Genotype-phenotype pitfalls in Gaucher disease

Gaucher disease (GD), caused by inherited deficiency of β‐glucocerebrosidase (β‐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 β‐Glc activity. Patient classification by identification of specific mutations is more promosing: homozygosity for the common A5841 ‐>(N370S) mutation invariably predicts type I; homozygosity for the T6433 ‐>C (L444P) mutation usually indicates type III (Norbottnian). Type II disease patients often carry the T6433 ‐>C allele together with a complex allele derived in part from the downstream pseudogene by crossover or gene conversion, producing a T6433 ‐>C substitution, plus 2 or 3 additional single base substitutions (fusion gene). Employing selective PCR amplification of the structural gene, we detected homozygous T6433C (L444P) point mutations in a Caucasian boy, initially classified as having GD type I, who succumbed to severe visceral GD before age 3 years. A second novel PCR procedure for discriminating between the normal gene and the fusion gene confirmed the homozygous point mutation results. Post mortem neuropathological findings showed neuronal complex lipid accumulation consistent with late‐onset type III disease. Although in Norbottnian patients it is generally accepted that onset of neurological findings is delayed, patients with the L444P/L444P genotype can only be initially classified as type Ill with this ancestry. Other patients described sporadically elsewhere are invariably considered type I until neurological findings arise. This is the first actual demonstration of a transition from type I to type Ill based on medical findings, not geography. © 1994 Wiley‐Liss, Inc.