Swallowing characterization of adult-onset Niemann-Pick, type C1 patients.

BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk. This study aims to characterize swallowing function in AO NPC1, addressing the gap in understanding and clinical management. METHODS: Fourteen AO NPC1 individuals in a prospective natural history study (NCT00344331) underwent comprehensive assessments, including history and physical examinations utilizing the NPC1 severity rating scale, videofluoroscopic swallowing studies with summary interpretive analysis, and cerebrospinal fluid (CSF) collection for biomarker evaluation at baseline visit. Descriptive statistics and multivariate statistical modeling were employed to analyze NPC1 disease covariates, along with the American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH Penetration Aspiration Scale (NIH-PAS). RESULTS: Our cohort, comprised of 14 predominately female (n = 11, 78.6%) individuals, had an average age of 43.1 ± 16.7 years at the initial visit. Overall, our AO patients were able to swallow independently with no/minimal cueing, with 6 (43%) avoiding specific food items or requiring more time. Upon risk analysis of aspiration, the cohort demonstrated no obvious aspiration risk or laryngeal aspiration in 8 (57%), minimal risk with intermittent laryngeal penetration and retrograde excursion in 5(36%), and moderate risk (7%) in only one. Dietary modifications were recommended in 7 (50%), particularly for liquid viscosities (n = 6, 43%) rather than solids (n = 3, 21%). No significant correlations were identified between swallowing outcomes and NPC1-related parameters or CSF biomarkers. CONCLUSION: Despite the heterogeneity in NPC1 presentation, the AO cohort displayed functional swallowing abilities with low aspiration risk with some participants still requiring some level of dietary modifications. This study emphasizes the importance of regular swallowing evaluations and management in AO NPC1 to address potential morbidities associated with dysphagia such as aspiration. These findings provide clinical recommendations for the assessment and management of the AO cohort, contributing to improved care for these individuals.

Phenotypic expression of swallowing function in Niemann-Pick disease type C1.

BACKGROUND: Niemann-Pick disease type C1 (NPC1) is a rare autosomal recessive disease characterized by endolysosomal accumulation of unesterified cholesterol with progressive deterioration in swallowing, often leading to premature death. Although documented, the natural history of NPC1 swallowing dysfunction has yet to be delineated systematically. This manuscript aims to provide a comprehensive characterization of the phenotypic spectrum and progression of swallowing dysfunction in NPC1. METHODOLOGY: The National Institutes of Health (NIH) NPC1 natural history study (NCT00344331) enrolled 120 patients, who underwent comprehensive interpretative swallow assessments for swallowing safety, dietary modifications, and aspiration risk. Longitudinal statistical modeling accounted for all outcomes with NPC1 disease covariates (first symptom onset, age at neurological symptom onset, seizure history, duration of neurological symptoms) as well as miglustat use (a glucosylceramide synthase inhibitor) and NIH study duration (NIHSD; the length of time an individual participated in the NIH study). Probabilities for disease progression and time to swallowing decline were conducted for the entire cohort. RESULTS: Time to swallowing decline with American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH-adapted Penetration Aspiration Scale (NIH-PAS) were identified: [Formula: see text] person-years and [Formula: see text] person-years, respectively. NIHSD and seizure history consistently and significantly were associated with decline (ORNIHSD = 1.34-2.10, 95% CI 1.04-3.4, p = 0.001-0.026; ORSeizure = 3.26-18.22, 1.03-167.79; p = 0.001-0.046), while miglustat use revealed protection (ORMiglustat = 0.01-0.43, 0.007-0.98; p = 0.001-0.044). The probability of decline with NPC1 neurological severity scale and annual severity increment scale were established with the aforementioned covariates, varying amongst subgroups. CONCLUSION: This study represents the most extensive collection of prospective, instrumental swallowing assessments in NPC1 to date with an interpretive analysis providing an improved understanding of NPC1 disease progression with swallowing function-serving as a foundation for clinical management and future NPC1 therapeutics.