John T. Dulaney

Ceramidase and ceramide synthesis in human kidney and cerebellum: Description of a new alkaline ceramidase

It has been shown that tissues of patients with Farbers disease characteristically lack acid (pH 4.0) ceramidase. In normal cerebellum, however, ceramide cleavage and the reverse reaction, free fatty acid-dependent ceramide synthesis, both occur not only at pH 4.0 but also at pH 9.0, although normal kidney exhibits these activities only at pH 4.0. Both tissues are capable of snythesizing ceramide via an acyl-COA-dependent pathway at neutral pH. The synthetic analog of ceramide, N-oleoyl-ethanolamine, is a potent inhibitor of ceramidase.

Ceramidase Deficiency in Farber's Disease (Lipogranulomatosis)

Ceramidase activity could not be demonstrated in the kidney and cerebellum from a deceased patient with Farbers disease, whereas the activities of six control acid hydrolase enzymes appeared normal. This enzyme defect presumably accounts for the accumulation that has been described in two patients and may represent the biochemical basis of this disorder.

Diagnosis of lipogranulomatosis (Farber disease) by use of cultured fibroblasts

The enzyme defect in Farber disease, a deficiency of acid ceramidase, has been demonstrated in cultured skin fibroblasts, which provides a means of confirming the diagnosis during life. The assay can also be performed using cultured amniotic fluid cells and is a potential tool for detection of carriers of the disease.

Detection of the carrier state of Hurler's syndrome by assay of α-l-iduronidase in leukocytes

Abstract The mean specific activity of α- l -iduronidase in leukocytes from six obligate heterozygotes for Hurlers syndrome was found to be slightly less than one-half of the mean in normal controls; no overlap of normal and known heterozygote values was encountered. The assay has been applied with success to six potential heterozygotes, siblings of a child with Hurlers syndrome. Thus heterozygote detection of Hurlers syndrome is clearly possible; this finding, as well as the ready availability of leukocytes for screening tests, recommends their use for examination of potential carrier status in this disorder.

The Biochemical Defect in Farber’s Disease

In 1967 Prensky et al. reported the accumulation of ceramide in the postmortem tissues of a patient with Faber’s disease (1), and in 1971 Samuelsson and Zetterstrom reported such an accumulation in a second case (2). In 1972 Sugita, Dulaney and Moser demonstrated the deficient activity of an acid ceramidase in the tissues of the case reported by Prensky et al., (3). Since this same enzymatic defect has now been demonstrated in three additional unrelated patients, it appears likely that the deficient activity of acid ceramidase represents the basic defect in this disease, and makes it appropriate to appraise our current knowledge about this striking rare disorder.