Abstract 815 Inborn Errors of Metabolism Platform, Monday, 5/3

Gaucher disease results from the inherited deficiency of lysosomal glucocerebrosidase. In patients with type 2 (acute neuronopathic) Gaucher disease, symptoms manifest prenatally or in early infancy, and a rapidly progressive and fatal neurologic deterioration occurs. Elevated levels of the substrate glucosylsphingosine have been reported in brains of type 2 patients. In the null allele mouse model of type 2 Gaucher disease, generated by targeted recombination, glucosylsphingosine accumulates in the brain, liver and spleen. Heterozygous null allele mice were mated and glucosylsphingosine levels were analyzed in fetal tissues using high performance liquid chromatography with a 4-fluro-7-nitrobenzofurazan-generated autofluorescent derivative of glucosylsphingosine. Accumulation of glucosylsphingosine was detected in samples from homozygous null mice as early as day 13 of gestation, although none was detected in heterozygous or wild-type littermates. The storage progressively increased throughout gestation in all tissues assayed. Samples were also studied from two human fetuses affected with type 2 Gaucher disease. Both fetuses had severe hydrops fetalis and were delivered to the same nonconsanguineous parents at 11 and 22 weeks of gestation respectively. They carried a rare splice junction mutation. IVS10+2, and a novel fusion allele resulting from a recombination between the glucocerebrosidase gene and its pseudogene in intron 3. Elevations of glucosylsphingosine were detected in the brain and the liver from both fetuses. The accumulation of this potentially neurotoxic compound during embryonal development may result in irreversible damage to developing nervous tissue and lead to the early demise of mice and patients with type 2 Gaucher disease.