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Niemann-Pick NPC

Diagnosing NPC

Niemann-Pick Type C (NPC) is an ultrarare neurovisceral cholesterol trafficking and storage disorder caused by mutations in the NPC1 and NPC2 genes. Diagnosis is challenging due the rarity of the disease, the wide range of disease onset and presentations, and the complexity of the laboratory diagnostics for NPC. As a result, the disease frequently goes unrecognized or misdiagnosed, with diagnostic delays averaging 4 to 5 years in the US. In the past diagnosis of NPC was accomplished through cholesterol staining with filipin of skin fibroblasts obtained by skin biopsy. Recent advances in mass spectrometry-based biomarker discovery have led to identification of several sensitive biomarkers for diagnosis of NPC. These markers include cholestane-3β,5α,6β-triol (C-triol) (1, 2), N-palmitoyl-O-phosphocholineserine (PPCS, also known as lysoSM-509) (3, 4), and N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (bile acid B) (5). The C-triol or “oxysterol” test is the most widely used and validated biochemical test for NPC, offered by >50 laboratories worldwide. In the US, this test is available through the Mayo Clinic Biochemical Genetics Laboratory. The glycinated bile acid test, a newer biomarker, is the most specific of the NPC biomarkers and is offered free of charge as a CLIA test through the Washington University Metabolomics Core. Biomarker testing has emerged as the principal, first-line diagnostic for NPC because it is rapid, low-cost and non-invasive. A critical review of these biomarkers for NPC diagnosis is provided by Vanier et al (6).

Confirmation of a diagnosis with high clinical suspicion and/or a biomarker profile consistent with NPC is primarily based on molecular study of the NPC1 and NPC2 genes. Genetic testing for NPC is offered in the US through GeneDx (Gaithersburg, MD) and Mayo Clinic Molecular Genetics Laboratory. A diagnostic algorithm for use of biomarker and genetic testing in NPC is provided by Patterson et al (7). In most cases, positive genetic testing results, or positive biomarker testing results combined with molecular genetic analysis, are sufficient to diagnose NPC.

Targeted gene and multigene panels that include NPC1 and NPC2 can also be used to screen patient groups with an increased risk of NPC. NPC1 and NPC2 are included in several gene panels, including infantile cholestasis, early-onset ataxia, epilepsy, dystonia, specific inborn errors of metabolism (e.g., lysosomal storage diseases), organic psychosis, early-onset cognitive decline, hepatosplenomegaly, and developmental delay (7). A cholestasis panel offered free of charge through EGL Genetics is increasingly being used and has led to increased recognition of NPC among newborns.


For additional information about options for genetic testing, contact the NNPDF.

Additional Information:

Contacts at:

Forbes D. “Denny” Porter, MD, PhD
National Institute of Child Health and Human Development at NIH
National Institutes of Health
10 Center Drive
Room 5-2571, MSC 1832
Bethesda, MD  20892-1832
Tele:  301-435-4432

Nicole Farhat, Nurse Practitioner
NPC Clinical Protocols
National Institute of Child Health and Human Development at NIH
10 Center Drive
Room 1-3330, MSC 1103
Bethesda MD 20892-1103
Tele:  301-594-1765

1. Jiang X, Sidhu R, Porter FD, Yanjanin NM, Speak AO, te Vruchte DT, Platt FM, Fujiwara H, Scherrer DE, Zhang J, Dietzen DJ, Schaffer JE, Ory DS. A sensitive and specific LC-MS/MS method for rapid diagnosis of Niemann-Pick C1 disease from human plasma. J Lipid Res. 2011;52(7):1435-45. PMCID: PMC3122908.
2. Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, Olzeski D, Sidhu R, Dietzen DJ, Fu R, Wassif CA, Yanjanin NM, Marso SP, House J, Vite C, Schaffer JE, Ory DS. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010;2(56):56ra81. PMCID: PMC3170139.
3. Giese AK, Mascher H, Grittner U, Eichler S, Kramp G, Lukas J, te Vruchte D, Al Eisa N, Cortina-Borja M, Porter FD, Platt FM, Rolfs A. A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease. Orphanet J Rare Dis. 2015;10:78. PMCID: PMC4479076.
4. Sidhu R, Mondjinou Y, Qian M, Song H, Kumar AB, Hong X, Hsu FF, Dietzen DJ, Yanjanin NM, Porter FD, Berry-Kravis E, Vite CH, Gelb MH, Schaffer JE, Ory DS, Jiang X. N-acyl-O-phosphocholineserines: structures of a novel class of lipids that are biomarkers for Niemann-Pick C1 disease. J Lipid Res. 2019;60(8):1410-24. PMCID: PMC6672039.
5. Jiang X, Sidhu R, Mydock-McGrane L, Hsu FF, Covey DF, Scherrer DE, Earley B, Gale SE, Farhat NY, Porter FD, Dietzen DJ, Orsini JJ, Berry-Kravis E, Zhang X, Reunert J, Marquardt T, Runz H, Giugliani R, Schaffer JE, Ory DS. Development of a bile acid-based newborn screen for Niemann-Pick disease type C. Sci Transl Med. 2016;8(337):337ra63. PMCID: PMC5316294.
6. Vanier MT, Gissen P, Bauer P, Coll MJ, Burlina A, Hendriksz CJ, Latour P, Goizet C, Welford RW, Marquardt T, Kolb SA. Diagnostic tests for Niemann-Pick disease type C (NP-C): A critical review. Mol Genet Metab. 2016;118(4):244-54. PubMed PMID: 27339554.
7. Patterson MC, Clayton P, Gissen P, Anheim M, Bauer P, Bonnot O, Dardis A, Dionisi-Vici C, Klunemann HH, Latour P, Lourenco CM, Ory DS, Parker A, Pocovi M, Strupp M, Vanier MT, Walterfang M, Marquardt T. Recommendations for the detection and diagnosis of Niemann-Pick disease type C: An update. Neurol Clin Pract. 2017;7(6):499-511. PMCID: PMC5800709.

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