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, swallowing,) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, 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.

Glycosylation Regulates Prestin Cellular Activity

“…Our finding that prestin NN163/166AA undergoes cholesterol-dependent endocytosis explains the associated decrease in charge density. Our findings suggest that, both during development and during conditions of cholesterolemia or lipid storage disease states (Tami et al 1985;Saito et al 1986;Sikora et al 1986;Preyer et al 2001;Evans et al 2006;Yanjanin et al 2009), glycosylation of prestin would play a vital role in regulating cell-surface expression of prestin to effect and maintain normal hearing. Based on our observations, we conclude that glycosylation regulates self-association and cellular trafficking of prestin, most likely by regulating its localization to and/or internalization from membrane microdomains by clathrin-and caveolin-dependent mechanisms.…”

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

“…Treatment was therefore primarily determined by insurance coverage but not formally randomized. Disease severity was scored as described previously (Yanjanin et al 2010). This phenotyping index ascertains neurological 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.…”

Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann–Pick disease type C in a retrospective study

“…Recent efforts have aimed to score the symptomatology of NP-C using a disease-specific Suspicion Index [5], as well as disease scales [6,7]. Tools like the NP-C Suspicion Index should help channel symptomatic patients towards expert medical centers for appropriate clinical evaluation, and genetic and biochemical diagnostic tests.…”