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 (OR(NIHSD) = 1.34–2.10, 95% CI 1.04–3.4, p = 0.001–0.026; OR(Seizure) = 3.26–18.22, 1.03–167.79; p = 0.001–0.046), while miglustat use revealed protection (OR(Miglustat) = 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02472-w.