Unreliable verification of prenatal diagnosis of Canavan disease: aspartoacylase activity in deficient and normal fetal skin fibroblasts.

Abstract

Canavan disease (McKusick 271900) is an untreatable severe disorder resulting from an inherited deficiency of aspartoacylase activity (EC 3.5.1.15). Prenatal diagnosis can be performed either in crude chorionic villus biopsy by measuring aspartoacylase activity or in amniotic fluid sampled at 15-18 weeks of amenorrhoea by measuring N-acetylaspartate (Bennett et al 1993). In both cases a result is obtained in one week and, if the fetus is predicted to be affected, an abortion can be done at 12-19 weeks. Fetal skin fibroblasts are then cultured to check enzymatic activity deficiency. Aspartoacylase is measured according to a modification of Hagenfeldt 's method (Hagenfeldt et al 1987). Two fetuses (12 and 17 weeks gestation) predicted to be affected by Canavan disease were tested by measuring aspartoacylase activity in cultured fetal skin fibroblasts, with unmatched age controls (>20 weeks), and aspartoacylase activity was said to be deficient. However, in order to establish normal values, aspartoacylase activity was determined in 30 fetal control skin fibroblasts (18 taken between 10 and 19 weeks and 12 between 20 and 30 weeks). These controls were fetuses affected by other metabolic disease (including lysosomal and peroxisomal diseases, adenosine deaminase deficiency and glycogen storage). In all the fetuses younger than 19 weeks (18/18), aspartoacylase activity was very low or undetectable (range 0-0.2/zkat/kg protein). In the 12 fetuses with gestation age between 20 and 30 weeks, aspartoacylase activity was 1.7 + 1.3/~kat/kg protein (range 0.3-3.7/zkat/kg protein). Aspartoacylase activity is known to be very low or undetectable in amniocytes and in cultured chorionic villi (Matalon et al 1993). On the other hand, activity can be measured in skin fibroblasts and crude chorionic villus tissue. This work shows that in Canavan disease verification of a positive prenatal diagnosis cannot be made in fetal skin fibroblasts when the fetus is younger than 20 weeks. Aspartoacylase activity in predicted affected and control fetuses must be measured in fetal kidney or liver if these tissues are available.