Dataset Information

Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery.

ABSTRACT: Niemann-Pick C is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation and the early non-specific symptoms. The discovery of disease-specific biomarkers - cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine (PPCS, initially referred to as lysoSM-509) - has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also proven useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

SUBMITTER: Jiang X

PROVIDER: S-EPMC8963791 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery.

Jiang Xuntian X Ory Daniel S DS

Exploration of neuroprotective therapy 20211201 3

Niemann-Pick C is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation and the early non-specific symptoms. The discovery of disease-specific biomarkers - cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and <i>N</i>-palmitoyl-O-phosphocholineserine (PPCS, initially referred to as lysoSM-509) - has led to development of non-inv ...[more]

PMID: 35356760

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Project description:ObjectivesThe aim of this study was to comprehensively evaluate the auditory phenotype in Niemann-Pick disease, type C1 (NPC1), to understand better the natural history of this complex, heterogeneous disorder, and to define further the baseline auditory deficits associated with NPC1 so that use of potentially ototoxic interventions (e.g., 2-hydroxypropyl-ß-cyclodextrin) may be more appropriately monitored and understood.DesignFifty patients with NPC1 ranging in age from 4 months to 21 years (mean = 9.3 years) enrolled in a natural history/observational study at the National Institutes of Health. The auditory test battery included, when possible, immittance audiometry, pure-tone and speech audiometry, otoacoustic emission testing, and a neurotologic auditory brainstem response study. Longitudinal data were collected on a subset of patients.ResultsOver half of the cohort exhibited hearing loss involving the high frequencies ranging from a slight to moderate degree, and 74% of patients presented with clinically significant hearing loss involving the frequencies most important to speech understanding (0.5, 1, 2, 4 kHz). Despite the heterogeneity of the sample, results among patients were sufficiently consistent to implicate retrocochlear dysfunction in the majority (66%) of individuals, with (22%) or without (44%) accompanying cochlear involvement. Some patients (10%) presented with a profile for auditory neuropathy spectrum disorder. The combination of cross-sectional and longitudinal data indicates these patients are at risk for a progressive decline in auditory function.ConclusionsThis is the largest cohort of patients with NPC1 evaluated comprehensively for auditory dysfunction, and results implicate the pathological processes of NPC1 in the manifestation of hearing loss. Patients with NPC1 should be monitored audiologically throughout their lives, beginning at the time of diagnosis. Clinicians and researchers should be aware of this historically overlooked aspect of the phenotype.

Dataset Information

Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery.

Publications

Advancing Diagnosis and Treatment of Niemann-Pick C disease through Biomarker Discovery.

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