In-depth phenotyping for clinical stratification of Gaucher disease

Abstract

Background: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-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 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; the skeletal and neurological manifestations are the main focus of this study.

Results: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. 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. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.

Conclusion: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.

Keywords: Cohort; Disease-modifying therapies; Enzyme replacement therapy; GAUCHERITE; Gaucher disease; Substrate reduction therapy.

Fig. 1

Radiographic imaging of skeletal manifestations in Gaucher disease. Generalized osteopaenia and lytic areas in iliac wings (A) and mid shafts of both femora (A, B), tibiae (B) and humeri (C). Pathological fractures both upper femora (A). Erlenmeyer flask deformity of both femurs, also known as metaphyseal flaring (B). Gross expansion and coarse trabeculation of the left femur (D). Extensive osteonecrosis of the right femoral head, which shows marked flattening with complete loss of joint space (E). Prominent thoracic kyphosis and exaggerated lumbar lordosis with minimal lumbar curve (F). H-shaped vertebrae of the thoracic spine consistent with osteonecrosis (G)

Fig. 2

Neurological signs in Gaucher disease type 1. At enrolment, 223 of 250 patients had been classified as non-neuronopathic type 1 Gaucher disease and 27 with neuronopathic type 3 Gaucher disease. During the prospective study period, forty patients originally assigned to the type 1 disease category were subject to re-examination by a neurologist who found central nervous system signs in 15, of whom 13 had type 3 disease with clinically evident saccadic abnormalities. Of the 25 patients without clinical neurological signs, based on oculography and other clinical features, only 3 meet the criteria for reclassification as type 3 disease (X² test with Yates correction, p-value < 0.00001)

Fig. 3

Cumulative hazard for first osteonecrosis event and fragility fracture. Controlling for gender, the hazard or risk of having a first osteonecrosis event (A) and first fragility fracture (B) after presentation of Gaucher disease was greater in patients who had splenectomy (hazard ratio of 3.32 [95% CI 1.74–5.00; p < 0.001] and 2.83 [95% CI 1.33–5.99; p = 0.01], respectively). Horizontal axis shows years after presentation with Gaucher disease

Fig. 4

Cumulative hazard for first osteonecrosis event according to treatment status. The hazard or risk of having a first osteonecrosis event after presentation of Gaucher disease was significantly lower after starting enzyme replacement therapy (ERT) than before (hazard ratio of 0.20; 95% CI 0.11–0.38; p < 0.001). The effects of substrate reduction therapy (SRT) and bone marrow transplantation (BMT) was difficult to assess owing to the low sample size (nine and two patients received SRT or BMT as first treatment, respectively). Of the two patients with BMT, one had their first episode of osteonecrosis after the procedure. Horizontal axis shows time in years after presentation of Gaucher disease