Genotypic heterogeneity and phenotypic variation among patients with type 2 Gaucher's disease.

Gaucher's disease, the inherited deficiency of glucocerebrosidase, manifests with vast phenotypic variation. Even among patients with type 2 (acute neuronopathic) Gaucher's disease, there is a spectrum of clinical presentations. DNA samples from 14 patients with type 2 Gaucher's disease with a course ranging from intrauterine death at 22 wk of gestation to survival until age 30 mo were studied. L444P was the only common mutation identified, found in 15 patients' alleles. Sequencing of genomic DNA amplified by long template PCR revealed that mutation L444P occurred as a single point mutation in seven mutant alleles and as part of a recombinant allele in eight mutant alleles. Two patients had a deletion of 55 bp in exon 9; in one patient the deletion was part of a recombinant allele, and in a second the deletion occurred alone. Direct sequencing identified R120W on one allele, P415R on another, and one fetus was homoallelic for a deletion of a C nucleotide at codon 139 in exon 5. Eight of the mutant alleles remain unidentified. Northern blots revealed an appropriately sized mRNA in all except one of the patients studied. Of the 14 type 2 Gaucher patients, three had hydrops fetalis and died in utero or at birth, five had congenital ichthyosis, and seven survived 5 mo or more. Patients who died in the neonatal period had decreased protein detected by Western blot, regardless of genotype observed. These studies demonstrate that genotypic heterogeneity exists in patients with type 2 Gaucher's disease, even among infants with the most severe phenotypes.