Course:MEDG550/Student Activities/Canavan Disease

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Canavan disease is a progressive, fatal disorder of the brain. It is caused by a change in the ASPA gene (similar to a spelling mistake or typo in an instruction manual) that normally directs the body to produce an essential enzyme called aspartoacylase (ASPA). Individuals affected with Canavan Disease have little to no functional ASPA enzyme, which is responsible for breaking down a molecule called N-acetylaspartic acid (NAA). The build-up of NAA is believed to cause damage to cells in the brain which results in intellectual disability and progressive developmental delays.[1]

Depending on the type of gene change and amount of functional ASPA enzyme, an individual can be severely affected (also known as “Neonatal/Infantile Canavan disease”) or mildly affected (“Juvenile Canavan disease”).[2] Many children that are severely affected show symptoms by the age of three to five months and do not live past 10 years of life.[1] Individuals that are more mildly affected are uncommon and often go unrecognized, and the mild form does not seem to have an effect on lifespan.[3][4]

Symptoms

Symptoms can vary in nature, severity, and age of onset in Canavan disease. In the severe form of the disease, symptoms generally include the following[1]:

  • Muscle tone weakness (i.e. stiffness or floppiness; hypotonia)
  • Poor head control
  • Larger than average head size (macrocephaly)
  • Lack of visual responsiveness
  • Delay of speech skills, i.e. inability to talk
  • Delay of motor skills, i.e. inability to sit, stand, or walk

Over time, the infant may become more irritable and experience sleep and feeding/swallowing difficulties.[1] They may also develop vision and/or hearing issues, paralysis and seizures.[5]

In the mild form of the disease, children may have normal or slight delay in speech or motor development.[1][6] Most children will have a normal head size, but some may have an enlarged head, partial blindness and develop seizures.[4][7]

Diagnosis

The diagnosis of Canavan disease in an infant can be done by a urine test. A severely affected infant will have a high amount of NAA in their urine.[1] However, for individuals with the more mild form of the disease, there is only a slight increase of NAA in urine that can be problematic for diagnosis.[6] The diagnosis can be supported by brain imaging, to look for the presence of NAA or white matter changes that indicate brain degeneration.[8][9]

Both forms of Canavan disease can be diagnosed by molecular genetic testing to identify changes in the ASPA gene.

Management

There is currently no cure for Canavan disease. Management involves follow-up by the appropriate physicians for evaluating brain, eye, nutrition, and developmental health, as well as a consultation with a genetics specialist (geneticist or genetic counsellor). The treatment focuses on managing the symptoms, such as treating seizures with medication or introducing a feeding tube for those with swallowing difficulties.[1][5] The affected child may also benefit from physical and speech therapy, as well as special education. Families affected by Canavan disease can consider hospice care.

Mildly affected children can similarly benefit from additional education assistance, but most can be educated in a typical classroom setting.[1]

Inheritance

Autosomal recessive pattern of inheritance. If both partners are carriers for the gene change, there is a 25% or 1/4 chance of having an affected child.

Each individual has two copies of the ASPA gene, where one comes from their mom and one comes from their dad. Canavan disease is inherited in an autosomal recessive manner, such that both copies of the ASPA gene in the affected individual have a change or mutation (often referred to as a “variant”).[2][8] An individual affected with Canavan disease can also be referred to as having two "non-working" copies of the gene.

Each parent of an affected child is considered a carrier, such that they have one copy of the ASPA gene that is normal and one copy with a gene change. Carriers are asymptomatic and are not at risk of developing the disorder since they have one working copy of the gene.

When both parents are carriers for an ASPA gene variant, there are the following possible outcomes:

  • 25% chance of having an affected child
  • 50% chance of having a child that is an asymptomatic carrier
  • 25% chance of having an unaffected child

The siblings of a carrier have a 50% chance of also being a carrier.

Prevalence

Canavan disease may occur in either gender or any ethnic group but is prevalent in individuals with Eastern European Jewish ancestry. About 1/40 (2.5%) of individuals with Ashkenazi Jewish ancestry are carriers.[10]

Genetic Counselling

As Canavan disease has a genetic basis, families that are impacted by Canavan disease may benefit from speaking to a genetic counsellor and learning about genetic testing options. A genetic counsellor can help review disease symptoms, genetics and inheritance, family planning options, as well as facilitate the genetic testing process among other things.

Carrier Testing

Carrier testing is a form of genetic testing to determine if someone is a carrier, ie. that they have one copy of the ASPA gene that has a change associated with Canavan disease. Carrier testing is recommended to individuals with Ashkenazi Jewish ancestry in which the gene change for Canavan disease is more prevalent.[11] Carrier testing is also available for at-risk relatives, such as parents or siblings of individuals known to be carriers.

Family Planning

Prenatal testing is available for pregnancies with a known increased risk (i.e. when both parents are known carriers) to determine the genetic status (i.e. affected, carrier or unaffected) of the fetus. The pregnant mother will undergo an invasive process to obtain material from the fetus for genetic testing - either chorionic villus sampling or amniocentesis. These processes can performed at 11-13 weeks gestational age and 15 weeks gestational age respectively. Both come with a risk of causing a miscarriage at 1% and 0.5% respectively. If the results indicate that the fetus has changes in both copies of the ASPA gene, then the couple can use this information to prepare to give birth to an affected child or choose to terminate the pregnancy. Alternatively, preimplantation genetic diagnosis is an option to look for a change in the ASPA gene in a fertilized egg (“embryo”) and implant only healthy embryos as a part of an assisted reproduction technique called in-vitro fertilization. Couples may also choose to pursue in-vitro fertilization with the use of donor eggs or sperm. Other options also include adoption or natural conception without any testing. A genetic counsellor can help review these options and cooperatively figure out what is agreeable for each couple.

Patient Resources

Canavan Foundation: http://www.canavanfoundation.org/

Canavan Research Illinois: https://www.canavanresearch.org/

The Canavan Research Foundation: http://www.canavan.org/

To find a genetics specialist near you, please visit www.cagc-accg.ca (Canada) or www.nsgc.org (United States).

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Matalon, R. & Matalon, K. M. Canavan Disease. in Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Fifth Edition (2014). doi:10.1016/B978-0-12-410529-4.00062-0
  2. 2.0 2.1 Volk, B. W. Spongy degeneration of the central nervous system (Van Bogaert and Bertrand type; Canavan’s disease): A review. Hum. Pathol. (1973). doi:10.1016/S0046-8177(73)80098-X
  3. Velinov, M., Zellers, N., Styles, J. & Wisniewski, K. Homozygosity for mutation G212A of the gene for aspartoacylase is associated with atypical form of Canavan’s disease. Clinical Genetics (2008). doi:10.1111/j.1399-0004.2007.00934.x
  4. 4.0 4.1 Janson, C. G. et al. Mild-onset presentation of Canavan’s disease associated with novel G212A point mutation in aspartoacylase gene. Ann. Neurol. (2006). doi:10.1002/ana.20787
  5. 5.0 5.1 Hoshino, H. & Kubota, M. Canavan disease: Clinical features and recent advances in research. Pediatrics International (2014). doi:10.1111/ped.12422
  6. 6.0 6.1 Surendran, S. et al. Mild elevation of N-acetylaspartic acid and macrocephaly: Diagnostic problem. J. Child Neurol. (2003). doi:10.1177/08830738030180111601
  7. Tacke, U. et al. Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics (2005). doi:10.1055/s-2005-865865
  8. 8.0 8.1 Matalon, R. & Michals-Matalon, K. Spongy degeneration of the brain, Canavan disease: Biochemical and molecular findings. Pediatr. Pathol. Mol. Med. (1998). doi:10.1080/152279598405625
  9. Karimzadeh, P. et al. The clinical features and diagnosis of canavan’s disease: A case series of iranian patients. Iran. J. Child Neurol. (2014). doi:10.22037/ijcn.v8i4.6767
  10. Kronn, D., Oddoux, C., Phillips, J. & Ostrer, H. Prevalence of canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population [4]. American Journal of Human Genetics (1995).
  11. ACOG committee opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of eastern european Jewish descent. Obstetrics and Gynecology (2009). doi:10.1097/AOG.0b013e3181bd12f4