Gaucher disease, the most common lysosomal storage disease results from the deficiency of the enzyme glucocerebrosidase. There are three major phenotypes and most patients have some residual glucocerebrosidase activity. However, we describe a unique fetus with severe prenatal lethal type 2 (acute neuronopathic) Gaucher disease lacking glucocerebrosidase activity. This 22-week fetus was the result of a first cousin marriage and had hydrops, multiple external abnormalities, hepatosplenomegaly, and Gaucher cells in several organs. Fetal fibroblast DNA was screened for common Gaucher mutations, none of which were detected. Southern blot analysis using the restriction enzymes SstII and SspI ruled out a fusion gene, deletion, or duplication of either allele and quantitative studies of SspI digested DNA indicated that both alleles were present. Northern blot analysis of total RNA from fetal fibroblasts revealed no detectable transcription, although RT-PCR successfully amplified several exons, suggesting the presence of a very unstable mRNA. Direct PCR sequencing of each exon and the 5′ untranslated region demonstrated the deletion of a C nucleotide on both alleles, resulting in a frameshift mutation in exon 5 which introduced a premature termination codon in exon 6. The absence of glucocerebrosidase protein was confirmed by Western analysis.

This unique case confirms the essential role of glucocerebrosidase in human development and, similar to the null allele Gaucher mouse, demonstrates the lethality of a homozygous null mutation. This novel mutation and the resulting unstable mRNA accounts for the severity of the phenotype observed in this fetus, and thus contributes to the understanding of genotype/phenotype correlation in Gaucher disease.