Abstract:
Niemann-Pick disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder
caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the
wide range in age of onset of NP-C and clinical presentation of the disease, combined with the complexity of the
cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays
in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C
of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several
sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and
bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have
greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation
and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations,
notably with unidentified mutations and the classification of new variants. This review is intended to increase
awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to
date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers
and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper
combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress,
definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical
markers do not provide a clear answer. Expertise and reference laboratories thus remain essential,
and further work is still required to fulfill unmet needs.
