Canavan Disease Case Study
Evanie Clay
BSCI201 – Section
Canavan Disease
Physiology of Canavan Disease Canavan disease caused by genetic mutations is found in young babies. These children appear to be normal develop slower than others and are typically hypotonic, have poor head control, are behind on motor and verbal skills, and have head lag (Matalon & Michals-Matalon, 1999). It is defined as a deadly leukodystrophy as a result of aspartoacylse (APSA) deficiency which typically results in death by the first decade (Maier, Wang-Eckhardt, Hartmann, Gieselmann, & Eckhardt, 2015). Aspartoacylase hydrolyzes N-acetylaspartate (NAA) into aspartate and acetate in the brain (Maier et al., 2015). When aspartoacylase is deficient, NAA is in abundance and causes “swelling and spongy degeneration of white matter of the …show more content…
brain” (Matalon & Michals-Matalon, 1999). A strange revelation has also shown that the synthesis of NAA is in the gray matter, making the disease more complicated (Matalon, Michals, & Kaul, 1995). Surprisingly there is a commonality among the populations that Canavan disease affects. The most common group affected are Ashkenazi Jewish individuals (Matalon et al., 1995). There are other outside populations but the genetic basis is different. In the Jewish patients there are two prevalent genetic mutations (Matalon et al., 1995). The first is a missense mutation in 83.6% of this population that occurs on codon 285 where alanine appears in place of glutamic acid (Matalon et al., 1995). The second is a nonsense mutation in 12.4% of this population on codon 231 where a stop codon is found in place of tyrosine (Matalon et al., 1995). In outside, non-Jewish, populations there is one common mutation. Here, a missense mutation on codon 305 replaces alanine to glutamic acid (Matalon et al., 1995). These mutations made in the genetic code result in severe consequences for the brain in the nervous system.
History of Treatment Treatment of Canavan disease has not been widely preformed. Typically it is currently symptomatic for humans because there is no definitive cure. Canavan disease was originally found by Myrtelle Canavan in 1931 however any ideas on how to treat it did not begin to appear in research articles until the 1990s (Pearce, 2013). Originally Canavan believed this disease to be related to Schilder’s disease because myelin damage in the white matter (Pearce, 2013). The most recent treatments are purely experimental because Canavan disease is genetically based and genetics are just beginning to be well understood and explored.
Current Research Current research is thriving in the treatment of Canavan disease as the understanding behind what causes it and what might help it have vastly increased. There have been many different trials on mice and some that have made it to human trials. One common treatment is the idea of gene therapy. One article describes the long term follow up of gene therapy in 2013 where the concentrations of NAA were reduced in both the frontal and periventricular regions of the brain (Leone et al., 2012). Also in this study it was shown that this was “evidence for a regional effect of gene therapy includes T1 normalization in the splenium of the corpus callosum” which meant an increase in the myelination of axons in the white matter and/or a decrease in water content (Leone et al., 2012). Overall this follow up was successful and contributes to current data on Canavan disease. A similar study done to this one discussed gene replacement therapy with rAAVs. One benefit of rAAVs was that it could cross the blood-brain barrier with ease (Ahmed et al., 2013). This trial was mainly done in mice and showed that it was somewhat successful in improving motor skills when treatment was done early in the youngest mice (Ahmed et al., 2013). If treatment started later, in older mice, then the conditions never improved, often worsened until these mice died (Ahmed et al., 2013). This study is important to show that in both cases it is the best solution to do treatment as soon as possible. Other studies have been done that did not include gene therapy. One in particular involved the modification of aspartoaclyase for enzyme replacement. Typically this has helped in metabolic disorders but is difficult due to the blood-brain-barrier (Zano, Malik, Szucs, Matalon, & Viola, 2011). In Canavan disease the enzyme that is deficient is being administered in a modified version (Zano et al., 2011). The results showed that the enzyme in mice lead to a correction of the metabolic defect and helped the accumulating NAA be able to hydrolyze more (Zano et al., 2011). This treatment could potentially be a less drastic change for humans while still providing an answer to Canavan disease.
Future Research
What current research has shown future research needs to answer. One of the most important factors shown is that early detection is necessary for successful treatment. This is difficult because babies typically have a normal appearance and are not detected to have Canavan disease until twelve months old (Matalon & Michals-Matalon, 1999). However if urine tests are done early enough in at risk populations, treatments might be able to work properly (Matalon & Michals-Matalon, 1999). Future research needs to focus on human trials, although this can be very difficult as the people affected are young infants and children. One of the trials mentioned “future gene therapy interventions for Canavan disease should focus on the neonatal age range (0 to 3 months) before irreversible structural changes have occurred, using newer vectors that target oligodenrocytes or amixed target cell population including glia, neurons, and arachnoid cells” (Leone et al., 2012). The facts known about Canavan disease and its association with genetics needs to lead to a more specific treatment.
General Synthesis Canavan disease now has more options than ever for treatment however these are all experimental. The research about gene therapy has not existed long enough to prove a person can live a long, full life. It is important to note that research occurring now is more vital than before because genetics can actually be manipulated. Doctors should look into all possible options for replacing the incorrect genes with ones that would stop the disease however be aware of the other damages this could cause. The strides made in a cure for Canavan disease will happen within the next few decades and when they do, many lives of children will be saved.
References
Ahmed, S.
S., Li, H., Cao, C., Sikoglu, E. M., Denninger, A. R., Su, Q., … Gao, G. (2013). A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice. Molecular Therapy, 21(12), 2136–2147.
Leone, P., Shera, D., McPhee, S. W. J., Francis, J. S., Kolodny, E. H., Bilaniuk, L. T., … Janson, C. G. (2012). Long-Term Follow-Up After Gene Therapy for Canavan Disease. Science Translational Medicine, 4(165), 165ra163.
Maier, H., Wang-Eckhardt, L., Hartmann, D., Gieselmann, V., & Eckhardt, M. (2015). N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time. The Journal of Neuroscience, 35(43), 14501-14516.
Matalon, R., Michals, K., & Kaul, R. (1995). Canavan disease: From spongy degeneration to molecular analysis. The Journal of Pediatrics, 127(4), 511-517.
Matalon, R., Michals-Matalon, K. (1999). Spongy degeneration of the brain, Canavan disease: Biochemical and molecular findings. Pediatric Pathology & Molecular Medicine, 18(6), 471-481.
Pearce, J. (2004). Canavan’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 75(10),
1410.
Zano, S., Malik, R., Szucs, S., Matalon, R., & Viola, R. E. (2011). Modification of Aspartoacylase for Potential Use in Enzyme Replacement Therapy for the Treatment of Canavan Disease. Molecular Genetics and Metabolism, 102(2), 176–180.
BSCI201 – Section
Canavan Disease
Physiology of Canavan Disease Canavan disease caused by genetic mutations is found in young babies. These children appear to be normal develop slower than others and are typically hypotonic, have poor head control, are behind on motor and verbal skills, and have head lag (Matalon & Michals-Matalon, 1999). It is defined as a deadly leukodystrophy as a result of aspartoacylse (APSA) deficiency which typically results in death by the first decade (Maier, Wang-Eckhardt, Hartmann, Gieselmann, & Eckhardt, 2015). Aspartoacylase hydrolyzes N-acetylaspartate (NAA) into aspartate and acetate in the brain (Maier et al., 2015). When aspartoacylase is deficient, NAA is in abundance and causes “swelling and spongy degeneration of white matter of the …show more content…
brain” (Matalon & Michals-Matalon, 1999). A strange revelation has also shown that the synthesis of NAA is in the gray matter, making the disease more complicated (Matalon, Michals, & Kaul, 1995). Surprisingly there is a commonality among the populations that Canavan disease affects. The most common group affected are Ashkenazi Jewish individuals (Matalon et al., 1995). There are other outside populations but the genetic basis is different. In the Jewish patients there are two prevalent genetic mutations (Matalon et al., 1995). The first is a missense mutation in 83.6% of this population that occurs on codon 285 where alanine appears in place of glutamic acid (Matalon et al., 1995). The second is a nonsense mutation in 12.4% of this population on codon 231 where a stop codon is found in place of tyrosine (Matalon et al., 1995). In outside, non-Jewish, populations there is one common mutation. Here, a missense mutation on codon 305 replaces alanine to glutamic acid (Matalon et al., 1995). These mutations made in the genetic code result in severe consequences for the brain in the nervous system.
History of Treatment Treatment of Canavan disease has not been widely preformed. Typically it is currently symptomatic for humans because there is no definitive cure. Canavan disease was originally found by Myrtelle Canavan in 1931 however any ideas on how to treat it did not begin to appear in research articles until the 1990s (Pearce, 2013). Originally Canavan believed this disease to be related to Schilder’s disease because myelin damage in the white matter (Pearce, 2013). The most recent treatments are purely experimental because Canavan disease is genetically based and genetics are just beginning to be well understood and explored.
Current Research Current research is thriving in the treatment of Canavan disease as the understanding behind what causes it and what might help it have vastly increased. There have been many different trials on mice and some that have made it to human trials. One common treatment is the idea of gene therapy. One article describes the long term follow up of gene therapy in 2013 where the concentrations of NAA were reduced in both the frontal and periventricular regions of the brain (Leone et al., 2012). Also in this study it was shown that this was “evidence for a regional effect of gene therapy includes T1 normalization in the splenium of the corpus callosum” which meant an increase in the myelination of axons in the white matter and/or a decrease in water content (Leone et al., 2012). Overall this follow up was successful and contributes to current data on Canavan disease. A similar study done to this one discussed gene replacement therapy with rAAVs. One benefit of rAAVs was that it could cross the blood-brain barrier with ease (Ahmed et al., 2013). This trial was mainly done in mice and showed that it was somewhat successful in improving motor skills when treatment was done early in the youngest mice (Ahmed et al., 2013). If treatment started later, in older mice, then the conditions never improved, often worsened until these mice died (Ahmed et al., 2013). This study is important to show that in both cases it is the best solution to do treatment as soon as possible. Other studies have been done that did not include gene therapy. One in particular involved the modification of aspartoaclyase for enzyme replacement. Typically this has helped in metabolic disorders but is difficult due to the blood-brain-barrier (Zano, Malik, Szucs, Matalon, & Viola, 2011). In Canavan disease the enzyme that is deficient is being administered in a modified version (Zano et al., 2011). The results showed that the enzyme in mice lead to a correction of the metabolic defect and helped the accumulating NAA be able to hydrolyze more (Zano et al., 2011). This treatment could potentially be a less drastic change for humans while still providing an answer to Canavan disease.
Future Research
What current research has shown future research needs to answer. One of the most important factors shown is that early detection is necessary for successful treatment. This is difficult because babies typically have a normal appearance and are not detected to have Canavan disease until twelve months old (Matalon & Michals-Matalon, 1999). However if urine tests are done early enough in at risk populations, treatments might be able to work properly (Matalon & Michals-Matalon, 1999). Future research needs to focus on human trials, although this can be very difficult as the people affected are young infants and children. One of the trials mentioned “future gene therapy interventions for Canavan disease should focus on the neonatal age range (0 to 3 months) before irreversible structural changes have occurred, using newer vectors that target oligodenrocytes or amixed target cell population including glia, neurons, and arachnoid cells” (Leone et al., 2012). The facts known about Canavan disease and its association with genetics needs to lead to a more specific treatment.
General Synthesis Canavan disease now has more options than ever for treatment however these are all experimental. The research about gene therapy has not existed long enough to prove a person can live a long, full life. It is important to note that research occurring now is more vital than before because genetics can actually be manipulated. Doctors should look into all possible options for replacing the incorrect genes with ones that would stop the disease however be aware of the other damages this could cause. The strides made in a cure for Canavan disease will happen within the next few decades and when they do, many lives of children will be saved.
References
Ahmed, S.
S., Li, H., Cao, C., Sikoglu, E. M., Denninger, A. R., Su, Q., … Gao, G. (2013). A Single Intravenous rAAV Injection as Late as P20 Achieves Efficacious and Sustained CNS Gene Therapy in Canavan Mice. Molecular Therapy, 21(12), 2136–2147.
Leone, P., Shera, D., McPhee, S. W. J., Francis, J. S., Kolodny, E. H., Bilaniuk, L. T., … Janson, C. G. (2012). Long-Term Follow-Up After Gene Therapy for Canavan Disease. Science Translational Medicine, 4(165), 165ra163.
Maier, H., Wang-Eckhardt, L., Hartmann, D., Gieselmann, V., & Eckhardt, M. (2015). N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time. The Journal of Neuroscience, 35(43), 14501-14516.
Matalon, R., Michals, K., & Kaul, R. (1995). Canavan disease: From spongy degeneration to molecular analysis. The Journal of Pediatrics, 127(4), 511-517.
Matalon, R., Michals-Matalon, K. (1999). Spongy degeneration of the brain, Canavan disease: Biochemical and molecular findings. Pediatric Pathology & Molecular Medicine, 18(6), 471-481.
Pearce, J. (2004). Canavan’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 75(10),
1410.
Zano, S., Malik, R., Szucs, S., Matalon, R., & Viola, R. E. (2011). Modification of Aspartoacylase for Potential Use in Enzyme Replacement Therapy for the Treatment of Canavan Disease. Molecular Genetics and Metabolism, 102(2), 176–180.