Diagnosis of Niemann-Pick Type C
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.