Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders

Julien Park¹, Tatiana Bremova-Ertl², Marion Brands³, Tomas Foltan⁴, Matthias Gautschi⁵, Paul Gissen⁶, Andreas Hahn⁷, Simon Jones⁸, Laila Arash-Kaps⁹, Miriam Kolnikova⁴, Marc Patterson¹⁰, Susan Perlman¹¹, Uma Ramaswami¹², Stella Reichmannová¹³, Marianne Rohrbach¹⁴, Susanne A Schneider¹⁵, Aasef Shaikh¹⁶, Siyamini Sivananthan⁶, Matthis Synofzik¹⁷, Mark Walterfarng¹⁸, Pierre Wibawa¹⁸, Kyriakos Martakis^{7

19}, Mario Manto²⁰

Affiliations

¹ Department of General Paediatrics, University of Münster, 48149, Münster, Germany. Julien.Park@ukmuenster.de.
² Department of Neurology, University Hospital Bern (Inselspital), Bern, Switzerland.
³ Department of Paediatric Metabolic Disease, Amsterdam University Medical Center, Amsterdam, Netherlands.
⁴ Department of Pediatric Neurology, National Institute of Children's Diseases, Comenius University in Bratislava, Bratislava, Slovak Republic.
⁵ Division of Paediatric Endocrinology, Diabetology and Metabolism, Department of Paediatrics, and Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁷ Department of Child Neurology, Justus Liebig University, Giessen, Germany.
⁸ Willink Unit, Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK.
⁹ SphinCS-Institute of Clinical Science in Lysosomal Storage Disorders, Hochheim, Germany.
¹⁰ Departments of Neurology, Pediatrics and Clinical Genomics, Mayo Clinic Children's Center, Rochester, MN, USA.
¹¹ Department of Neurology, University of California, Los Angeles, CA, USA.
¹² Lysosomal Storage Disorder Unit, Royal Free London NHS Foundation Trust, London, UK.
¹³ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹⁴ Division of Metabolism, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
¹⁵ Department of Neurology, Ludwig Maximilians University, Munich, Germany.
¹⁶ Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹⁷ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ Department of Neuropsychiatry, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁹ Department of Pediatrics, Medical Faculty and University Hospital, University of Cologne, Cologne, Germany.
²⁰ Unité Des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000, Charleroi, Belgium.

PMID: 39225743
PMCID: PMC11447074
DOI: 10.1007/s00415-024-12664-y

Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders

Julien Park et al. J Neurol. 2024 Oct.

. 2024 Oct;271(10):6888-6902.

doi: 10.1007/s00415-024-12664-y. Epub 2024 Sep 3.

Authors

Affiliations

¹ Department of General Paediatrics, University of Münster, 48149, Münster, Germany. Julien.Park@ukmuenster.de.
² Department of Neurology, University Hospital Bern (Inselspital), Bern, Switzerland.
³ Department of Paediatric Metabolic Disease, Amsterdam University Medical Center, Amsterdam, Netherlands.
⁴ Department of Pediatric Neurology, National Institute of Children's Diseases, Comenius University in Bratislava, Bratislava, Slovak Republic.
⁵ Division of Paediatric Endocrinology, Diabetology and Metabolism, Department of Paediatrics, and Institute of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁷ Department of Child Neurology, Justus Liebig University, Giessen, Germany.
⁸ Willink Unit, Manchester Centre for Genomic Medicine, Royal Manchester Children's Hospital, University of Manchester, Manchester, UK.
⁹ SphinCS-Institute of Clinical Science in Lysosomal Storage Disorders, Hochheim, Germany.
¹⁰ Departments of Neurology, Pediatrics and Clinical Genomics, Mayo Clinic Children's Center, Rochester, MN, USA.
¹¹ Department of Neurology, University of California, Los Angeles, CA, USA.
¹² Lysosomal Storage Disorder Unit, Royal Free London NHS Foundation Trust, London, UK.
¹³ Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.
¹⁴ Division of Metabolism, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
¹⁵ Department of Neurology, Ludwig Maximilians University, Munich, Germany.
¹⁶ Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
¹⁷ Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
¹⁸ Department of Neuropsychiatry, The Royal Melbourne Hospital, Melbourne, VIC, Australia.
¹⁹ Department of Pediatrics, Medical Faculty and University Hospital, University of Cologne, Cologne, Germany.
²⁰ Unité Des Ataxies Cérébelleuses, Service de Neurologie, Médiathèque Jean Jacquy, CHU-Charleroi, 6000, Charleroi, Belgium.

PMID: 39225743
PMCID: PMC11447074
DOI: 10.1007/s00415-024-12664-y

Abstract

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.

Keywords: Clinical outcome assessments; Lysosomal storage disorders; Scale for the assessment and rating of ataxia.

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Conflict of interest statement

T. Bremova-Ertl received honoraria for lecturing from Sanofi and Acetlion and fees from IntraBio to serve as a blinded rater for the IB1001-201 and IB1001-202 clinical trials. P. Gissen received consulting fees from Mandos Health and is the Co-Founder and shareholder of Bloomsbury Genetic Therapies. M. Patterson is a shareholder in IntraBio and his institution has received research grants from Azafaros, Glycomine, Idorsia, Maggie’s Pearl, Takeda, and Zevra, and consulting fees (directed to his institution) from Zevra. U. Ramaswami has received research and/or investigator-initiated research grants from Amicus and Takeda and honoraria for advisory boards and lectures from Amicus, Takeda, and Sanofi. All other authors. The authors have no competing interests to declare that are relevant to the content of this article.

Figures

**Fig. 1**
Study schemes from IB1001 clinical trials

See this image and copyright information in PMC

References

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Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders

Affiliations

Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

LinkOut - more resources

Full Text Sources