Prenatal diagnosis of Krabbe disease

Krabbe disease was diagnosed prenatally in Göteborg (Sweden) and Lyon (France) by assaying the cerebroside-beta-galactosidase activity with galactosylceramides and lactosylceramides as substrates in cultivated amniotic fluid cells. Altogether, 48 pregnancies at risk were monitored between 1972 and 1980. Ten pregnancies at risk were terminated because of a predicted affection of the fetus. Biochemical examination of material available from 7 of the 10 abortuses confirmed the diagnoses. All the remaining 36 pregnancies ended in the birth of a healthy infant. The study showed that prenatal diagnosis of Krabbe disease is difficult because of the relatively high residual cerebroside-beta-galactosidase activity in some affected fetuses. Except for the large biological variation, the enzyme activity was sensitive to variation in cultivation conditions and differed strikingly between morphologically different cell types. These two factors were controlled by including control cell samples cultivated under identical conditions and by relating the cerebroside-beta-galactosidase activity to that of two marker enzymes. The biological variation was investigated further by measuring the cerebroside-beta-galactosidase activity in cultured skin fibroblasts from infants with Krabbe disease and from their parents. Results obtained in 18 unrelated patients with Krabbe disease, 26 obligate heterozygotes and 63 controls showed a wide range of variation in enzyme activity in the controls, a large overlap between the controls and obligate heterozygotes, and a high residual activity in some patients. Nevertheless, a high residual activity in a patient was combined with a relatively high enzyme activity in the two parents. In the light of the above findings and deliberations, it appears warranted to conclude that laboratories with experienced personnel can make a reliable prenatal diagnosis of Krabbe disease and that the examination should be offered to all known couples at risk.