Gaucher disease type 3: Classification of the chronic neuronopathic variant informed by genotype in a phenotypically diverse cohort.

PURPOSE: Type 3 Gaucher disease (GD), the chronic neuronopathic form caused by biallelic pathogenic variants in GBA1, is clinically heterogeneous, and there have been few comprehensive studies of its natural history and phenotypic diversity. The greatest unmet clinical need is for a disease-modifying treatment for the neurological manifestations; however, the inability to identify unifying features in the existing nomenclature that would facilitate establishment of eligibility criteria and suitable endpoints in clinical trials is a major challenge for therapeutic development. METHODS: A multicenter cohort study in England, GAUCHERITE, undertook retrospective and prospective clinical evaluation of patients with GD; this substudy is focused on patients with neuronopathic GD. The research cohort is registered with ClinicalTrials.gov, NCT03240653. RESULTS: A total of 42 patients with neuronopathic GD were recruited: 16 males and 26 females. Nine patients had died (age of death 4-28 years); living patients aged 6 to 61 years. We categorized them clinically ("attenuated," "intermediate," and "severe") and on the basis of defined pathogenic variants in GBA1. Childhood disease manifestations provide prognostic utility, especially in context of genotype. CONCLUSION: This work captures the full phenotypic spectrum and striking clinical diversity of neuronopathic GD that is not encompassed by the existing nomenclature. We propose a novel descriptive system of phenotypic categorization: although this requires refinement and validation across the global population, it seeks to stimulate further exploration of disease behaviors that can be clearly stratified. By these means, we contend that identification of disease manifestations that are likely to respond to interventions with distinct modes of action in appropriate patient groups will enhance the value of clinical trial programs and accelerate much-needed therapeutic development.