Scale name	List of domains measured	How the scales have been used to date
		Use in clinical practice	Patient registries	Recruitment of patients into clinical trials	Outcomes measures in clinical trials	Additional notes
Disability Scale (NPC-specific) [4]	The Disability Scale was developed via a cohort of 30 NPC patients It measures four domains: ambulation, manipulation, language and swallowing, with scores 1–4 or 5	No information available	No information available	No information available	No information available regarding use in clinical trials to date	Used in a study that examined the structure of the callosum in a group of adult patients with NPC and compared callosal structure with a group of matched controls, and to relate callosal structure with state and trait illness variables [21]
Disease-specific Disability Scale [19]	In an adaption of the scale developed by Iturriaga et al. (2006) [3], the Disease-specific Disability Scale assigns weighted scores for each parameter on a scale from 0–1 It measures four domains: ambulation, manipulation, language and swallowing	This study incorporates findings from an observational retrospective cohort study conducted to further assess the effects of miglustat on neurological disease progression in NPC patients treated with miglustat in the clinical practice setting, outside the context of clinical trials	The authors anticipated that this scale would be included as one of the standard monitoring assessments in the planned international disease registry for NPC patients and yield further, valuable long-term information on the utility of the scale in monitoring disease progression and treatment response	No information available	Primary outcomes in the study: Clinical experience with miglustat therapy in pediatric patients with Niemann–Pick disease type C: a case series [22] modified with scores to calculate an overall (composite) disability score	Used to evaluate the efficacy and course of disease in patients treated with miglustat using two neuroimaging modalities [23] Used in a study to identify retinal degeneration in NPC1-disease and to investigate possible subclinical retinal degeneration in NPC1-MC [24]
NPC Clinical Severity Score (NPCCSS) [18]	Comprises 17-domains based on a cohort of 18 then-current NPC patients and 19 historical cases from the National Institutes of Health The NPCCSS measures: nine major domains: ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing eight minor domains: auditory brainstem response, behaviour, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems	No information available	No information available	According to the authors, the ability to combine data from patients of variable age of onset will facilitate recruitment for clinical trials	Primary outcomes in the study: Long-Term Treatment of Niemann–Pick Type C1 Disease With Intrathecal 2-Hydroxypropyl-β-Cyclodextrin [25] Secondary outcomes in the study: Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann–Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial [26] Primary outcomes in the study: VTS-270 for the treatment of Niemann–Pick disease type C. Molecular Genetics and Metabolism [27] Primary outcomes in the study: Arimoclomol Prospective Study in Patients Diagnosed With Niemann Pick Disease Type C [28] Primary objectives in the study: Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study [29]	Evaluated whether the lower corpus callosum fractional anisotropy, volume, and cross-sectional area significantly correlate with higher severity score in patients with NPC [30] Used to systematically describe the neurocognitive phenotype of children and adolescents with NPC1, identifying heterogeneity and decline, aiding in understanding the natural history of the disease to plan treatment studies [31]
NPC-cdb Scale [20]	Unlike previous scales, the NPC-cdb scale represents the sum of all past and current symptoms present in a patient at any given time, with each symptom contributing a severity-weighted summand	The authors note that the scale’s ease of use should prove useful in clinical settings. It could also complement the widely used, but less comprehensive, scales that only poorly reflect the heterogeneous clinical picture of NPC	This is used in the INPDR registry for registering NPC symptoms at baseline and how they evolve over time	No information available	Primary outcomes in the study: Arimoclomol Prospective Study in Patients Diagnosed With Niemann Pick Disease Type C [28] Primary objectives in the study: Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study [29]
ASIS [16]	The Annual Severity Increment Score (ASIS) measures rate of disease progression using Yanjanin et al.’s (2009) scale [18] The only data required to calculate ASIS is the total severity score and the precise age of the patient when the score was ascertained	Authors denoted that their annual severity increment score (ASIS), that measures rate of disease progression, could easily be used in clinical practice	Anticipated contribution to pre-trial longitudinal data for individual patients held by patient registries (International Niemann–Pick Disease Alliance)	Authors note that ASIS provides an evidence-based stratification/ recruitment tool that is easy to calculate and apply in any clinical setting	Secondary outcomes in the study: Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann–Pick type C disease [32]	Validated in an observational clinical study in NPC patients treated with the drug Tanganil (acetyl-DL-leucine)
Severity rating scale of neurological manifestations and dysphagia [33	A clinical scoring scale for a series of neurological parameters. Developed to measure the treatment efficacy of miglustat It measures six domains: gait abnormalities, dysmetria, dystonia, dysarthria developmental delay/cognitive impairment and dysphagia	No information available	No information available	No information available	Primary outcomes in the study: Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann–Pick disease type C [33]
5-Domain NPCCSS [16]	Based on the 17-domain NPCCSS, the 5-domain NPCCSS measures ambulation, cognition, fine motor, speech and swallowing Five domains, selected by NPC individuals, their caregivers and NPC experts as the most clinically relevant, reduce variability and increase the suitability for use in clinical trials	The authors note that when combined, these five domains correlated well with total severity, suggesting they may be the most relevant domains to analyse in clinical trials with direct QoL relevance	No information available	No information available	Primary outcomes in the study: Arimoclomol Prospective Study in Patients Diagnosed With Niemann Pick Disease Type C [28] Primary objectives in the study: Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study [29]
Functional Disability Scale [3]	Modified from Pineda et al. (2009) [19], this clinical severity assessment measures seven domains: ambulation, manipulation, language, swallowing, eye movements, seizure and neurocognitive development (for patients under 12 years of age) However, it has not been formally validated for treatment monitoring	The authors note that these guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC	Backed by expert physicians, geneticists, allied healthcare professionals and patient support groups involved in the International Niemann–Pick Disease Registry (INPDR) project (www.inpdr.org), which is supported by the EU Directorate General for Health and Consumers (DG-SANCO) via the Consumers, Health, Agriculture and Food Executive Agency (CHAFEA)	No information available	No information available regarding use in clinical trials to date