GENOTYPE-PHENOTYPE PITFALLS IN GAUCHER DISEASE

Gaucher disease (GD), caused by inherited deficiency of beta-glucocerebrosidase (beta-Glc, EC 3.1.2.45), is classified type I if the CNS is not involved (non-neuronopathic), type II if CNS involvement is early and rapidly progressive (acute neuronopathic), and type III if CNS involvement occurs later and is slowly progressive (subacute neuronopathic). The clinical course is not predictable by measurement of residual beta-Glc activity. Patient classification by identifcation of specific mutations is more promising: homozygosity for the common A(5841)->G (N370S) mutation invariably predicts type I; homozygosity for the T-6433->C (L444P) mutation usually indicates type III (Norbottnian). Type II disease patients often carry the T-6433->C allele together with a complex allele derived in part from the downstream pseudogene by crossover or gene conversion, producing a T-6433->C substitution, plus 2 or 3 additional single base substitutions (fusion gene). Employing selective PCR amplification of the