The NPC1 gene is associated with autosomal recessive Niemann-Pick disease type C (MedGen UID: 465922).
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Approximately 95% of Neimann-Pick C cases are due to pathogenic variants in NPC1 (PMID: 25425283).
The NPC1 gene encodes a membrane protein believed to be localized to the late endosomal / lysosomal compartment. The exact function of the NPC1 protein is not clearly understood but it plays an important role in the intracellular sorting of cholesterol and other glycosphingolipids. Dysfunctional NPC1 protein results in impaired cholesterol homeostasis and the progressive intracellular accumulation of cholesterol and glycosphingolipids (PMID: 24664998).
NPC1 (OMIM: 607623) is associated with Niemann-Pick disease type C (OMIM: 257220), which is a lysosomal lipid storage disorder with an extremely variable clinical course, involving visceral, neurologic, and psychiatric symptoms (PMID: 24135395). Classification is usually determined by the age of onset, but 90% of patients will present with progressive neurodegeneration.
NPC suspicion indexes have been developed to identify affected individuals at earlier ages. Although their usefulness is mixed, they may be most helpful in identifying patients with early-onset ataxia as having NPC (PMID: 27314965, 27449637).
The definitive biochemical test has been used to detect impaired cholesterol esterification and filipin staining on fibroblasts. Cholesterol accumulation in the lysosomes is visualized by filipin, but the interpretation can be challenging (PMID: 25665455). Gene sequencing is currently the recommended confirmatory diagnostic test; although, with the finding of only one pathogenic variant or one pathogenic variant and a variant of unknown significance, a filipin study may also be useful (PMID: 19647672). Chitotriosidase may be elevated in NPC and is used as a biomarker for other lysosomal storage disorders (PMID: 17869233).
In the neonatal and infantile presentations, symptoms may mimic congenital infections, liver disease, and other storage disorders, including Gaucher, Niemann-Pick type A, and Niemann-Pick type B.
In childhood, GM2 gangliosidosis, mitochondrial disorders, maple syrup urine disease, dystonia, Wilson disease, aminoacidurias, organic acidurias, neuronal ceroid lipofuscinosis, and the periodic paralysis disorders should be considered.
In adulthood, Alzheimer’s disease, including Pick disease, and the frontotemporal dementias can have a similar presentation to NPC (PMID: 20301473).
NPC1 encodes a membrane protein believed to be localized to the late endosomal or lysosomal compartment. The exact function of the NPC1 protein is not clearly understood, but it plays an important role in the intracellular sorting of cholesterol and other glycosphingolipids. Dysfunctional NPC1 protein results in impaired cholesterol homeostasis and the progressive intracellular accumulation of cholesterol and glycosphingolipids (PMID: 24664998).
Among individuals with a clinical diagnosis of NPC, 95% have two pathogenic variants in NPC1, and approximately 4% have biallelic pathogenic variants in NPC2. Less than 1% of cases with clinical and biochemical findings have pathogenic variants in neither NPC1 nor NPC2.
NPC is inherited in an autosomal recessive manner.
Management for NPC is focused on delaying the onset and progression of symptoms. Early diagnosis and appropriate multidisciplinary care is essential.
Evaluation and management should include (PMID: 27134677):
Substrate reduction therapy with miglustat has been shown to stabilize neurological disease for 12 months or longer in both adults and juvenile patients with NPC with the following side effects: diarrhea, flatulence, weight loss, and tremor. Treated pediatric NPC patients showed improved swallowing and cognitive functions for the first 3 months and then stabilized for as many as 5 years (PMID: 22476655, 29047377).
Clinical trials are underway to assess 2-hydroxypropyl-beta-cyclodextrin efficacy in treating NPC via intrathecal infusions. There is concern regarding hearing loss, which may be attributed to the drug and not to disease progression (PMID: 27134677).
Genetic testing for NPC is essential to ensure that the earliest possible diagnosis is made for appropriate treatment initiation and timely clinical trial enrollment. Testing at-risk family members as well as preconception and prenatal testing may be done when indicated.
Saudubray J-M et al., eds. Inborn Metabolic Diseases Diagnosis and Treatment. 6th ed. Berlin, Germany: Springer; 2016.
Review date: December 2017
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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