scholarly journals Eye Movement Biomarkers Allow for the Definition of Phenotypes in Gaucher Disease

2020 ◽  
Author(s):  
Aimee Donald ◽  
Chong Yew Tan ◽  
Anupam Chakrapani ◽  
Derralyn Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of b-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with Enzyme Replacement Therapy (ERT), however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. MethodsWe undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. ResultsWe confirmed the saccadic abnormality in patients with type 3 Gaucher disease andidentified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared aGBA1 variant. ConclusionsThis striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

scholarly journals Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aimee Donald ◽  
Chong Y. Tan ◽  
Anupam Chakrapani ◽  
Derralyn A. Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood–brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

scholarly journals Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

2020 ◽  
Author(s):  
Aimee Donald ◽  
Chong Yew Tan ◽  
Anupam Chakrapani ◽  
Derralyn Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with Enzyme Replacement Therapy (ERT), however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2296-2301 ◽  
Author(s):  
Deborah Elstein ◽  
Altoon Dweck ◽  
Drorit Attias ◽  
Irith Hadas-Halpern ◽  
Shoshana Zevin ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Pharmacokinetic Profile ◽  
Disease Type ◽  
Type I ◽  
Open Label ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Gaucher Disease Type 1 ◽  
Chitotriosidase Activity

Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.

scholarly journals Gaucher's Disease- A case report

2014 ◽  
Vol 3 (2) ◽  
pp. 45-48
Author(s):  
ASM Ruhul Quddush ◽  
Md Kamruzzaman ◽  
Md Badruzzaman ◽  
Mirja Hamidul Haque ◽  
Nazma Parvin Ansari ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Abdominal Distension ◽  
Disease Type ◽  
X Ray ◽  
Enzyme Replacement ◽  
Gaucher Disease Type 1 ◽  
Form Type ◽  
Type 3

A 3 years old immunized girl of consanguineous parents presented abdominal distension with hepatosplenomegaly. She was moderately anemic, moderately wasted and stunted. Neurological examination was normal. Musculoskeletal system examination revealed no abnormality. Diagnosis was supported by typical bone involvement in X-ray film (thin cortex in limb bone) and gaucher cell in the bone marrow and also in the splenic aspiration. There are three subtypes Type1: Non neuropathic form, Type 2: Acute neuropathic form, Type 3: Chronic neuropathic form. However some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited. So, this patient more or less correlates with Gaucher disease type 1. Treatment option for type 1 and 3 include medicine and enzyme replacement therapy, which is usually very effective. CBMJ 2014 July: Vol. 03 No. 02 P: 45-48

scholarly journals PP044 Adherence To Enzyme Replacement Therapy In Gaucher Disease

2017 ◽  
Vol 33 (S1) ◽  
pp. 91-92
Author(s):  
Amanda Quevedo ◽  
Alicia Dornelles ◽  
Livia Paskulin ◽  
Taciane Alegra ◽  
Barbara Krug ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Gaucher Disease ◽  
High Rate ◽  
Reference Center ◽  
Enzyme Replacement ◽  
Brazilian Government ◽  
Type 3 ◽  
Very High

INTRODUCTION:Gaucher disease (GD) is a genetic autosomic disorder for which treatment has been funded by the Brazilian government since the 1990s. In our state most patients are treated with enzyme replacement therapy (ERT) and followed by our Reference Center under the recommendation of the Ministry of Health Brazilian guidelines. There is a lack in the literature about adherence of patients to treatment. The objective was to describe adherence to the treatment in a cohort of all GD patients in the southern state of Brazil.METHODS:This was a cohort study of all GD patients treated with velaglucerase α, taliglucerase α and imiglucerase from January 2010 to January 2015. Adherence was measured as recommended by the Brazilian guidelines as to perform more than 50 percent of the anticipated infusions per year.RESULTS:Our study included thirty-seven patients of both genders. Doses of ERT varied from 15 to 45IU/kg for type 1 patients and from 30 to 60 IU/kg for type 3 patients. A mean of 83 percent of anticipated infusions were performed and from all patients only one did not adhere to the treatment during the 5 years of our study. The majority of the patients performed at least 50 percent of all anticipated infusions.CONCLUSIONS:We noted a very high rate of adherence to treatment with a very few adverse effects. Our data might be showing that the very high rate of adherence in these chronic disease patients may be attributed to the value of treatment by patients and their family, and also due to the existence of a multidisciplinary team at the reference center. These data might be useful for public health policy making in other countries.

scholarly journals Glucosylsphingosine (lyso-Gb1) as a Biomarker for Monitoring Treated and Untreated Children with Gaucher Disease

2019 ◽  
Vol 20 (12) ◽  
pp. 3033 ◽  
Author(s):  
Noa Hurvitz ◽  
Tama Dinur ◽  
Michal Becker-Cohen ◽  
Claudia Cozma ◽  
Marina Hovakimyan ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Medical Center ◽  
Progressive Increase ◽  
Clinic Visit ◽  
Enzyme Replacement ◽  
Type 3 ◽  
Blood Spot

The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (<18 years), 35 with mild type 1 GD (GD1), 34 with severe GD1 and 12 with type 3 GD (GD3), followed at Shaare Zedek Medical Center between 2014–2018. Disease severity for GD1 was based on genotypes. Forty children (87%) with severe GD1 and GD3 received enzyme replacement therapy (ERT) compared to two children (6%) with mild GD1. Lyso-Gb1 measurements were conducted on dried blood spot samples taken at each clinic visit. Lyso-Gb1 levels were significantly lower in children with mild compared to severe GD1 (p = 0.009). In untreated children, lyso-Gb1 levels were inversely correlated with platelet counts. During follow-up, lyso-Gb1 increased in almost 50% of untreated children, more commonly in younger children. In treated children, lyso-Gb1 levels were inversely correlated with hemoglobin levels. The increase of lyso-Gb1 while receiving ERT, seen in eight children, was partly associated with compliance and weight gain. Lyso-Gb1 seems to be a useful biomarker for monitoring children with GD and should be included in the routine follow-up. Progressive increase in lyso-Gb1 levels in untreated children suggests ERT initiation.

scholarly journals Two cases of neuronopathic form of Gaucher disease – diagnostic difficulties

2021 ◽  
Author(s):  
Grazina Kleinotiene ◽  
Austeja Ivaskeviciene ◽  
Anna Tylki-Szymanska
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Central Nervous System Involvement ◽  
Saccadic Eye Movements ◽  
Neurological Symptoms ◽  
Lysosomal Storage ◽  
Hematopoietic Organ ◽  
Enzyme Replacement ◽  
Type 3

Background: Gaucher disease is one of the most common inherited lysosomal storage diseases caused by the deficiency of the enzyme β-glucocerebrosidase, leading to the accumulation of glucocerebroside. Depending on the clinical manifestations, two different forms of the disease are distinguished – the non-neuronopathic form (type 1) with a variety of presentations – from asymptomatic to symptomatic patients (characterized by hepatosplenomegaly, thrombocytopenia, anemia and osteopenia), and the neuronopathic form (known as types 2 and 3). Besides visceral, osseous, and hematopoietic organ lesions, neuronopathic forms are associated with central nervous system involvement (bulbar and pyramidal signs, horizontal saccadic eye movements, myoclonic epilepsy, progressive development delay). In type 2, the neurological symptoms appear earlier and are more severe, the survival time is shorter. In type 3, the neurological symptoms are milder and allow patients to live a fully productive life. Case presentation: This article includes a review of two cases of neuronopathic Gaucher disease: type 2 and severe type 3. Both patients presented symptoms during infancy and the manifestations were similar but varied in intensity and the dynamics of progress. Enzyme replacement therapy was started in both cases, which decreased visceral symptoms. Conclusions: Both described cases indicate the lack of knowledge and the tendency of doctors to disregard the possibility of Gaucher disease in their paediatrics patients.

CLINICAL TRIALS IN INFANTS OF ORALLY ADMINISTERED ATTENUATED POLIOMYELITIS VIRUSES

PEDIATRICS ◽  
1959 ◽  
Vol 23 (6) ◽  
pp. 1041-1062
Author(s):  
Stanley Alan Plotkin ◽  
Hilary Koprowski ◽  
Joseph Stokes
Keyword(s):  
Clinical Trials ◽  
Fecal Excretion ◽  
Jackson Type ◽  
Poliomyelitis Virus ◽  
Minor Illness ◽  
The Difference ◽  
Antibody Levels ◽  
Type 3

Forty-six infants, ranging from less than 1 day to 6 months of age, were given more than 100 feedings of living, attenuated poliomyelitis viruses without the occurrence of major or minor illness. The strains used were CHAT (type 1), Wistar (type 1), Jackson (type 2), P-712 (type 2) and Fox (type 3). All strains except the Jackson strain were found to be antigenic on oral administration. Response to vaccination was demonstrated in these infants by the presence after vaccination of antibody levels significantly in excess of those attributable to transplacentally acquired antibodies, and by the detection of fecal excretion of poliomyelitis virus. Infants less than 2 months old were more difficult to immunize than older infants. The evidence suggests that biologic immaturity rather than transplacental antibodies caused the difference. When the three types of poliomyelitis virus were fed at 3-week intervals, responses occurred to all types. No interference between types was observed when they were fed in all possible sequences. Three infants given a second feeding of homotypic, attenuated poliomyelitis virus 3 to 5 months after a successful vaccination showed resistance to intestinal reinfection.

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