Canavan disease
Canavan disease is a severe inherited neurological disorder characterized by the progressive degeneration of brain tissue, ultimately leading to fatal outcomes. It falls under a category of disorders known as leukodystrophies and is caused by a deficiency in the enzyme aspartoacylase, which is crucial for breaking down N-acetylaspartic acid in the brain. This enzyme deficiency leads to the accumulation of this substance, resulting in damage to myelin, the protective insulation of nerve fibers, and causing a spongy appearance in brain tissue.
Typically, symptoms appear in infancy, with developmental delays, macrocephaly (enlarged head), and motor skill impairments being prominent. Unfortunately, most children with Canavan disease become severely disabled and do not survive past the age of ten. The disease is inherited in an autosomal recessive pattern primarily affecting those of Ashkenazi Jewish descent, where carrier rates are notably higher. While there is currently no cure, supportive therapies and experimental treatments, including gene therapy, are under investigation to improve outcomes. Genetic screening and counseling are recommended for at-risk couples to help prevent the disease in future generations.
Canavan disease
DEFINITION Canavan disease is an inherited disorder that causes progressive, fatal degeneration of the brain. It is one of the neurologic disorders known as the leukodystrophies. Canavan disease is named for Myrtelle Canavan, the researcher who first described it in 1931.
ALSO KNOWN AS: Spongy degeneration of the brain; Canavan-Van Bogaert-Bertrand disease; aspartoacylase deficiency; ASPA deficiency
Risk Factors
Parents who carry the Canavan gene may transmit it to their offspring in an autosomal recessive genetic pattern. For the disease to occur, both parents must carry the gene. Each child has a 25 percent chance of inheriting both abnormal genes and suffering from this incurable disease. The genetic mutation is more common in Jews of Eastern and Central European background (Ashkenazi) than in the population at large, though it has been found in all ethnic groups. It is estimated that one in forty Ashkenazi Jews are carriers of the Canavan gene, resulting in a disease risk of about one in 6,400 births in this group.
Etiology and Genetics
Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown of a substance in the brain called N-acetylaspartic acid. The lack of the enzyme leads to the accumulation of N-acetylaspartic acid, which in turn destroys myelin, a substance that acts as essential insulation in the brain. This destruction causes brain tissue to degenerate, resulting in a spongelike appearance and progressive disability and death.
The gene for aspartoacylase has been located on chromosome 17, and recent work in molecular genetics has identified three common alterations in DNA that are responsible for the disease. The first is a mutation in 285 (a section or location of DNA in the gene); the second is in codon 231; and the third is in codon 305. These three mutations are the cause of greater than 90 percent of cases of Canavan disease in Ashkenazi Jews and more than 55 percent in other ethnic groups.
The disease is inherited as an autosomal recessive trait and must be carried by both parents for children to be affected. The inheritance of two altered genes leads to the deficiency of aspartoacylase. If only one parent carries the Canavan gene, then children will have a 50 percent chance of inheriting the altered gene and being carriers but will not have the disease. A single gene is sufficient for the production of the enzyme that prevents buildup of N-acetylaspartic acid. If both parents carry the Canavan gene mutation, then each pregnancy carries a 25 percent risk of disease and a 50 percent risk of carrier status.
Symptoms
Newborns with Canavan disease appear normal. Symptoms of the disease begin to appear in infancy, most often by age six months. The hallmark is developmental delay, which is most often noted when infants fail to achieve early developmental milestones such as head control. The size of the head begins to increase (macrocephaly) and muscle tone and strength decrease. Motor skills are most severely affected. As damage to critical brain tissue continues, severe feeding problems, seizures, and blindness follow. Brain degeneration is progressive, and most children with the disease become severely disabled and die by age ten.
Researchers report a less severe form of the disease has been observed. Children with this form have a slightly increased NAA level in the urine. Their development may be delayed but they are able to attend school and learn. Macrocephaly is present but less pronounced.
Screening and Diagnosis
Because of the increased of the Canavan gene in the Ashkenazi population, prepregnancy screening is recommended for couples in this group. Molecular diagnostic testing of blood samples is required to identify the three common gene mutations described above. If both parents are carriers of the gene, then prenatal diagnosis is available. Chorionic villus sampling may be performed in the first trimester of pregnancy, while amniocentesis is available in the second trimester.
Diagnosis of Canavan disease in at-risk infants is based on the presence of elevated amounts of N-acetylaspartic acid in the urine.
Treatment and Therapy
There is no cure or specific treatment for Canavan disease. Therapy is directed at modification of symptoms. Supportive measures such as the placement of feeding tubes, anticonvulsant medication, communication assistance, and physical therapy are often used. Antibiotics are used to treat common infections such as pneumonia.
Experimental studies for the treatment of Canavan disease are focused on gene therapy, including the introduction of functional aspartoacylase genes into an affected child’s brain to attempt to increase the missing enzyme. One such gene therapy was approved for clinical trials in the United States in 2024. Myrtelle was approved for trials with rAAV-Olig001-ASPA was approved for the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program. It is hoped that the treatment will target the ASPA gene that is at the root of Canavan's disease. In addition to gene therapies, medications to reduce the amount of destructive N-acetylaspartic acid in the brain are also being studied.
Prevention and Outcomes
Screening and genetic counseling are suggested for couples of Ashkenazi Jewish background and for those with a family history of Canavan disease. DNA testing is reliable and can identify whether one or both parents carry the Canavan gene in more than 99 percent of those screened. Parent screening and prenatal diagnosis are currently the only effective prevention for the disease.
Canavan disease is invariably fatal, with death often occurring by eighteen months of age, though there have been rare cases of children living into the teen years.
Bibliography
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"Canavan Disease." National Organization for Rare Disorders, 2015, rarediseases.org/rare-diseases/canavan-disease/. Accessed 2 Sept. 2024.
Holovac, Jordana. "Myrtelle Announces That the FDA Has Selected rAAV-Olig001-ASPA Gene Therapy Candidate for the Treatment of Canavan Disease for the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) Pilot Program." Myrtelle, 5 June 2024, myrtellegtx.com/fda-selects-myrtelle-for-start-pilot-program/. Accessed 2 Sept. 2024.
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Surendran, Sankar. Neurochemistry of Metabolic Diseases: Lysomal Storage Diseases, Phenylketonuria, and Canavan Disease. New York: Nova Science, 2012. Print.