The Canavan's disease Is a rare genetic disease that occurs because the nerve cells of the brain are damaged and unable to communicate with each other.
This disease is present in any society and ethnicity, although it is much more frequent in the Jewish Ashkenazí population (settled in the east the center of Europe) and its descendants, where they are affected 1 of each 6.400-13.00 people. The global prevalence is unknown.
Characteristics of Canavan's disease
This disease is within the group of Leukodystrophies . This category covers all genetic disorders in which the Myelin That envelops the axons of the neurons is damaged and, therefore, there is no good communication between neurons .
The most common and at the same time most serious form of this disease is the neonatal or infantile. This form of Canavan's disease affects newborn infants or in their first years of life.
The children who suffer from this disease do not present any problems during the first months of life, but these begin to bloom between the 3 and 5 months.
The main symptoms are due to developmental deficits, where children have motor problems that prevent them from turning around, turning their heads or sitting down without any support.
Other common symptoms are muscle weakness (hypotonia), abnormal development of the head ( Macrocephaly ) And irritability. To a lesser extent, they may also have trouble eating, Convulsions Y Sleep problems .
Another less common form is Canavan's disease onset in middle childhood or adolescence. Children and adolescents with this disease have Language development problems And motor skills, but often these problems are so mild that they are not identified as symptoms of Canavan's disease.
The life expectancy of people who have Canavan's disease is very heterogeneous, varying significantly depending on the time of onset of the disease.
Children who suffer from the neonatal or childhood form usually live only a few years, although some reach adolescence and very few until adulthood. While those who suffer the juvenile form have a normal life expectancy.
symptom
As already mentioned, there are two well differentiated forms of Canavan's disease: neonatal or childhood onset and onset in middle childhood or adolescence.
Neonatal or infantile onset
Symptoms of Canavan disease of neonatal or infantile onset are very severe, not usually noticed until 3-50 months of age and include macrocephaly, loss of motor control of the head and deficits in development. Deficits in development are becoming more evident as the child grows.
The most severe symptoms are those related to motor problems, as children are unable to sit or stand without braces, walking or talking. When the Hypotonia Can lead to a Spasticity .
Although they have all these motor problems they can learn how to interact socially, smile, point objects...
Some children also suffer from optic atrophy, which causes visual problems, although they can still identify objects visually.
As symptoms grow, they worsen causing sleep problems, seizures, and trouble feeding. The child becomes totally dependent, needing help to perform any task.
The life expectancy of these children is quite short, most die in a few years, although some live until adolescence or adulthood.
Middle childhood or adolescence
Canavan disease onset in middle childhood or adolescence is milder than the former. Symptoms include some difficulties in verbal and motor development.
Although they are usually so mild that they are not identified as symptoms of Canavan's disease, so this disease is usually diagnosed after a urine analysis, since one of the markers is the high concentration of N-acetyl aspartic acid (NAA) in the urine.
Causes
This disease is caused by a mutation in a gene called ASPA. This gene controls the enzyme aspartoacillase, which is responsible for degrading NAA molecules.
Mutation of the ASPA gene causes aspartoacillase to reduce its effectiveness, so it will not degrade enough NAA molecules and there will be a high concentration of this substance. The earlier this mutation occurs the worse effects it has.
Although the functioning of NAA molecules is not well understood, they appear to be involved in the transport of water molecules through neurons, and the excess of this substance prevents new myelin from forming and destroying the existing myelin. This causes the connections between the neurons do not work properly and the brain is unable to develop normally.
In addition, this disease can be Autosomal recessive . So if each member of the pair carries the pathogenic variant of the ASPA gene and decides to have a child, they are likely to:
- The child presents the disease in 25% of the cases.
- The child is a carrier in 50% of cases, but does not present problems.
- The child is not even a carrier in 25%.
Source of Image: National Institute of Health, NIH, 2016. Carrier = Affected = Unaffected.
It is very important that individuals belonging to the at-risk population, in this case the offspring of the Ashkenazi Jews, undergo genetic analysis to see if they are carriers of the ASPA gene before having a child.
Treatment
Treatment depends on the form of the disease and the symptoms that each individual presents.
Treatment for Neonatal or Child Canavan Disease
There is currently no cure for Canavan's disease, so available therapies focus on improving the patient's quality of life by providing support, nourishing and moisturizing and preventing and treating infections.
It is recommended that children receive a physiotherapeutic treatment to improve their posture and motor skills, to avoid and treat contractures and muscle problems, such as decubitus ulcers. They can also participate in therapeutic and educational programs to improve their communicative skills.
Treatment with medication includes Antiepileptics (AEDs) if your child has seizures, acetazolamide (trade name Diamox ® ) To reduce intracranial pressure and injections of botulinum toxin (Botox ® ) To treat spasticity if it is present.
It is necessary to follow up every 6 months to check in what state the child is and how it develops.
Treatment for Canavan's disease in middle childhood or adolescence
People suffering from this form of the disease experience much milder symptoms, so they only often need therapies to improve their language or special educational programs. They do not need any medication.
Annual monitoring of the child's condition is recommended.
New treatment therapies
The effectiveness of other therapies in both human and animal models is currently being studied.
Studies with humans
- Non-viral vector
The effectiveness of a genetic transplant is being investigated in the brains of children with Canavan's disease using a non-viral vector.
The first results show that this type of transplant is well tolerated by children and causes some biochemical, radiological and metabolic changes, but is not useful for curing the disease, so tests are still being performed (Leone et al 2000, Janson et al. To 2002).
- Vector VAAV2
McPhee et al. (2006) are carrying out a study in which the healthy ASPA gene is transplanted in several places of the body of the children, using AAV2 as a vector. In one of the tests in which 10 volunteer children participated. In 3 of them the transplantation functioned and neutralized their antibodies, but none of the children improved.
- Lithium citrate
Lithium citrate may reduce the level of NAA concentration in the brain, so Assadi et al. (2010) decided to perform an experiment in which they administered 6-lithium citrate with Canavan's disease for 60 days.
It was found that levels of NAA concentration in the basal ganglia and in the white matter of the frontal lobe, although no clinical improvements were found.
- Glycerol triacetate
The lack of aspartoacilases enzymes causes low levels of acetate in the brain, so Mahavarao and his team (2009) decided to administer glycerol triacetate to two patients with Canaval disease to raise their levels of acetate and see if that increased Also aspartoacillase levels.
The compound was well tolerated by the patients, although no clinical improvement was found. They are currently conducting tests by administering a greater amount of glycerol triacetate.
Animal studies
One of the ways to create animal models that represent an illness is to create animals knockout. These animals, usually mice, are genetically modified to remove or change the gene that is altered in the disease. In this case the modified gene is the ASPA gene.
The animal models serve to know better the disease, to study its biological correlate and to verify the effectiveness of new treatments.
Matalon et al. (2003) used mice knockout To test the efficacy of AAV2 gene therapy as a vector. They found that improvements had been made in myelin sheaths, but only in parts, not in the whole brain.
The Surendran team in collaboration with the Genzyme Corporation (2004), tested a stem cell transplant treatment. They found that they had occurred Oligodendrocytes New, but not enough to restore all myelin sheaths.
Another team tested a therapy that was to replace aspartoaciclase enzymes that did not work well for new ones that were injected into the peritoneum of mice knockout.
The short-term results showed that the enzymes were able to pass the Blood brain barrier (Reaching their goal) and managed to significantly decrease NAA levels in the brain. Although these results are promising, a longitudinal study is needed to test for long-term effects (Zano et al., 2011).
Diagnosis
The first signs that warn doctors that something is not right are physical, especially hypotonia and Macrocephaly .
Usually, if these signs are observed, a neuroimaging study is usually done to check for signs of leukodystrophy, such as a lower density of white matter. It is noteworthy that this test is less effective in children with Canavan's disease beginning in middle childhood or adolescence.
Once it has been proven that the child is suffering from Leukodystrophy , More specific tests are done to rule out other diseases, these include:
- Check NAA levels
- Urine analysis.
- Analyzing the amniotic fluid (if the child is not yet born).
- Check the activity of aspartoaciclase enzymes through:
- Crops of skin cells to check the levels of Fibroblasts (Although this test is unreliable).
- Levels of this enzyme in white blood cells and platelets.
- Amniocytes (fetal cell) if the child is not yet born.
The last step to confirm the disease would be to perform a genetic study as follows:
- It is checked if any of the pathogenic variants of the ASPA gene are present (the best known are p.Glu285Ala, p.Tyr231Ter and p.Ala305Glu).
- If only one of these variants is present or none is present, a sequencing analysis is performed.
- If a single or variant is found in the sequencing analysis, a duplication and deletion analysis is performed.
References
- Assadi M, Janson C, Wang DJ, Goldfarb O, Suri N, Bilaniuk L, Leone P. Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease. Eur J Paediatr Neurol. 2010; 14: 354-9.
- Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A, Wang DJ, Shera D, Hurh P, Rupin J, Saslow E, Goldfarb O, Goldberg M, Larijani G, Sharrar W, Liouterman L, Camp A , Kolodny E, Samulski J, Leone P.
- Leone, P., Janson, C., Bilaniuk, L., Wang, Z., Sorgi, F., Huang, L., et al. . . McPhee SW, M.E. (2000). Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol, 48 , 27-38.
- Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grunberg NE, Gahl WA, Namboodiri AM. Glyceryl triacetate for Canavan disease: the low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis. 2009; 32: 640-50.
- Matalon R, Surendran S, Rady PL, Quast MJ, Campbell GA, Matalon KM, Tyring SK, Wei J, Peden CS, Ezell EL, Muzyczka N, Mandel RJ. Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease. Mol Ther. 2003; 7: 580-7.
- Matalon, R., & Michals-Matalon, K. (2011). Canavan Disease. In R. Pagon, M. Adam, & H. Ardinger, GeneReviews (Internet page). Seattle: University of Washington.
- McPhee SW, Janson CG, Li C, Samulski RJ, Camp AS, Francis J, Shera D, Lioutermann L, Feely M, Freese A, Leone P. Immune responses to AAV in a phase I study for Canavan disease. J Gene Med. 2006; 8: 577-88.
- National Institute of Health, NIH. (June 21, 2016). Canavan Disease . Retrieved from the Genetics Home Reference.
- Surendran S, Shihabuddin LS, Clarke J, Taksir TV, Stewart GR, Parsons G, Yang W, Tyring SK, Michals-Matalon K, Matalon R. Neural mouse progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan disease . Brain Res Dev Brain Res. 2004; 153: 19-27.
- Zano S, Malik R, Szucs S, Matalon R, Viola RE. Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan disease. Mol Genet Metab. 2011; 102: 176-80.