Dataset Information

Infantile gangliosidoses: Mapping a timeline of clinical changes.

ABSTRACT: Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastrointestinal side effects. Development of effective treatments will require identification of meaningful outcomes in the setting of rapidly progressive and fatal diseases.This study aimed to establish a timeline of clinical changes occurring in infantile gangliosidoses, prospectively, to: 1) characterize the natural history of these diseases; 2) improve planning of clinical care; and 3) identify meaningful future treatment outcome measures.Patients were evaluated prospectively through ongoing clinical care.Twenty-three patients were evaluated: 8 infantile GM1, 9 infantile Tay-Sachs disease, 6 infantile Sandhoff disease. Common patterns of clinical change included: hypotonia before 6months of age; severe motor skill impairment within first year of life; seizures; dysphagia and feeding-tube placement before 18months of age. Neurodevelopmental testing scores reached the floor of the testing scale by 20 to 28months of age. Vertebral beaking, kyphosis, and scoliosis were unique to patients with infantile GM1. Chest physiotherapy was associated with increased survival in iGM1 (p=0.0056). Miglustat combined with a low-carbohydrate ketogenic diet (the Syner-G regimen) in patients who received a feeding-tube was associated with increased survival in infantile GM1 (p=0.025).This is the first prospective study of the natural history of infantile gangliosidoses and the very first natural history of infantile GM1. The homogeneity of the infantile gangliosidoses phenotype as demonstrated by the clinical events timeline in this study provides promising secondary outcome measure candidates. This study indicates that overall survival is a meaningful primary outcome measure for future clinical trials due to reliable timing and early occurrence of this event. Combination therapy approaches, instead of monotherapy approaches, will likely be the best way to optimize clinical outcomes. Combination therapy approaches include palliative therapies (e.g., chest physiotherapy) along with treatments that address the underlying disease pathology (e.g. miglustat or future gene therapies).

SUBMITTER: Jarnes Utz JR

PROVIDER: S-EPMC5727905 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Infantile gangliosidoses: Mapping a timeline of clinical changes.

Jarnes Utz Jeanine R JR Kim Sarah S King Kelly K Ziegler Richard R Schema Lynn L Redtree Evelyn S ES Whitley Chester B CB

Molecular genetics and metabolism 20170429 2

<h4>Background</h4>Infantile gangliosidoses include GM1 gangliosidosis and GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease). To date, natural history studies in infantile GM2 (iGM2) have been retrospective and conducted through surveys. Compared to iGM2, there is even less natural history information available on infantile GM1 disease (iGM1). There are no approved treatments for infantile gangliosidoses. Substrate reduction therapy using miglustat has been tried, but is limited by gastro ...[more]

PMID: 28476546

Similar Datasets

Project description:Elevated serum chitotriosidase (CHITO) is an indication of macrophage activation, and its capacity have been explored as a marker of inflammation in a number of disease states. For over a decade, CHITO plasma levels have been used by clinicians as a biomarker of inflammation in the lysosomal disease, Gaucher disease, including monitoring response to therapies in patients with Gaucher disease type I. Although it is becoming increasingly recognized that inflammation is a prominent component of many lysosomal diseases, the relation of CHITO levels to disease burden has not been well-characterized in the large majority of lysosomal diseases. Moreover, the role of CHITO in lysosomal diseases that affect the central nervous system (CNS) has not been systematically studied. In this study, one hundred and thirty-four specimens of CSF and serum were collected from 34 patients with lysosomal diseases affecting the CNS. This study included patients with GM1-gangliosidosis, GM2-gangliosidosis, mucopolysaccharidoses (MPS), multiple sulfatase deficiency and Gaucher disease. CHITO levels in the CSF were significantly higher in patients with more rapidly progressing severe neurological impairment: GM1-gangliosidosis vs MPS (p < 0.0001); GM2-gangliosidosis vs MPS (p < 0.0001). CHITO levels were higher in patients with the more severe phenotypes compared to milder phenotypes in GM1-gangliosidosis and GM2-gangliosidosis (serum CHITO in GM1-gangliosidosis infantile vs juvenile p = 0.025; CSF CHITO in Tay-Sachs infantile vs Tay-Sachs late-onset p < 0.0001). Moreover, higher CHITO levels in the CSF were significantly associated with lower cognitive test scores in patients with GM1-gangliosidosis, GM2-gangliosidosis, and MPS (p = 1.12*10-5, R2 = 0.72). Patients with infantile GM1-gangliosidosis showed increasing CSF CHITO over time, suggesting that CSF CHITO reflects disease progression and a possible surrogate endpoint for future clinical trials with infantile GM1-gangliosidosis. In summary, these results support the use of CSF CHITO to diagnose between different disease phenotypes and as a valuable tool for monitoring disease progression in patients. These results necessitate the inclusion of CHITO as an exploratory biomarker for clinical trials.

Project description:BackgroundPharmacovigilance consists in monitoring and preventing the occurrence of adverse drug reactions (ADR). This activity requires the collection and analysis of data from the patient record or any other sources to find clues of a causality link between the drug and the ADR. This can be time-consuming because often patient data are heterogeneous and scattered in several files. To facilitate this task, we developed a timeline prototype to gather and classify patient data according to their chronology. Here, we evaluated its usability and quantified its contribution to routine pharmacovigilance using real ADR cases.MethodsThe timeline prototype was assessed using the biomedical data warehouse eHOP (from entrepôt de données biomédicales de l'HOPital) of the Rennes University Hospital Centre. First, the prototype usability was tested by six experts of the Regional Pharmacovigilance Centre of Rennes. Their experience was assessed with the MORAE software and a System and Usability Scale (SUS) questionnaire. Then, to quantify the timeline contribution to pharmacovigilance routine practice, three of them were asked to investigate possible ADR cases with the "Usual method" (analysis of electronic health record data with the DxCare software) or the "Timeline method". The time to complete the task and the data quality in their reports (using the vigiGrade Completeness score) were recorded and compared between methods.ResultsAll participants completed their tasks. The usability could be considered almost excellent with an average SUS score of 82.5/100. The time to complete the assessment was comparable between methods (P = 0.38) as well as the average vigiGrade Completeness of the data collected with the two methods (P = 0.49).ConclusionsThe results showed a good general level of usability for the timeline prototype. Conversely, no difference in terms of the time spent on each ADR case and data quality was found compared with the usual method. However, this absence of difference between the timeline and the usual tools that have been in use for several years suggests a potential use in pharmacovigilance especially because the testers asked to continue using the timeline after the evaluation.

Dataset Information

Infantile gangliosidoses: Mapping a timeline of clinical changes.

Publications

Infantile gangliosidoses: Mapping a timeline of clinical changes.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets