Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update

Abstract

Purpose of review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice.

Recent findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified.

Summary: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

Figure. Revised Niemann-Pick disease type C (NP-C) diagnostic algorithm for the use of biomarkers and genetic testing

Individual steps can be omitted if not locally available. ^aAt-risk patient populations are defined in table 1. ^bNegative biomarkers may be suggestive that the diagnosis is not NP-C. ^cSingle-gene sequencing (exons or known mutations) or other. ^d+1 Variant of unknown significance optional. ^eCovers deep intronic sequencing and if possible gene transcription regulatory regions. ^fTwo different alleles. ^gBiomarker(s) profiling (if not initially conducted), or extended biomarkers profiling (in addition to those already conducted). Despite comprehensive investigations, it may not be possible to definitively confirm a diagnosis of NP-C in a few patients. In such cases, a thorough reappraisal of longitudinal clinical data, more in-depth genomic analyses (e.g., whole exome and whole genome sequencing), and cell biological assessments could be considered. cDNA = complementary DNA; MLPA = multiplex ligation-dependent probe amplification.