Neuronopathic Gaucher disease, or âtype 3â Gaucher disease is an inherited deficiency of lysosomal acid ï-Glucosylceramidase resulting from bi-allelic variants of GBA1. Type 3 Gaucher disease is distinguished from type 1 Gaucher disease by presence of progressive neurological features and from âtype 2â Gaucher disease by the slower progression of symptoms. Systemic manifestations of disease primarily result in hepatosplenomegaly and bone marrow disruption and displacement resulting from substrate accumulation primarily in macrophages. A secondary profound impairment of bone metabolism occurs in patients who remain untreated. Therapy for disease consists of enzyme replacement (ERT) which is effective peripherally but not within the CNS. There is no proven therapy which modifies neurological aspects of disease. Development of such a molecule requires a robust natural history dataset from which outcome may be measured and well-defined clinically meaningful endpoints defined. In a series of eleven manuscripts, the demographic, genetic and clinical features of approximately 90% the UK cohort of patients living with Gaucher disease are described. A subsequent focus on patients with neuronopathic subtypes, who constitute a larger proportion of the overall cohort than described in international studies (15% versus 5% previously reported) is undertaken. A study (with inclusion of deceased patients) reports on the natural history of type 3 disease in 42 patients evaluates determinants of outcome which show relationship to broad genotypic groups. A study describing the combined outcomes of nine patients who underwent Haematopoietic Stem Cell Transplantation approaches some of the unanswered questions surrounding CNS reconstitution of deficient enzyme with use of donor cells. A consistent neurological progression over thirty years was seen in this cohort reflecting failure of HSCT to correct disease centrally. Specific description of comorbidities (kyphosis and Gaucher-related liver disease) and the relationship to GBA1 variants and broader phenotypes are described in detail. These retrospective reviews and detailed analysis of patient characteristics offer insight into disputed genotype-phenotype relationships and add new considerations for the way patients are classified. Findings of an attenuated neuronopathic phenotype in association with the variant p.Arg502Cys are further supported by saccadic eye movement analysis which highlight a subgroup of patients with type 1 disease in the presence of p.Arg502Cys with slowing of horizontal saccades (a feature almost pathognomic of type 3 Gaucher disease), many in the absence of any other neurology, findings which prompt ethical and practical considerations for patient management and counselling. Exploration of existing tools for measuring disease activity, neurocognitive testing and MRI brain imaging offer new insights into the role of these tools clinically and for therapeutic trial purposes and novel approaches to measuring disease activity, utilising gait analysis, wearable activity monitors and patient reported outcomes through phone applications show feasibility for future exploration.
|Date of Award||1 Aug 2019|
- The University of Manchester
|Supervisor||William Newman (Supervisor), Simon Jones (Supervisor) & Siddharth Banka (Supervisor)|