Maternity Care Calendar and Guidelines: Screening for Canavan Disease Carriers

Current MCC Guideline (1998):
no guideline currently given.

Literature Search:
Medline was searched for the years 1966 to present under the MeSH heading Canavan disease/pc,ep [Prevention & Control, Epidemiology] and separately using the search strategy canavan disease (MeSH heading) AND screen$ (keyword and MeSH heading). Lastly the all EBM reviews (CDSR, ACP Journal Club, DARE, and CCTR) were search for the years 1998 to present using the keyword canavan disease. All articles pertaining to screening for Canavan disease in the Ashkenazi Jewish population were reviewed.

Summary of Evidence:
Canavan disease is a pan-ethnic disorder with a carrier frequency in the Ashkenazi Jewish population of 1/37-1/40.^1,2,3 The incidence of this disorder in this population is 1/6000^1,2 and as such the Ashkenazi jewish population is considered to be at high risk for the disorder. There do not appear to be other high-risk ethnic populations.³

Canavan disease is inherited as an autosomal recessive condition and is a neurological disorder caused by a defect in the enzyme aspartoacyclase. Aspartoacyclase is found in the white matter of the brain, the kidneys, lungs, liver and other tissues. However, the enzyme is not present in plasma or red or white blood cells. The enzymatic defect is caused by two main mutations in the Jewish population: a missense mutation Glu285Ala and nonsense mutation Tyr231X. The enzymatic defect causes the buildup of the substrate, N-acetylaspartic acid, leading to the spongy degeneration of the brain.^1,2

Canavan disease is a severe, progressive neurological disease characterized in infancy by developmental delay, macrocephaly and hypotonia. These children do not sit, stand, walk or talk. As the disease progresses, children often develop seizures, spasticity, nystagmus, difficulty swallowing and optic atrophy. Children often die within the first decade of life, although survival into the second or even third decade is not rare. There is no cure for Canavan disease.^3,4 Currently the main treatment for Canavan disease is symptomatic therapy aimed at seizure management.

As the enzyme apartoacyclase cannot be measured in blood, screening for Canavan disease involves molecular diagnostic testing.^1,2 This DNA-based testing is performed in a limited number of specialized laboratories. Simple enzymatic assays, as commonly used in Tay Sachs screening cannot be used.³

Recommendations of Others:
The American College of Obstetricians and Gynecologists recommend that screening for Canavan disease be offered when both members of the couple are of Ashkenazi Jewish descent in conjunction with Tay-Sachs screening. When possible screening should be offered preconceptually and if no preconception consultation is made screening may also be offered during pregnancy.³ If only one partner is of a high risk group, this partner should be screened first . If the woman is already pregnant, both partners may need to be screened simultaneously so that the results are obtained in a timely fashion. If both partners are carriers of Canavan disease, prenatal diagnosis should be offered using DNA testing of fetal cells obtained by amniocentesis or chorionic villus sampling.

The American College of Medical Genetics recommends carrier testing for Canavan disease be offered before pregnancy if both reproductive partners have an Ashkenazi Jewish background. If a family member is affected, relatives should be offered screening for the particular mutation the affected individual has.⁵

The US Preventive Services Task Force and the Canadian Task Force of Preventive Health Care have not developed guidelines for Canavan disease carrier screening.

In some Canadian provinces, including British Columbia, the provincial government has not provided funding for molecular genetic testing for Canavan disease or familial dysautonomia which has a similar carrier frequency.

Conclusion:
The new guideline on the Maternity Care Calendar will be as follows:

offer Canavan carrier screening to Ashkenazi Jews
It will be in plain font as the test is not universally available.
It will be located under "Investigations" suggested for preconception visit (or alternatively, early pregnancy)

Reviewers:
Amrit Kahlon, (medical student) August 2002
Colleen Kirkham, MD, CCFP October 2002

Thank you to Dr. Sylvie Langlois (Department of Medical Genetics, Children's and Women's Health Centre of British Columbia) and Dr. Hilary Vallance (Biochemical Genetics lab, Department of Pathology, Children's and Women's Health Centre of British Columbia) for their helpful comments.

1/29/03 3:56 PM

References:
¹Matalon R, Michals-Matalon K. Molecular basis of Canavan disease. European Journal of Paediatric Neurology 1998; 2: 69-76.

²Matalon R, Michals-Matalon K. Recent Advances in Canavan Disease. Advances in Pediatrics 1999; 46: 493-506.

³Committee on Genetics. ACOG committee opinion: Screening for Canavan disease. International Journal of Gynecology & Obstetrics 1999; 65(1): 91-92.

⁴Traeger EC, Rapin I. The Clinical Course of Canavan Disease. Pediatric Neurology 1998; 18(3): 207-212.

⁵American College of Medical Genetics: www.acmg.net