Prenat. Diagn. 19: 669–670 (1999)

INVITED COMMENTARY: CURRENT ISSUES IN OBSTETRICS AND GENETICS

Prenatal Diagnosis of Canavan Disease

Reuben Matalon* and Kimberlee Michals-Matalon

Department of Pediatrics, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX77555-0359, U.S.A.

*Correspondence to: R. Matalon, Department of Pediatrics,University of Texas Medical Branch at Galveston, 301 UniversityBoulevard, Galveston, TX 77555-0359, U.S.A. E-mail:rmatalon@utmb.edu

Canavan disease is an autosomal recessive leuko-dystrophy caused by deficiency of the enzyme,aspartoacylase. Aspartoacylase deficiency leads toaccumulation of N-acetylaspartic acid in the brain andexcretion of N-acetylaspartic acid in urine (Matalonet al., 1988). There is no effective method of treatmentfor Canavan disease, therefore prenatal diagnosis is animportant method of avoiding this disease.

The finding of aspartoacylase activity in culturedskin fibroblasts and its deficiency in fibroblasts frompatients with Canavan disease, raised the hope ofprenatal diagnosis using the enzyme assay in amnio-cytes or cultured chorionic villi, even though activity ofthis enzyme in cultured chorionic villi or culturedamniocytes is about one-tenth the activity found incultured fibroblasts. Another possibility for prenataldiagnosis is measuring the level of N-acetylasparticacid in the amniotic fluid. Documenting elevation ofthis biochemical marker can be used as an indicator ofan affected fetus (Bennett et al., 1993; Kelley, 1993).The isolation of cDNA for aspartoacylase and identi-fication of specific mutations leading to Canavan dis-ease introduced a high level of accuracy in thediagnosis of Canavan disease and added the possibilityof molecular diagnosis in informative families (Kaulet al., 1993).

The assay for aspartoacylase activity in culturedamniocytes or chorionic villi samples has been foundunsuitable for prenatal diagnosis of Canavan disease.False-negative results occurred in a series of 19 preg-nancies (Matalon et al., 1992). The reason for thisfailure was the aforementioned low activity of aspar-toacylase in amniocytes and chorionic villi. Changes inaspartoacylase activity were not significant enough todiscern a normal from an abnormal fetus. Therefore,determination of aspartoacylase activity for the pur-poses of prenatal diagnosis of Canavan disease is notreliable.

The determination of N-acetylaspartic acid levels inamniotic fluid emerged as an alternative method forthe prenatal diagnosis of Canavan disease. However,only specialized laboratories that use stable isotopedilution methods for quantitation of N-acetylasparticacid should be relied upon (Bennett et al., 1993; Kelley,

CCC 0197–3851/99/070669–02$17.50Copyright ? 1999 John Wiley & Sons, Ltd.

1993). A recent report showing slight elevation ofN-acetylaspartic acid in the amniotic fluid caused someconcern as to whether the fetus was affected. A secondamniocentesis was done with similar results. Thefamily elected to continue the pregnancy whichresulted in a baby heterozygous for Canavan disease asdetermined by molecular diagnosis (Besley et al., 1998).This case highlights the need for caution in interpretingN-acetylaspartic acid data in prenatal diagnosis.

DNA diagnosis is the method of choice for prenataldiagnosis of Canavan disease in families where themutations are known. Among Ashkenazi Jewishindividuals there are only two mutations that havebeen described in about 99 per cent of Jewish patientswith Canavan disease, mutation 231 tyrosine to stopcodon, and mutation 285 glutamic acid to alanine(Kaul et al., 1994). Among this risk population prefer-ably preconception carrier testing and prenatal diagno-sis for these two mutations should be obtained. Thefrequency of carriers among Ashkenazi Jewish peopleis 1 in 38, and carrier screening is routinely used.Among non-Jewish individuals the mutations can bevaried and sometimes it may be difficult to reach amolecular diagnosis. One mutation, 305 alanine toglutamic acid, has been found in about 35–40 per centof non-Jewish individuals of European ancestry (Kaulet al., 1994). The other mutations in non-Jewish indi-viduals are scattered on the aspartoacylase gene. Whenusing the method of DNA analysis we recommend theuse of polymorphic markers to be sure that the cells arefetal and not contaminated with maternal cells. Wehave had two pregnancies where short tandem repeatswere used as polymorphic markers from the father,mother and the fetus (Matalon et al., 1995). Thiscombination of markers assures the fetal origin of theamniocytes or chorionic villi, since the father’s poly-morphic markers must be present in the amniotic orchorionic villi cells.

In conclusion, the choice for prenatal diagnosis ofCanavan disease is to perform both molecular determi-nation of mutations in cultured amniocytes or chori-onic villi samples and determine N-acetylaspartic acidin the amniotic fluid. When the mutations have notbeen determined on both parents, N-acetylasparticacid determination in the amniotic fluid is the onlyoption. Slight elevations of N-acetylaspartic acid maybe difficult to interpret.

Received 10 March 1999Accepted 29 March 1999

670 R. MATALON AND K. MICHALS-MATALON

REFERENCES

Bennett MJ, Gibson KM, Sherwood WG, Divry P, Rolland MO,Elpeleg ON, Rinaldo P, Jakobs C. 1993. Reliable prenatal diag-nosis of Canavan disease (aspartoacylase deficiency): comparisonof enzymatic and metabolite analysis. J Inher Metab Dis 16:831–836.

Besley GTN, Elpeleg ON, Shaag A, Manning NJ, Jakons C, WalterJW. 1998. Prenatal diagnosis of Canavan disease—problems anddilemmas. J Inher Metab Dis 21: 48.

Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, MichalsK, Matalon R. 1994. Canavan disease: mutations among Jewishand non-Jewish patients. Am J Hum Genet 55: 34–41.

Kaul R, Gao GP, Balamurugan K, Matalon R. 1993. Cloning of thehuman aspartoacylase cDNA and a common missense mutation inCanavan disease. Nature Genet 5: 118–123.

Copyright ? 1999 John Wiley & Sons, Ltd.

Kelley RI. 1993. Prenatal diagnosis of Canavan disease by measure-ment of N-acetyl-L-aspartate in amniotic fluid. J Inher Metab Dis16: 918–919.

Matalon R, Kaul R, Gao GP, Michals K, Gray, RGF, Bennett-Britton J, Norman A, Smith H, Jakobs C. 1995. Prenatal diagnosisfor Canavan disease: the use of DNA markers. J Inher Metab Dis18: 215–217.

Matalon R, Michals K, Gashkoff P, Kaul R. 1992. Prenataldiagnosis of Canavan disease. J Inher Metab Dis 15: 392–394.

Matalon R, Michals K, Sebesta D, Deanching M, Gashkoff P,Casanova J. 1988. Aspartoacylase deficiency and N-acetylasparticaciduria in patients with Canavan disease. Am J Med Genet 29:463–471.

The Invited Commentary: Current Issues in Obstetrics and Genetics section of Prenatal Diagnosis aims to present acommentary on topical issues in prenatal diagnosis which are of relevance to both obstetricians and medical geneticists. Thesecommentaries are invited and each represents a personal critical analysis of the current studies of a particular subject, puttingthe latest research into the context of earlier work, and providing implications for clinical practice.ZZ

Prenat. Diagn. 19: 669–670 (1999)