On 7/22/08, Denny Porter updated us:
The natural history study has started to provide some promising results. We currently have 26
patients enrolled, with approval for up to 50 patients. A major goal of this protocol is to build a
biorepository of samples from well characterized patients that can be used by NPC researchers
and correlate results with the clinical severity scale. The purpose of this is two-fold:
1. Identify an outcome measure that could be used in a future therapeutic trial
2. Identify a laboratory test that can be used for diagnostic screening for NPC. Currently we
are collaborating with the following laboratories:
Dr. Fran Platt (University of Oxford)
Dr. Yiannis Ioannou (Mount Sinai School of Medicine)
Dr. Dan Ory (Washington University)
Dr. Al Yergey (NICHD, NIH)
Dr. Chris Austin (Chemical Genomics Section, NHGRI, NIH)
Dr. Alan Remaly (NHLBI, NIH)
Dr. Gordon Francis (University of Alberta)
Denny
Disease Progression in Niemann-Pick Disease, type C: Longitudinal
Evaluation of Current and Historical Cohorts
Nicole M. Yanjanin1, Jorge I. Vélez2, Andrea Gropman5, Kelly King3, Carmen C. Brewer3,
Beth Solomon4, William Pavan2, Mauricio Arcos-Burgos2,
Marc C. Patterson6 and Forbes D. Porter1*
1
NICHD, 2 NHGRI, 3NIDCD, and 4CC NIH, DHHS, Bethesda, Maryland, 5Children’s National
Medical Center, Washington, DC, 6Mayo Clinic, Rochester, Minnesota
* fdporter@mail.nih.gov 301-435-4432
Introduction: The absence of a universally accepted outcome measure is an impediment to the
development of therapeutic trials for Niemann-Pick Disease, type C (NPC). The heterogeneous
clinical nature and variable age of onset compounds the characterization of potential biomarkers.
In an effort to identify potential clinical or biochemical outcome measures, a longitudinal
observational trial has been initiated at the NIH and to quantify disease progression, a clinical
severity scale was developed. Our goals are to determine if this clinical scale can be used to 1)
quantify disease progression in NPC, 2) correlate potential biomarkers with disease status, and 3)
provide a long-term outcome measure to evaluate therapeutic efficacy.
Methods: Clinical data were collected from 18 NPC patients enrolled in an observational study
at the NIH and historical data were extracted from medical records of 19 patients. Clinical
symptoms in nine major (scored 0-5: eye movement, ambulation, speech, swallowing, fine
motor, cognition, hearing, memory, seizures) and eight minor domains (scored 0-3: gelastic
cataplexy, narcolepsy, behavior, psychiatric, hyperreflexia, incontinence, ABR, respiratory
problems) typically noted in a comprehensive medical history were scored.
Results: Analysis of both the current and historical cohorts showed a linear increase in severity
scores over time. Cross-sectional evaluation of 18 patients currently enrolled in the NIH
observational study showed a linear increase (r2=0.64, p<0.0001) in the severity score when
plotted against the time interval between the age of initial presentation and initial NIH
evaluation. The slope suggested a mean rate of progression of 1.37 ± 0.26 points per year. The
rate of progression (1.38 ± 0.25) was not significantly altered when patients on off-label
miglustat were excluded from this analysis. The clinical progression scale was also applied in a
longitudinal chart review of 19 NPC patients evaluated at least three times. Although age of
onset varied significantly, the rate of progression appeared to be independent of age of onset and
similar in all patients. The mean progression slope was 1.9 ± 1.0 points per year. Excluding one
patient with a progression greater than three standard deviations above the mean yielded a mean
progression slope of 1.7 ± 0.6 points per year. Combining the data from both cohorts,
population progression could be modeled by the following equation: Ŝ=-10.7+1.87(age). The
standard error and the 95% CI for the slope were ±0.18 and 1.6 to 2.3 respectively, allowing for
power estimates to be obtained. In addition, correlations between domains have been analyzed.
Conclusions: Both cohorts show similar linear disease progression independent of age of
onset. Our observation that disease progression is similar in patients and independent of age of
onset is consistent with a biphasic pathological model for NPC. In addition, this scale may
prove useful in the characterization of potential biomarkers, and as an outcome measure to
monitor disease progression in NPC patients.