• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

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).


OMIM: 607623

Clinical condition

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.

  • Perinatal or neonatal form: This form is characterized by fetal hydrops or fetal ascites (Saudubray J-M et al.), and after the child is born, by prolonged neonatal cholestatic icterus with hepatosplenomegaly. Some of these patients succumb to liver disease or severe respiratory insufficiency. NPC can be a common cause of perinatal liver failure but does not show neurological manifestations (PMID: 20525256, 28951965).
  • Infantile severe neurologic form: Infants with the severe neurologic form have hepatosplenomegaly and develop hypotonia and developmental delay between the age of 9 months and 2 years. Cognition may be less affected than motor development. Loss of motor milestones may also occur, followed by spasticity and cognitive decline. Survival for this group is usually less than 5 years (PMID: 20525256).
  • Late-infantile and juvenile-onset neurologic forms: This form of NPC is considered the classic form and is the most common, accounting for 60-70% of NPC. Children with hepatosplenomegaly present with ataxia and clumsiness between 3 and 5 years of age. Speech delay is common in this group of patients, as is hearing loss. Motor problems worsen and cognitive decline is noted. Cataplexy may be the presenting sign (PMID: 205525256). In the juvenile-onset form, neurological symptoms manifest between 6 and 15 years of age with ataxia and learning difficulties. In both of these forms, vertical supranuclear gaze palsy (VSGP) with increased latency of vertical saccades can be an important diagnostic clue (Saudubray J-M et al., PMID: 24135395). Worsening of ataxia, dysphagia, dysarthria, and cognition continue, with approximately half of the patients developing seizures. Swallowing difficulties lead to the placement of gastrostomy tubes, and death typically occurs between 7 and 12 years of age for the late-infantile group. For the juvenile-onset patients, survival is highly variable and some affected individuals survive into their 30s (Saudubray J-M et al.).
  • Adult-onset: Adults have been diagnosed with NPC as late as 70 years of age (PMID: 205525256). Patients may present with ataxia (76%), VSGP (75%), dysarthria (63%), movement disorders (58%), or splenomegaly (54%), while others present with psychiatric symptoms (45%; PMID: 17003072). NPC is an underdiagnosed disorder in adults. Ninety percent of affected adults show cognitive impairment issues, most prominently in attention span and executive functioning (PMID: 29047377).

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).

Differential diagnosis

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).

Gene information

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 and treatment

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):

  • neurologic evaluation and treatment for seizures, sleep disturbance, and gait
  • ophthalmologic evaluation
  • psychiatric evaluation and behavioral treatment or medications
  • pain management
  • evaluation by gastroenterologist for constipation, reflux, and swallowing difficulties
  • orthopedic management for complications of hip contractures, hip dislocations, and kyphoscoliosis
  • respiratory evaluation
  • physiotherapy
  • occupational therapy
  • speech and language therapy
  • psychological evaluation
  • social services assessment

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.

Additional reference

Saudubray J-M et al., eds. Inborn Metabolic Diseases Diagnosis and Treatment. 6th ed. Berlin, Germany: Springer; 2016.

Review date: December 2017

Assay and technical information

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.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
NPC1 NM_000271.4