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Canavan Disease
12
CANAVAN DISEASE
SANDRA SIKHAURULIDZE
18/04/2022
WHAT IS CANAVAN DISEASE?
ABOUT THE DISEASE
Canavan disease is a rare genetic disorder in which nerve cells (neurons) in the brain lose their capacity to transmit and receive information. This condition belongs to the leukodystrophies group of inherited disorders. (Canavan disease: MedlinePlus Genetics, 2020) Leukodystrophies are a set of rare, progressive, metabolic, and genetic illnesses that can damage the brain, spinal cord, and peripheral nerves. It is caused by a mutation in a single gene, which leads to improper development of one of the more than ten chemicals that make up the brain's white matter. White matter is found in the deeper tissues of the brain and contains nerve fibers that are surrounded by myelin. Myelin is a combination of lipids and proteins that covers many of these nerve fibers. It also functions as an insulator and enhances the speed with which nerve signals are transmitted. The formation of the myelin sheath is disrupted in leukodystrophies. Different types of leukodystrophy, affect specific parts of the myelin sheath. (National Organization for Rare Disorders, 2015)
FIGURE 1
(Canavan disease: MedlinePlus Genetics, 2020)
SIGNS OF CANAVAN DISEASE
Affected newborns seem healthy for the first few months of life, but developmental difficulties become apparent by the age of 3 to 5 months. Some not developed motor abilities include turning over, regulating head movement, and sitting without assistance. Other typical symptoms include hypotonia (poor muscular tone), macrocephaly (abnormally big head size), and irritability. There can also be side effects such as feeding and swallowing problems, seizures, and lack of sleep. Canavan illness in its mild/juvenile form is less frequent. Children with the disease experience somewhat delayed development of speech and motor abilities. Canavan illness can produce delays that are so minor and nonspecific that they are never detected. (Canavan disease: MedlinePlus Genetics, 2020)
A minor type of Canavan illness has been identified in recent years, with classic ASPA gene mutations and slightly raised NAA in the urine. These children may be little delayed, however are capable of learning and attending school. Although the skull may be larger, the white matter changes related with Canavan may not be present. (Canavan Disease - NORD (National Organization for Rare Disorders), 2015)
People with Canavan illness have a variable life expectancy. The neonatal/infantile type affects the majority of people until they reach childhood, while some may live until adolescence or beyond. The mild/juvenile form does not lead to a shorter lifetime.(Canavan disease: MedlinePlus Genetics, 2020)
SYMPTOMS
(Chunk, 2019)
(Floppy Baby, 2004)
HOW COMMON IS CANAVAN?
Mutations That Occur in Different Populations
(Mirsky, 2018)
The most common and severe type of Canavan disease is neonatal/infantile Canavan illness. It affects people of all ethnic backgrounds, although it impacts Ashkenazi (eastern and central European) Jews more frequently. Affected children born to Ashkenazi Jewish parents have a risk of 1 in 6,400 to 1 in 13,456. (Canavan disease: MedlinePlus Genetics, 2020)
(Ashkenazi Jews and Canavan Disease — The Canavan Research Foundation,2019)
INHERITANCE
How is the Canavan Disease Inherited?
Canavan disease is an autosomal recessive disorder, meaning both copies of the gene in each cell have mutations. When a child receives the same mutated gene from both parents, they are considered to have a recessive genetic disease. The risk equally applies to both men and women. If they were born with one normal and one damaged gene, the child will be a carrier, but will not show symptoms. With each pregnancy, there is a 25% chance that two carrier parents will both pass on the faulty gene and, as a result, have an affected kid. In addition, there is a 50% chance of having a kid who is a carrier of the disease such as the parents. The child also has a 25% probability of receiving standard genes from both parents and being genetically healthy. (Autosomal recessive: MedlinePlus Genetics, 2022)
(Nain, 2016)
FIGURE 7 AND 8
DIAGRAMS
The Cerebellum With White Spots (holes) in the Myelin
Areas of White Matter
(Richardson, 2015)
(Dahmoush, 2016)
NORMAL FUNCTION OF THE ASPA GENE
ASPA GENE MUTATIONS
The Aspartoacylase is the official name of the ASPA gene. This gene encodes an enzyme that breaks down the molecule N-acetyl-L-aspartic acid (NAA) in the brain into aspartic acid and acetic acid. The ASPA gene is located on chromosome 17 of the human genome. The creation and breakdown of NAA is essential for sustaining the white matter of the brain, which is made up of nerve fibers covered in a myelin sheath. The myelin sheath is a protective layer that helps the effective transmission of nerve impulses while also protecting nerve fibers. (ASPA gene: MedlinePlus Genetics, 2020)
OTHER NAMES FOR THE GENE
The Aspartoacylase (ASPA) gene is also known as the:
- ACY2
- ACY2_HUMAN
- Aminoacylase 2
- ASP
- N-acyl-L-aspartate amidohydrolase
(ASPA gene: MedlinePlus Genetics, 2020)
(Hapak, 2007)
(Aspartoacylase - Wikipedia, 2021)
CAUSE
Genetic Mutations that Cause the Canavan Disease
Canavan disease is caused by mutations in the ASPA gene, which impacts the N-acetylaspartic acid breakdown. The spongiform degeneration of the white matter caused by extraordinarily high levels of NAA leads to symptoms of Canavan disease. (National Organization for Rare Disorders, 2015)
In the Ashkenazi Jewish culture there are two common ASPA gene mutations that lead to the Canavan disease. At position 285 of the enzyme, one of these mutations changes the amino acid glutamic acid with the amino acid alanine. The amount of active aspartoacylase is severely reduced as a result of this genetic mutation. The other mutation, causes protein synthesis to stop early, causing an unusually tiny, non-functional form of the enzyme. Individuals who are not part of the origin are likely to have different ASPA gene mutations. At position 305 of aspartoacylase, this mutation replaces the amino acid alanine with glutamic acid, and a non-functional form of the enzyme is also produced. Mutations in the non-Jewish population are more varied meaning that the DNA mutational analysis of blood samples may often not detect the condition. Full sequencing of the ASPA gene may be necessary, however, it only identifies around 87% of mutant alleles in this group. (ASPA gene: MedlinePlus Genetics, 2020)
(Aspa, 2022)
HEALTH CONDITIONS
Health Conditions Related to the Genetic Changes of the Aspa Gene
Canavan disease is caused by more than 80 mutations in the ASPA gene. Two primary types of Canavan disease were identified, the neonatal/infantile (most severe form) and mild/juvenile (less common).
The symptoms of the disorder are related to an increase of NAA in the brain. As the nervous system develops, If NAA is not correctly broken down, the imbalance in the chemicals will disrupt the formation of the myelin sheath. The increase of NAA also causes the destruction of the present myelin sheaths. Without this protection nerves stop to function, affecting the brain growth. (ASPA gene: MedlinePlus Genetics, 2020)
(Mutation Story: Canavan Disease | Zayd's Blog, 2016)
THERAPIES FOR CHILDREN AFFECTED BY CANAVAN
The therapy for Canavan disorder is unique for each patient. Pain and discomfort may be relieved with supportive treatment such as physical therapy and early diagnosis that may improve posture and communication skills. Feeding tubes may be used to guarantee sufficient nutrition and hydration if swallowing issues occur. In addition, anti-seizure medicines can be used to treat epilepsy.
Researchers have been looking at a gene therapy that will help children who are suffering from Canavan disease. In this gene therapy, healthy copies of the damaged ASPA gene are implanted into the brains of affected kids. These genes then create the aspartoacylase enzyme, which is needed to break down NAA. Children treated with gene therapy have shown significant improvement in their symptoms. However, more testing and investigation need to be done in order to prove the long-term safety and effectiveness of this treatment method. (National Organization for Rare Disorders, 2015)
TREATMENT
(Regalado, 2022)
Bibliography
(information)
BIBLIOGRAPHY
- Conditions, G., 2020. Canavan disease: MedlinePlus Genetics. [online] Medlineplus.gov. Available at: <https://medlineplus.gov/genetics/condition/canavan-disease/> [Accessed 11 April 2022].
- Database, G., 2022. ASPA Gene - GeneCards | ACY2 Protein | ACY2 Antibody. [online] Genecards.org. Available at: <https://www.genecards.org/cgi-bin/carddisp.pl?gene=ASPA#:~:text=ASPA%20Gene%20%2D%20Aspartoacylase&text=This%20gene%20encodes%20an%20enzyme,NAA%20scavenger%20in%20other%20tissues.> [Accessed 11 April 2022].
- Medlineplus.gov. 2020. ASPA gene: MedlinePlus Genetics. [online] Available at: <https://medlineplus.gov/genetics/gene/aspa/> [Accessed 11 April 2022].
- NCBI. 2021. Protein Family Models. [online] Available at: <https://www.ncbi.nlm.nih.gov/genome/annotation_prok/evidence/NF002601/> [Accessed 11 April 2022].
- NORD (National Organization for Rare Disorders). 2015. Canavan Disease -. [online] Available at: <https://rarediseases.org/rare-diseases/canavan-disease/> [Accessed 11 April 2022].
- ScienceDirect. 2014. Aspartoacylase. [online] Available at: <https://www.sciencedirect.com/topics/nursing-and-health-professions/aspartoacylase/> [Accessed 11 April 2022].
IMAGES BIBLIOGRAPHY
- Aspa | a BridgeBio Company. 2022. Aspa | Aspa. [online] Available at: <https://aspatx.com/> [Accessed 11 April 2022].
- Disease, J., 2019. NTSAD - Jase's Benefit for a Cure for Canavan Disease. [online] Ntsad.org. Available at: <https://ntsad.org/index.php/family-events/jase-s-benefit-for-a-cure-for-canavan-disease> [Accessed 11 April 2022].
- En.wikipedia.org. 2021. Aspartoacylase - Wikipedia. [online] Available at: <https://en.wikipedia.org/wiki/Aspartoacylase> [Accessed 11 April 2022].
- Hapak, M., 2007. Canavan Disease. [online] Solczyk.tripod.com. Available at: <https://solczyk.tripod.com/biology07olczyk/id21.html> [Accessed 11 April 2022].
- MIRSKY, M., 2018. East Bay parents trying to save twins from rare Ashkenazi disease – J.. [online] J. Available at: <https://jweekly.com/2018/12/28/east-bay-parents-trying-to-save-twins-from-rare-ashkenazi-disease/> [Accessed 11 April 2022].
- Myriverside.sd43.bc.ca. 2016. Mutation Story: Canavan Disease | Zayd's Blog. [online] Available at: <http://myriverside.sd43.bc.ca/zayda2016/2016/12/12/mutation-story-canavan-disease/> [Accessed 11 April 2022].
- Nain, Z., 2016. [online] researchgate.net. Available at: <https://www.researchgate.net/figure/The-flow-of-gene-in-an-autosomal-recessive-pattern-Image-Credit-US-National-Library_fig3_308433714> [Accessed 11 April 2022].
- Regalado, A., 2022. This family raised millions to get experimental gene therapy for their children. [online] MIT Technology Review. Available at: <https://www.technologyreview.com/2021/04/13/1022210/gene-therapy-expensive-treatment-genetic-diseases/> [Accessed 11 April 2022].
- Richardson, M., 2022. Canavan Disease. [online] Brainfacts.org. Available at: <https://www.brainfacts.org/diseases-and-disorders/neurodegenerative-disorders/2015/image-of-the-week-canavan-disease> [Accessed 11 April 2022].
- ScienceDirect. 2014. Aspartoacylase. [online] Available at: <https://www.sciencedirect.com/topics/nursing-and-health-professions/aspartoacylase/> [Accessed 11 April 2022].
- Syllabus.cwru.edu. 2004. Floppy Baby. [online] Available at: <http://syllabus.cwru.edu/YearThree/neuroscience/NeurLrngObjectives/Floppy%20Baby.htm> [Accessed 11 April 2022].
- The Canavan Research Foundation. 2022. Ashkenazi Jews and Canavan Disease — The Canavan Research Foundation. [online] Available at: <http://www.canavan.org/ashkenazi-jews-and-canavan-disease> [Accessed 11 April 2022].