In-Depth Phenotyping for Clinical Stratification of Gaucher Disease
Background The Gaucher Investigative Therapy Evaluation (GAUCHERITE) is a national clinical cohort of 250 patients aged 5–87 years with Gaucher disease - an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular
... cluding molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years. Results At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Intensive neurological phenotyping in a subgroup of 40 originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 patients had other neuronopathic features. This revised the number affected by type 3 Gaucher disease to a total to 43. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Analysis of the longitudinal real-world data permitted stratification of Gaucher disease on the basis of exposure to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, osteonecrosis and orthopaedic surgery; after splenectomy, there were marked gender differences in the risk of fragility fractures over time. Combined with associated surgical procedures, the skeletal manifestations represent a heavy burden of illness, especially in patients formerly unable to access disease-modifying therapies. Conclusion Gaucher disease has been explored during a period of transformation by disease-modifying interventions. With the introduction of advanced therapies, repeated longitudinal measures in this real-world cohort allowed the condition to be stratified into clear clinical endotypes. Our study reveals diverse and changing phenotypic manifestations with neurological, systemic and skeletal disease as inter-related sources of disability. Electronic Supplementary Material The online version of this article contains supplementary material, which is available to authorized users.