Abstract:
BACKGROUND: Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a
profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease
type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn
errors of metabolism (IEMs).
A comprehensive, non-systematic review of published information from NP-C screening studies was conducted,
focusing on diagnostic methods and study designs that have been employed to date. As a key part of this analysis,
data from both successful studies (where cases were positively identified) and unsuccessful studies (where the
chosen approach failed to identify any cases) were included alongside information from our own experiences
gained from the planning and execution of screening for NP-C. On this basis, best-practice recommendations for
ultra-rare IEM screening are provided. Twenty-six published screening studies were identified and categorised
according to study design into four groups: 1) prospective patient cohort and family-based secondary screenings
(18 studies); 2) analyses of archived ‘biobank’ materials (one study); 3) medical chart review and bioinformatics data
mining (five studies); and 4) newborn screening (two studies). NPC1/NPC2 sequencing was the most common
primary screening method (Sanger sequencing in eight studies and next-generation sequencing [gene panel or
exome sequencing] in five studies), followed by biomarker analyses (usually oxysterols) and clinical surveillance.
CONCLUSIONS: Historically, screening for NP-C has been based on single-patient studies, small case series, and
targeted cohorts, but the emergence of new diagnostic methods over the last 5–10 years has provided
opportunities to screen for NP-C on a larger scale. Combining clinical, biomarker and genetic diagnostic methods
represents the most effective way to identify NP-C cases, while reducing the likelihood of misdiagnosis. Our
recommendations are intended as a guide for planning screening protocols for ultra-rare IEMs in general.
