Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C

Abstract

Niemann-Pick disease, type C is a neurodegenerative, lysosomal storage disorder with a broad clinical spectrum and a variable age of onset. The absence of a universally accepted clinical outcome measure is an impediment to the design of a therapeutic trial for NPC. Thus, we developed a clinical severity scale to characterize and quantify disease progression. Clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, and swallowing) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, and respiratory problems) domains were scored. Data were collected from 18 current NPC patients and were extracted from records of 19 patients. Both patient cohorts showed a linear increase in severity scores over time. Cross-sectional evaluation of current patients showed a linear increase in the severity score. Longitudinal chart review of historical data demonstrated that although age of onset varied significantly, the rate of progression appeared linear, independent of age of onset, and similar in all patients. Combining the data from both cohorts, disease progression could be modeled by the following equation: ŝ(t0+x) = ŝ(t0) + 1.87x; where ŝ(t0) is the initial score and ŝ(t0+x) is the predicted future score after x years. Our observation that disease progression is similar across patients and independent of age of onset is consistent with a biphasic pathological model for NPC. This scale may prove useful in the characterization of potential biomarkers, and as an outcome measure to monitor disease progression in NPC patients.

(c) 2009 Wiley-Liss, Inc.

Figures

Figure 1

NPC clinical progression. A) Clinical severity scores for the current cohort as a function of age. B) The change in the clinical severity score between onset of symptoms and the first NIH evaluation. Patients on off-label miglustat use are indicated by open circles. C) Longitudinal severity scores in a cohort of 19 historical patients. D) The progression slope was determined by linear regression of each of the curves depicted in Fig. 1C. E) Contribution of the major domains to the total score for the current cohort and the historical cohort. For the historical cohort, we compared early findings (0–5 years after onset) to late findings (>6 years after onset).

Figure 2

Statistical modeling. To model phenotypic progression in NPC, data from all patients was combined. Patients ranged in age from 2 to 51 years (mean=18.6, SD=11.5), number of visits ranged from 1 to 8 (mean=3.4, SD=2.1), and the total scores ranged from 1 to 46 (mean 18.6, SD=10.7). The figure shows the individual data points, the model curves for individual patients (dashed lines), and the predicted population curve (heavy solid line).

Figure 3

Theoretical modeling. Two hypothetical pathological models are presented. In the first model (A) a single pathological process leads to progressive neuronal loss or dysfunction. Neurological symptoms occur once given thresholds appear. The rate of neuronal loss determines both age of onset and the rate of clinical progression (inset). This model predicts that later onset would be associated with slower clinical progression. In the second biphasic model (B) we propose that one pathological process occurs at variable rates that results in neuronal toxicity. Once a given “toxicity threshold” is crossed, a second reactive pathological process results in neuronal loss or dysfunction. The rate of the second process is constant, and like in the first model symptoms occur once given thresholds of neuronal loss are crossed. In this model, age of onset is determined by the first process; whereas, appearance of symptoms will subsequently occur at a similar rate in different patients.