Canavan disease, or Canavan-Van Bogaert-Bertrand disease, is a rare genetic disorder primarily affecting the central nervous system. It falls under the category of leukodystrophies, disorders characterized by abnormal development or destruction of the white matter in the brain. Canavan disease is caused by mutations in the ASPA gene, leading to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited in an autosomal recessive manner, meaning both parents must carry a mutated ASPA gene for their child to be affected. Carriers (individuals with one regular and one mutated gene) are typically asymptomatic. The incidence of the pathology in the general population is estimated to be between 1 in 200.000 and 1 in 400.000 individuals. It increases markedly in Ashkenazi Jews, in whom there is 1 case in 5.000 to 6.700 individuals.
Canavan disease genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features and aspects of Canavan disease include:
- Progressive White Matter Damage: The hallmark of Canavan disease is the progressive degeneration of the white matter in the brain. The white matter contains myelin, a fatty substance that insulates nerve fibers and facilitates proper nerve signal transmission.
- Symptoms Onset: Symptoms of Canavan disease typically become apparent in early infancy, usually within the first few months of life.
- Neurological Impairment: Children with Canavan disease may experience developmental delays, intellectual disability, and impaired motor function. Hypotonia (low muscle tone) and difficulties with movements, such as sitting and crawling, are common.
- Macrocephaly: Children with Canavan disease often have an enlarged head, a condition known as macrocephaly.
- Seizures: Seizures are common in individuals with Canavan disease and may be observed during the disease.
- Visual and Hearing Impairments: Vision and hearing impairments may also be associated with Canavan disease.
- Limited Lifespan: Canavan disease is typically a progressive and severe disorder. In most cases, affected individuals have a limited lifespan, often not surviving beyond childhood.
- Management and Supportive Care: There is currently no cure for Canavan disease. Management is primarily supportive and focuses on addressing symptoms and improving the quality of life for affected individuals and their families. Due to the genetic basis of Canavan disease, genetic counseling is essential for families at risk. Prenatal testing is available for couples with a known risk of having a child with Canavan disease, allowing them to make informed decisions about family planning.
Diagnosis involves genetic testing to identify mutations in the ASPA gene. Brain imaging studies, such as magnetic resonance imaging (MRI), may reveal characteristic changes in the white matter.
There is a mild form of Canavan disease (juvenile type) in which children have standard or slightly delayed motor and speech development without regression, usually requiring only speech therapy to improve their communication skills.
Canavan disease is caused by pathogenic variants in the ASPA gene, which codes for an enzyme that transforms N-acetyl aspartic acid (NAA) into L-aspartate. This reaction is essential in the brain as it helps maintain the integrity of the white matter. When NAA is not metabolized correctly, it accumulates in body fluids.
More than 150 pathogenic or possibly pathogenic variants in ASPA are known. The predominant variant in the Ashkenazi Jewish population is c.854A>C (p.Glu285Ala), which results in the base change A to C at nucleotide 854. The ASPA protein affects the catalytic domain of aspartoacylase, causing a loss of function of the enzyme. Another variant usually present in this population is c.693C>A (p.Tyr231Ter), which causes the appearance of an early stop codon. The most frequent pathogenic variant in the general population is c.914C>A (p.Ala305Glu), which reduces enzyme activity by up to 10%. All three variants are associated with the severe disease that appears in early childhood.
On the other hand, c.212G>A (p.Arg71His) is associated with the mild juvenile form of Canavan. Two copies of c.212G>A or one copy of c.212G>A in combination with another copy of a severe pathogenic variant (e.g., c.854A>C, c.693C>A or c.914C>A) can cause juvenile-type Canavan.
The genetic test of Canavan Disease analyzes the five most frequent pathogenic mutations of the ASPA gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
