Gaucherite - A Study to Stratify Gaucher Disease

Study Overview
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Brief Summary
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The purpose of this research is to review data already collected and to collect new data from adults and children in England with Gaucher Disease to determine clinical factors which predict severity and response to therapy of Gaucher disease especially in the areas of bone, cancer and brain conditions.

Detailed Description
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Gaucher disease is part of a rare group of genetic metabolic diseases which are caused by an inherited deficiency of the enzyme glucocerebrosidase. The most common form, Type 1 affects 1 in 40,000 to 60,000 individuals in the general population. In Type 1 symptoms may appear at any time from infancy to old age. The disease is associated with anaemia (a decrease in the amount of red blood cells), fatigue (tiredness), bruising and an increased tendency to bleed. An enlarged spleen and liver with stomach swelling may also occur as well as bone pain, fractures and bone deterioration. Type 1 was formerly considered not to affect the brain or nervous system. Some patients with Type 1 Gaucher disease have no symptoms, while others develop serious symptoms that can be life threatening; latterly Parkinsonism and Dementia with Lewy bodies has been noted to occur with increased frequency in patients with this variant of Gaucher disease compared with healthy control subjects in an age-matched population. In Gaucher Disease Type 3 the brain and spinal cord are affected. Type 3 is rare and affects fewer than 1 in 100,000 people. The brain and spinal cord symptoms in Type 3 are less severe than in those who have evidence of florid neurologocal disease in infancy years of age. The symptoms of the brain and spinal cord appear in early to late childhood, and patients with Type 3 Gaucher disease live often, but not always, well into adulthood. Gaucher disease is not gender-specific and its signs and symptoms may appear in affected individuals at any age, with Type 3 being commonly diagnosed in childhood. Although individuals from any ethnic background may develop Gaucher disease, Type 1 Gaucher disease is most common among Jews of Ashkenazi (Eastern European) descent. Among this group, about 1 in 900 people are at risk of Gaucher disease. There are approximately 280 people in England diagnosed with Gaucher Disease, who receive treatment or management at one of the treating hospitals. Patients with Gaucher disease have an increased risk of developing myeloma and Parkinson's disease. Myeloma, also known as multiple myeloma, is a type of bone marrow cancer affecting the white blood cells of the immune system which generate antibodies. Approximately 1 in 10 Gaucher patients have a specific blood protein - a monoclonal antibody called a paraprotein, which is found in both malignant and non-malignant conditions, including myeloma. Parkinson disease is a neurological condition which develops over time as specific brain cells that control movement, die. The failure to produce less of a chemical called dopamine, reduces communication between brain cells involved in the coordination of movement, behaviour, learning and memory. The investigators will collect information from patients diagnosed with Gaucher disease and any of the conditions mentioned above (for which the patient is already being monitored). Further information required about their clinical status will be obtained from their past and on-going medical records; this will be done as the participants attend hospital as part of their routine care for Gaucher disease. The information we need for the research is no different from the information which is already recorded and will be recorded in their medical notes when they come to the hospital for their routine care, every 6 months. For the purpose of this study, the investigators will take a few extra blood samples from the participant. These samples will be used to conduct biochemical and cellular analysis solely for the purpose of this research. The Investigators also request permission from participants to allow access and use for the purpose of the research any archived biological material (blood serum and/or tissue) which may be available from the medical procedures that has been received in the past. In addition, for the purpose of this research, at each visit, investigators request that the participant also completes questionnaires about physical and social abilities, mental health and quality of life. All the research-specific procedures (i.e. procedures that the participant would not normally receive during their standard of care hospital visits) can be carried out at either their routine clinic appointments or at another time that the participant would find convenient.

Official Title
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Predictive Measures to Stratify Clinical Outcomes in Children and Adults With Gaucher Disease and Responses to Specific Therapies

Conditions
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Gaucher Disease, Type I, Gaucher Disease, Type III

Intervention / Treatment
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* Other: Stratified response to Enzyme Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must meet all of the following criteria to be enrolled in this study: Confirmed biochemical diagnosis of Type I, Type II or Type III Gaucher disease Written Ethics Committee (EC) approved informed consent obtained from the patient, or patient's parent or legal guardian and patient assent if appropriate Male or Female patients, no age limitation Willing and able to comply with study schedule and procedures Deceased patients for whom the EC determines that patient data can be collected without a new consent from the patient Exclusion Criteria: Patients meeting any of the following criteria will be excluded from the study: Unrelated co-morbid condition limiting life expectancy to less than 6 months Patient or if applicable, parent or legal guardian is unable to comprehend, sign and date the EC approved informed consent form and patient assent as appropriate If determined unsuitable for the study by the investigator
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients Type III<br>Stratified response to EnzymeTherapy Substrate Reduction Therapy (expected) Splenectomy (and interactions) | Other: Stratified response to Enzyme Therapy<br>* Observational study involves review of retrospective and prospective data of participants' medical history, pathology, imaging and health questionnaires.<br>* Other names: Splenectormy;|
| Patients Type I<br>Stratified response to Enzyme Therapy and Substrate Reduction Therapy- Splenectomy (and interactions) | Other: Stratified response to Enzyme Therapy<br>* Observational study involves review of retrospective and prospective data of participants' medical history, pathology, imaging and health questionnaires.<br>* Other names: Splenectormy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurological outcome | Presence of saccadic ocular deficits | 2029 | 
| Fragility Fracture | Dual energy absorptive photiometry (DEXA) will allow us to measure the bone mineral density (BMD g/cm2) to enable stratification into treatment strands and predict and prevent future fragility fractures. | 2029 | 
| Disease Severity | Biochemical biomarkers (PARC/CCL18 ng/ml and Chitotriosidase umol/L/h) will be used to perform decease severity and follow-up response to treatment. | 2029 | 
| Bone Marrow Involvement | MRI will allow us to assess the extent of Bone Marrow involvement and thus response to treatment by using the Bone Marrow Burden Score (BMB). The BMB is a semi quantitative MRI scoring system, using the sagittal T1 and T2 images of the lumbar spine and the coronal T1 and T2 of the femurs. | 2029 | 
| Bone avascular necrosis | MRI will allow us to assess new avascular necrosis events (osteonecrosis). | 2029 | 
| Cognitive Function | Frontal Assessment Battery (FAB) is used to assess early cognitive impairment in Type III patients and patients with diagnosis of Parkinson disease. | 2019 | 
| Cognitive Function | Addenbrooke's Cognitive Examination - ACE-R and National Adult Reading Test are used in combinations to establish attention and orientation, memory, fluency, language and visuospatial orientation | 2029 | 
| Neurological Physical Assessment | Modified Severity Scoring Tool (MSSt) is used to monitor neurological manifestations of NGD (Type III). | 2029 | 
| Multiple Myeloma | Characterisation of new biomarkers in the peripheral blood mononuclear cells. (PBMCs), lipid analysis and Metabolomics screen. | 2029 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life and disease severity measures | SF36; will be used to assess the patient reported quality of life. It is a generic measure of health status, as opposed to one that targets a specific age, disease, or treatment group. It has proven useful for conducting surveys of general and specific populations, comparing the relative burden of diseases, and differentiating the health benefits produced by a wide range of treatments. | 2029 | 
| Quality of life and disease severity measures | EQ5D5L; the dimensions are (mobility, self care, usual activities, pain/discomfort, anxiety/depression). it provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health. This tool will help facilitating the calculation of quality-adjusted life years (QALYs) that are used to inform economic evaluations of health care interventions. | 2029 | 
| Quality of life and disease severity measures | Hospital anxiety & depression scale (HADs); Assist researchers in detection of emotional disorder in patients under investigation and treatment | 2029 | 
| Quality of life and disease severity measures | PedsQL (multidimensional fatigue scale); Enable researcher to assess if there is a link to level of patient reported fatigue and disease severity | 2029 | 
| Quality of life and disease severity measures | PedsQL qual of life for paediatric ages. To assess participant reported quality of life. | 2029 | 
| Parkinson severity | Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a clinical rating scale for Parkinson's disease (PD) | 2029 | 
| Biobank | Biobank storage of historical and prospective human samples. | 2020 | 
| EyeSeeCam | Objective quantifiable eye examination measuring eye movement | 2029 |