OBJECTIVE: To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change. METHODS: We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator's, Caregiver's, and Patient's Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. RESULTS: The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator's, Caregiver's, and Patient's CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient's everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. CONCLUSION: Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.

Department of Child Neurology Justus Liebig University Giessen Germany

Department of General Paediatrics University of Münster 48149 Münster Germany

Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research and Center of Neurology University of Tübingen Tübingen Germany

Department of Neurology Case Western Reserve University School of Medicine Cleveland OH USA

Department of Neurology Ludwig Maximilians University Munich Germany

Department of Neurology University Hospital Bern Bern Switzerland

Department of Neurology University of California Los Angeles CA USA

Department of Neuropsychiatry The Royal Melbourne Hospital Melbourne VIC Australia

Department of Paediatric Metabolic Disease Amsterdam University Medical Center Amsterdam Netherlands

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pediatric Neurology National Institute of Children's Diseases Comenius University in Bratislava Bratislava Slovak Republic

Department of Pediatrics Medical Faculty and University Hospital University of Cologne Cologne Germany

Departments of Neurology Pediatrics and Clinical Genomics Mayo Clinic Children's Center Rochester MN USA

Division of Metabolism University Children's Hospital and Children's Research Centre Zurich Switzerland

Division of Paediatric Endocrinology Diabetology and Metabolism Department of Paediatrics and Institute of Clinical Chemistry Inselspital Bern University Hospital University of Bern Bern Switzerland

Lysosomal Storage Disorder Unit Royal Free London NHS Foundation Trust London UK

NIHR Great Ormond Street Hospital Biomedical Research Centre University College London London UK

SphinCS Institute of Clinical Science in Lysosomal Storage Disorders Hochheim Germany

Unité Des Ataxies Cérébelleuses Service de Neurologie Médiathèque Jean Jacquy CHU Charleroi 6000 Charleroi Belgium

Willink Unit Manchester Centre for Genomic Medicine Royal Manchester Children's Hospital University of Manchester Manchester UK

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