nutrition, hydration, managing infectious diseases and protecting the airway. Some children benefit from physical therapy to manage abilities and seating posture, and other therapies to enhance communication skills. Seizures may be treated with anti-epileptic drugs and feeding gastrostomies may be required to maintain adequate intake and hydration when swallowing difficulties are noticed. The drug Diamox is used to reduce intracranial pressure and Botox injections are used to relieve spasticity.

Individuals with only mild Canavan disease may require speech therapy or tutoring but generally will not require special medical care.

Recommended Links:
Birken DL, Oldendorf WH. (1989) N-Acetyl-L-Aspartic acid: A literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci Biobehav Rev. 13(1): 23–31.

Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.

Matalon R, Michals-Matalon K. (1999) [Updated 2011 Aug 11]. Canavan Disease. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Olsen TR, Tranebjærg L, Kvittingen EA, Hagenfeldt L, Møller C, Nilssen O. (2002) Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease. J Med Genet. 39(9): e55