Yanjanin et al. TABLE 1: Npc clinical severity scale Robert Power Acknowledgements: Dr. Kasturi Haldar Barbara Calhoun

Background NPC No definitive therapy Autosomal recessive lysosomal storage disorder Intracellular accumulation of cholesterol/glycosphingolipids Major clinical problems are neurological 95% of cases caused by mutation Npc1 gene No definitive therapy Cholesterol-lowering drugs/low cholesterol diet Hepatic transplantation Miglustat Improved horizontal saccidic eye movement velocities after 1 year No universally accepted clinical outcome measure Major impediment to designing therapeutic trials for NPC Iturriaga et al. developed a step-wise progression of disease severity 4 domain “disability scale” for NPC patients Limited dynamic range of 4 to 18 Yanjanin et al. expanded on Iturriaga’s scale Validated in cross-sectional study of NPC patients No effect on neurological problems

NPC Clinical Severity Scale

Strengths of Data 9 major and 8 minor domains Most comprehensive scale to date Extensive analysis of each individual domain Extensively dynamic range Scores vary from 0 to 61 Majority of domains can be applied to patients of all ages of onset Ability to add scores within certain domains e.g. Swallow: More accurate representation of severity

Weaknesses of Data No patient-specific clinical info is comprehensively covered Scale quantifies deterioration or improvement within defined symptom domains Requires complete evaluation of each domain at each visit Percentage of patients may progress more aggressively Must be careful when providing anticipatory guidance Difficult to differentiate between some options e.g. Cognition Difficult to categorize some modifier domains Choose between no history and definitive history (nothing in between) Long duration of clinical appointment Ambulation may not apply to neonates/infants Doesn’t account for laboratory studies/data Poor characterization of seizures No reference to different types (e.g. grand mal, absence, etc.)

Significance of Data May predict rate of disease progression regardless of age of onset Families can be given anticipatory guidance Potential to provide insights into pathological mechanisms underlying the disorder Correlation of biomarkers with disease progression and long-term outcome The most significant application/utility of such a clinical severity scale Potential to index other quantitative biochemical, imaging, or clinical data Validate link between biomarkers and disease progression Such a scale is necessary for NPC therapeutic trials However, there is obviously much room for improvement