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Diagnosing Niemann-Pick type C disease

Diagnosing Niemann-Pick type C (NP-C) is not straightforward and the highly varied pattern of symptoms means it is often misdiagnosed or goes undetected.

A Patient and Healthcare Professional Survey conducted amongst patients and their families or carers highlighted that lack of diagnosis or misdiagnosis of NP-C is a great burden to all involved.2

The healthcare professionals interviewed felt that early diagnosis halts the ‘carousel’ of specialists and ends the insecurity and frustration of not knowing the cause of the problem.

For some families, it opens the door to a support network and ends the feeling of isolation.

From a clinical perspective, the value of early diagnosis is particularly important with the availability of a disease-specific treatment that can potentially slow or stabilize disease progression.

It provides the healthcare professional with an opportunity to advise and educate the family about NP-C and treatment, provide access to social and psychological support and also facilitate earlier genetic counselling.

The identification and diagnosis of patients with NP-C follows three broad approaches:3

Clinical assessment

Biomarker testing

Genetic analysis

The three approaches incorporate recent advances in biomarker profiling, genetic technologies and clinical examination, and can be used to screen and diagnose large cohorts of at-risk patients, in addition to individuals with a high clinical suspicion of NP-C.


Guidelines for the management and diagnosis of NP-C

The first international guidelines for the clinical management of NP-C, developed by the NP-C Guidelines Working Group, were published in 2009, addressing an important gap in the published literature.1

Following a significant increase in published data regarding the epidemiology, detection/diagnosis and treatment of NP-C, revised guidelines were published in 2012.4

In the following years, substantial progress was made in the field of NP-C screening and diagnosis, justifying an update to the 2012 recommendations for clinical practice. Consequently in May 2016, the NP-C Diagnostic Recommendations Expert Panel convened to assess recent, publicly available data and develop updated recommendations for the detection and diagnosis of NP-C.3 The new recommendations include the following updates:3

New biomarkers (e.g. oxysterols, lysosphingomyelin-509, lysosphingomyelin and bile acids)

Next-generation sequencing (NGS) technologies

Biomarkers and NGS technologies are now advocated as first-line diagnostic tests and the combination of these analyses is deemed sufficient to confirm a diagnosis of NP-C

The filipin staining test is only recommended for unclear cases

Clinical screening tools (NP-C Suspicion Index)

Updated best practice guidance for the clinical assessment of patients

A detailed description of at-risk clinical patient cohorts who may be enriched with patients with NP-C

An updated, simplified diagnostic algorithm is included

Figure 1: A revised laboratory diagnostic algorithm for the use of biomarkers and genetic testing in NP-C. Local factors (e.g. availability of, and access to, services) determine the choice and order of diagnostic tests.3


aAt-risk patient populations are defined in Table 1; bSingle-gene sequencing (exons or known mutations) or other; c2 different alleles; dCovers deep intronic sequencing and if possible gene transcription regulatory regions; eBiomarker(s) profiling (if not initially conducted), or extended biomarkers profiling (in addition to those already conducted). Note: In spite of 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; NP‑C, Niemann-Pick disease Type C; VUS, variant of unknown significance.





  1. Wraith E, Baumgartner M, Bembi B, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab 2009;98:152–65.
  2. Klünemann H, Wraith E, Wijburg F. Niemann-Pick Type C Disease – Report on Results from the Niemann-Pick Type C Patient and Healthcare Professional Survey. Eur Neurol Rev 2011;6:12–5.
  3. Marquardt T, Clayton P, Gissen P, et al, on behalf of the NP-C Diagnostics Working Group. New consensus recommendations for the detection and diagnosis of Niemann-Pick disease type C. J Inherit Metab Dis 2016;39:35. 
  4. Patterson MC, Hendriksz CJ, Walterfang M, et al., on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update Mol Genet Metab 2012;106:330–44.