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

2. 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

3. NPC Clinical Severity Scale

4. 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

5. 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.)

6. 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