AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS Note: This page reflects emerging clinical and scientific advances as of the date issued and is subject to change. The information should not be construed as dictating an exclusive course of treatment or procedure to be followed. The American College of Obstetricians and Gynecologists 409 12th Street, SW PO Box 96920 Washington, DC 20090-8020 Number 212, November 1998 SCREENING FOR CANAVAN DISEASE Canavan Disease is a severe progressive genetic disorder of the central nervous system. The clinical features of Canavan disease usually appear after the first few months of life and include developmental delay, macrocephaly, hypotonia, and poor head control. As the disease progresses, seizures, optic atrophy, gastrointestinal reflux, and deterioration of swallowing develop. Most children with Canavan disease die in the first decade of life. presently, there is no cure or effective therapy for Canavan disease. Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which leads to increased excretion of its substrate, N-acetylaspartic acid (NAA). A diagnosis of Canavan disease is established by determining an increased level of urinary NAA by organic acid analysis. These abnormally high levels of NAA lead to demyelination and spongy degeneration of the brain, which cause the neurologic features of Canavan disease. As in Tay-Sachs disease, Canavan disease is inherited as an autosomal recessive condition and is more prevalent among individuals of Eastern European Jewish (Ashkenazi) background. It is estimated that the carrier frequency in the Askenazi Jewish population is approximately 1 per 40. Thus, the risk from an affected offspring in this population approximates 1 in 6,400 births. Unlike Tay-Sachs disease, however, there do not appear to be other high-risk ethnic populations, although Canavan disease has been reported in individuals of non-Ashkenazi Jewish background. Molecular studies have revealed two specific mutations in the aspartoacylase gene on chromosome 17. These account for approximately 97% of the mutations causing Canavan disease in the Ashkenazi jewish population. One is a mutation in codon 285 of the aspartoacylase gene, and the other is a mutation in codon 231. Screening of Ashkenazi Jewish individuals can be performed by analyzing for these two mutations. In non-Jewish persons, the mutations may be different and more diverse. The most common mutation is in codon 305, which has been noted in approximately 36% of the 70 identified alleles from unrelated non-Jewish individuals. Carrier screening for Canavan disease requires molecular diagnostic methods. Simple enzymatic assays, as commonly used in Tay-Sachs screening, cannot be used for Canavan disease because the activity of the deficient enzyme, aspartoacylase, is not detectable in blood. testing for the three most common Canavan disease mutations will identify about 97$ of Ashkenazi Jewish carriers and 40-50% of non-jewish carriers. When both parents are carriers of identifiable Canavan disease mutations, prenatal diagnosis by chorionic villus sampling (CVS) or amniocentesis can be accomplished using DNA analysis. In couples where one or both members have unknown mutations, biochemical analysis of NAA levels in the amniotic fluid can be used reliably. Elevated NAA levels can be used to detect an affected fetus. The analysis should be done in a laboratory that has personnel who have expertise in performing this test. Enzyme analysis of aspartoacylase in cultured fetal cells from CVS or amniocentesis is not reliable. Based on the preceding information, the Committee on Genetics makes the following recommendations: 1. Ideally, molecular carrier screening for Canavan disease should be offered preconceptionally if both members of the couple are of Ashkenazi Jewish genetic background. This screening could be combined with screening for Tay-Sachs disease because both disorders are more common in this group. Many specialized laboratories already offer screening for both diseases. Those with a family history consistent with Canavan disease also should be offered screening, which should be voluntary; informed consent and assurance of confidentiality are required. If potential carriers have not been screened preconceptionally, screening may be offered during early pregnancy. 2. If only one partner is of high risk (of Ashkenazi Jewish descent or with a family history consistent with Canavan disease), this partner should be screened first. Ideally, this should be performed preconceptionally. If it is determined that the high-risk partner is a carrier, the other partner should be offered screening. The couple, however, must be informed of the limitations of testing. If the woman is already pregnant, it may be necessary to screen both partners simultaneously so that results are obtained in a timely fashion and to ensure that all options are available for the couple. 3. If it is determined by DNA-based analysis that both partners are carriers of Canavan disease, prenatal diagnosis should be offered either by CVS or amniocentesis, using DNA-based testing of the fetal cells. BIBLIOGRAPHY American College of Medicine Genetics Board of Directors. Position statement on carrier testing for Canavan disease. Bethesda, Maryland: January 10, 1998 American College of Obstetricians and Gynecologists. Screening for Tay-Sachs disease. ACOG Committee Opinion 162. Washington, DC ACOG, 1995 Bennett, M., Gibson, K., Sherwood, W., Divry, P., Rolland, M., Eipeleg, O., Rinaldo, P., and jakobs, C. Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis. J.Inherit.Metab.Dis.1993:16:831-836 Kaul,R., Gao, G., Matalon, M., Aloya, M., Su, Q., Jin, M., Johnson, A., Schutgens, R., and Clarke, J. Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. Am J. Hum Genet 1996:59:95-102 Kronin, D., Oddoux C., Phillips J., and Ostrer H. Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi jewish population. Am J. Hum Genet 1995; 57: 1250-1252 Matalon, R. Canavan disease; diagnosis and molecular analysis. Genetic Testing 1997; 1:21-25 Matalon, R., Michals, K., and Kaul, R. Canavan disease: From spongy degeneration to molecular analysis. J. of Pediatr. 1995: 127:511-517.