Elevated cerebrospinal fluid ubiquitin C-terminal hydrolase-L1 levels correlate with phenotypic severity and therapeutic response in Niemann-Pick disease, type C1

Abstract

Background: Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive disorder due to pathological variants of NPC1. The NPC1 phenotype is characterized by progressive cerebellar ataxia and cognitive impairment. Although classically a childhood/adolescent disease, NPC1 is heterogeneous with respect to the age of onset of neurological signs and symptoms. While miglustat has shown to be clinically effective, there are currently no FDA approved drugs to treat NPC1. Identification and characterization of biomarkers may provide tools to facilitate therapeutic trials. Ubiquitin C-terminal hydrolase-L1 (UCHL1) is a protein which is highly expressed by neurons and is a biomarker of neuronal damage. We thus measured cerebrospinal fluid (CSF) levels of UCHL1 in individuals with NPC1.

Methods: CSF levels of UCHL1 were measured using a Quanterix Neuroplex 4 assay in 94 individuals with NPC1 and 35 age-appropriate comparison samples. Cross-sectional and longitudinal CSF UCHL1 levels were then evaluated for correlation with phenotypic measures and treatment status.

Results: CSF UCHL1 levels were markedly elevated (3.3-fold) in individuals with NPC1 relative to comparison samples. The CSF UCHL1 levels showed statistically significant (adj p < 0.0001), moderate, positive correlations with both the 17- and 5-domain NPC Neurological Severity Scores and the Annual Severity Increment Scores. Miglustat treatment significantly decreased (adj p < 0.0001) CSF UCHL1 levels by 30% (95% CI 17-40%).

Conclusions: CSF UCHL1 levels are elevated in NPC1, increase with increasing clinical severity and decrease in response to therapy with miglustat. Based on these data, UCHL1 may be a useful biomarker to monitor disease progression and therapeutic response in individuals with NPC1.

Keywords: Biomarker; Miglustat; NPC1; Niemann-Pick disease, type C1; UCHL1; Ubiquitin C-terminal hydrolase-L1.

Figure 1.. Elevated cerebrospinal fluid UCHL1 levels in individuals with Niemann-Pick Disease, type C1.

CSF UCHL1 levels were log₁₀ transformed to better approximate normality. A) Baseline UCHL1 levels were significantly elevated (adj p<0.0001) in CSF from individuals with NPC1 relative to non-NPC1 comparison samples. Although still elevated, baseline CSF UCHL1 levels were significantly (p<0.0001) lower in the NPC1 samples from individuals being treated with miglustat (Mig). Error bars correspond to mean ± SD, two-sample t-test. B) CSF UCHL1 levels were stratified by age groups corresponding to early infantile (0<2 years), late infantile (2<6 years), juvenile (6<15 years), and adolescent/adult (≥ 15 years) disease onset. Mean baseline levels decreased significantly with increased age (p=0.0088, one-way ANOVA). Error bars indicate mean ± SD.

Figure 2.. Spearman correlation of cerebrospinal fluid UCHL1 levels with baseline clinical outcome measures.

CSF UCHL1 levels were correlated with A) Age of Neurological Onset, B) Annual Severity Increment Score or ASIS, C) the 17-domain NPC Neurological Severity Score and D) the 5-domain NPC Neurological Severity Score (NPC NSS). Open circles and solid line indicate data from untreated individuals. Filled circles and dashed line indicate data from miglustat treated individuals.

Figure 3.. Cerebrospinal fluid levels of UCHL1 and NEFL in individuals with NPC1.

A) There is a significant positive correlation (slope 2.3, p<0.0001) between baseline CSF UCHL1 and NEFL levels in individual samples. B) Separation of baseline levels by miglustat treatment status. Solid line and filled circles, no miglustat (slope 3.1, p<0.0001). Dashed line and open circles, miglustat treated (slope 1.0, p<0.0001).