This study was approved by the National Institute of Child Health and Human Development Institutional Review Board. Consent and, when appropriate, assent were obtained. A clinical severity scale was developed to ascertain clinical symptoms in nine major and eight minor clinical areas (Table I). Four of the domains (Ambulation, Fine Motor Skills, Speech, and Swallowing) were modified from the disability scale developed by Iturriaga et al [Iturriaga et al., 2006 (link)]. The scoring of each domain was designed to allow a score to be derived from a comprehensive clinical evaluation. A Likert-like scale was used to assign nine major domain scores of 0–5 and eight minor domain scores of 0–2. Clinical experience was used to weight the various scales. Summation of all 17 domains yielded total possible scores that range from 0–61, with a higher score indicating more severe clinical impairment. A comprehensive medical history form was developed to document both the clinical history of current patients and to serve as a guide in extraction of data from medical records. To be scored, seizures, cataplexy, and narcolepsy had to be definitive and not questionable. For the swallowing domain, one point was scored if the patient had a history of cough while eating. Additional points were added if the patient had intermittent or consistent dysphagia with either liquids or solids. Hearing loss refers to sensorineural hearing loss and not hearing loss secondary to conductive defects. The diagnosis of NPC was established by either biochemical testing or mutation analysis. All patients have NPC1 by either molecular or complementation group testing. Two patient groups were studied. The first group consisted of 18 NPC patients (current cohort) who were enrolled in an observational study at the National Institutes of Health Clinical Center (NIH CC) between August 2006 and September 2007 (Table II). The second patient cohort consisted of 19 NPC patients (historical cohort) for whom we had sufficient medical records to generate at least three scores at different time points. Medical records were reviewed for 36 patients followed at the NIH CC by other investigators between 1972 and 2005. Of the 36 previous NIH CC patients with a diagnosis of NPC, 16 patients had three or more NIH admissions with adequate documentation to generate a severity score. Of the current patients, patient 1 had previous NIH admissions for which records were available and patients 13 and 15 had sufficient outside medical records from which we could derive longitudinal data.