NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Niemann-Pick Disease Type C

Synonym: Juvenile Niemann-Pick Disease

, MD.

Author Information

Initial Posting: ; Last Revision: August 29, 2019.

Estimated reading time: 27 minutes


Clinical characteristics.

Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs. Other infants, without liver or pulmonary disease, have hypotonia and developmental delay. The classic presentation occurs in mid-to-late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), and dementia. Dystonia and seizures are common. Dysarthria and dysphagia eventually become disabling, making oral feeding impossible; death usually occurs in the late second or third decade from aspiration pneumonia. Adults are more likely to present with dementia or psychiatric symptoms.


The diagnosis of NPC is confirmed by biochemical testing that demonstrates impaired cholesterol esterification and positive filipin staining in cultured fibroblasts. Biochemical testing for carrier status is unreliable. Most individuals with NPC have NPC1, caused by pathogenic variants in NPC1; fewer than 20 individuals have been diagnosed with NPC2, caused by pathogenic variants in NPC2. Molecular genetic testing of NPC1 and NPC2 detects pathogenic variants in approximately 94% of individuals with NPC.


Treatment of manifestations: Symptomatic therapy for seizures, dystonia, and cataplexy; a nocturnal sedative to help disordered sleep; physical therapy to maintain mobility as long as possible.

Prevention of secondary complications: Chest physical therapy with aggressive bronchodilation and antibiotic therapy of intercurrent infection; regular bowel program for mobility-impaired individuals to prevent severe constipation and resulting increased seizure frequency and/or increased spasticity.

Surveillance: Swallowing is monitored to allow placement of a gastrostomy tube when aspiration or nutritional compromise is imminent.

Agents/circumstances to avoid: Drugs that cause excessive salivation or that may exacerbate seizures by interacting with antiepileptic drugs; alcohol and other drugs that may exacerbate ataxia.

Genetic counseling.

NPC is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The phenotype (i.e., age of onset and severity of symptoms) usually runs true in families. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.


Clinical Diagnosis

The diagnosis of Niemann-Pick disease type C (NPC) should be considered in individuals presenting with the following [Vanier 1997]:

  • Fetal ascites or neonatal liver disease, particularly when the latter is accompanied by prolonged jaundice and pulmonary infiltrates
  • Infantile hypotonia without evidence of progression for months to years, followed by features outlined in Brady et al [1989]; see VSGP (following)
  • Vertical supranuclear gaze palsy (VSGP), followed by progressive ataxia, dysarthria, dystonia, and, in some cases, seizures and gelastic cataplexy, beginning in middle childhood, and progressing slowly over many years. Rarely, such presentations may begin later in childhood or in adulthood.
  • Psychiatric presentations, mimicking depression or schizophrenia, with few or subtle neurologic signs, beginning in adolescence or adulthood
  • Enlargement of the liver or spleen, particularly in early childhood

A quantitative scoring system that weights the manifestations of NPC has been developed to assist clinicians in selecting appropriate individuals for further laboratory investigation [Wijburg et al 2012].


Biochemical. Until recently, definitive diagnosis of NPC required demonstration of abnormal intracellular cholesterol homeostasis in cultured fibroblasts [Pentchev et al 1985]. These cells show reduced ability to esterify cholesterol after loading with exogenously derived LDL-cholesterol. Filipin staining demonstrates an intense punctate pattern of fluorescence concentrated around the nucleus, consistent with the accumulation of unesterified cholesterol:

  • Classic. Most individuals have zero or very low esterification levels with a classic staining pattern.
  • Variant. About 15% of individuals have intermediate or "variant" levels of cholesterol esterification and a less distinctive staining pattern. More precise characterization of the biochemical defect in this group can be achieved by the use of BODIPY-lactosylceramide to identify lipid trafficking abnormalities [Sun et al 2001].

Assay of oxysterols has largely replaced skin biopsy, and is now regarded as both a robust screening test and a first-line diagnostic test for Niemann-Pick disease, type C [Porter et al 2010, Jiang et al 2011, Geberhiwot et al 2018].

Histology. Other tests, including tissue biopsies and tissue lipid analysis, which were essential for diagnosis before recognition of the biochemical defect in NPC, are now rarely needed. These tests include examination of bone marrow, spleen, and liver, which contain foamy cells (lipid-laden macrophages); sea-blue histiocytes may be seen in the marrow in advanced cases. Electron microscopy of skin, rectal neurons, liver, or brain may show polymorphous cytoplasmic bodies [Boustany et al 1990].

Molecular Genetic Testing

Genes. Pathogenic variants in two genes are known to cause Niemann-Pick disease type C (NPC): NPC1 and NPC2.

Evidence for further locus heterogeneity. No direct evidence exists for other loci; however, in some individuals with the typical clinical and biochemical phenotype, pathogenic variants have not been found in NPC1 or NPC2.

Table 1.

Molecular Genetic Testing Used in Niemann-Pick Disease Type C

Gene 1Proportion of NPC Attributed to Mutation of Gene 2MethodVariants Detected 3Variant Detection Frequency by Gene and Method 4
NPC190% 5Sequence analysis 6Sequence variants80%-90% 7
Deletion/duplication analysis 8Partial- and whole-gene deletionsUnknown 9
Targeted analysis for pathogenic variantsVary panels differ by laboratoryVary 10
NPC24%Sequence analysis 6Sequence variantsClose to 100%
Deletion/duplication analysis 8Partial- and whole-gene deletionsUnknown; none reported 11
Targeted analysis for pathogenic variantsVariant panels differ by laboratoryVary

Percent of individuals with NPC who have at least one identifiable pathogenic variant [Greer et al 1999, Yamamoto et al 1999, Park et al 2003] using a variant scanning testing method


See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Detection rates using sequence analysis may be comparable to those found using scanning for pathogenic variants, which has identified NPC1 variants in 90% of affected individuals [Park et al 2003, Patterson et al 2012].


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Most individuals with NPC1 are compound heterozygotes with pathogenic variants unique to their family; to date, pathogenic variants in one or both NPC1 alleles cannot be identified in a substantial number of cases [Greer et al 1999, Yamamoto et al 1999, Park et al 2003].


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Few have been reported; the frequency of such variants may be rare.


Of note, individuals with NPC1 from Nova Scotia (previously said to have Niemann-Pick type D) almost uniformly have the p.Gly992Trp variant [Greer et al 1998].


No large insertions or deletions have been reported in NPC2. Based on the high sensitivity of the NPC2 sequencing test, a screening test for large deletions/duplications may have a very low yield.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Biochemical testing demonstrating elevated levels of oxysterols is now the mainstay of diagnosis and may be supported in selected cases by demonstration of abnormal intracellular cholesterol homeostasis in cultured fibroblasts or by ultrastructural changes on skin or rectal biopsy.
  • Molecular genetic testing is necessary to confirm the diagnosis in all individuals with suspected NPC.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Niemann-Pick disease type C (NPC) may present at any age.

Neonatal and infantile presentations. The presentation of NPC in early life is nonspecific and may go unrecognized by inexperienced clinicians. On occasion, ultrasound examination in late pregnancy has detected fetal ascites; infants thus identified typically have severe neonatal liver disease with jaundice and persistent ascites.

Infiltration of the lungs with foam cells may accompany neonatal liver disease or occur as a primary presenting feature (pulmonary failure secondary to impaired diffusion).

Many infants succumb at this stage. Of those who survive, some are hypotonic and delayed in psychomotor development, whereas others may have complete resolution of symptoms, only to present with neurologic disease many years later. Liver and spleen are enlarged in children with symptomatic hepatic disease; however, children who survive often "grow into their organs," so that organomegaly may not be detectable later in childhood. Indeed, many individuals with NPC never have organomegaly. The absence of organomegaly never eliminates the diagnosis of NPC.

Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group usually do not have vertical supranuclear gaze palsy (VSGP) at the onset but acquire this sign after a variable period, when other evidence of progressive encephalopathy supervenes.

Childhood presentations. The classic presentation of NPC is in middle-to-late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical gaze, which is an early manifestation. VSGP first manifests as increased latency in initiation of vertical saccades, after which saccadic velocity gradually slows and is eventually lost. In late stages of the illness, horizontal saccades are also impaired. The physical manifestations are accompanied by insidiously progressive cognitive impairment, often mistaken at first for simple learning disability. Some children are thought to have primary behavioral disturbances, reflecting unrecognized dyspraxia in some instances. As the disease progresses, it becomes clear that the child is mentally deteriorating.

In addition to the manifestations outlined above, many children develop dystonia, typically beginning as action dystonia in one limb and gradually spreading to involve all of the limbs and axial muscles. Speech gradually deteriorates, with a mixed dysarthria and dysphonia. Dysphagia progresses in parallel with the dysarthria, and oral feeding eventually becomes impossible.

Approximately one third of individuals with NPC have partial and/or generalized seizures. Epilepsy may be refractory to medical therapy in some cases. Seizures usually improve if the child's survival is prolonged, this improvement presumably reflecting continued neuronal loss. About 20% of children with NPC have gelastic cataplexy, a sudden loss of muscle tone evoked by a strong emotional (humorous) stimulus. This can be disabling in those children who experience daily multiple attacks during which injuries may occur.

Mild demyelinating peripheral neuropathy has been described in a child with otherwise typical late-infantile NPC [Zafeiriou et al 2003]. This finding is likely a rare manifestation of NPC because prospective nerve conduction studies in a cohort of 41 affected individuals participating in a clinical trial of miglustat have identified only one case to date [Patterson, personal communication (2006)].

Polysomnographic and biochemical studies have demonstrated disturbed sleep and variable reduction in cerebrospinal fluid hypocretin concentration in individuals with NPC, suggesting that the disease could have a specific impact on hypocretin-secreting cells of the hypothalamus [Kanbayashi et al 2003, Vankova et al 2003].

Death from aspiration pneumonia usually occurs in the late second or third decade [Walterfang et al 2012b].

Adolescent and adult presentations. Adolescents or adults may present with neurologic disease as described in the preceding section, albeit with a much slower rate of progression. The author has seen one individual who survived into the seventh decade, having first developed symptoms 25 years earlier. Older individuals may also present with apparent psychiatric illness [Imrie et al 2002, Josephs et al 2003], sometimes appearing to have major depression or schizophrenia. The psychiatric manifestations may overshadow neurologic signs, although the latter can usually be detected with careful examination. An adult presenting with bipolar disorder has been described [Sullivan et al 2005].

A German report describes two individuals with adult-onset dementia associated with frontal lobe atrophy and no visceral manifestations, as is common in adult-onset disease [Klünemann et al 2002].

Imaging. MRI of the brain is usually normal until the late stages of the illness. At that time, marked atrophy of the superior/anterior cerebellar vermis, thinning of the corpus callosum, and mild cerebral atrophy may be seen. Increased signal in the periatrial white matter, reflecting secondary demyelination, may also occur. In one adult, areas of confluent white matter signal hyperintensity mimicked multiple sclerosis [Grau et al 1997]. Quantitative MRI studies in adults with NPC have found widespread gray and white matter abnormalities [Walterfang et al 2010], and reduction in callosal volume as the disease progresses [Walterfang et al 2011]. In addition, the pontine:midbrain ratio correlates with oculomotor function and disease severity [Walterfang et al 2012a].

Studies of magnetic resonance spectroscopy (MRS) suggested that MRS may be a more sensitive imaging technique in NPC than standard MRI [Tedeschi et al 1998]. A French group has reported improvement in MRS parameters with miglustat therapy [Galanaud et al 2009].

Heterozygotes. A recent report described an NPC1 heterozygote with tremor that the authors attributed to the mutated allele [Josephs et al 2004]. This observation notwithstanding, the question of manifesting heterozygotes must remain moot pending systematic prospective studies.

Genotype-Phenotype Correlations

NPC1. In the approximately 200 pathogenic variants described in NPC1 [Scott & Ioannou 2004, Fernandez-Valero et al 2005], genotype-phenotype correlation is limited because most affected individuals are compound heterozygotes; and correlation of the trafficking defects demonstrable in culture and the clinical phenotype is poor. Nonetheless, some correlations have been possible for homozygous variants and the more common variants in heterozygous state:

  • One international study documented phenotypes associated with a pathogenic variant leading to a p.Ile1061Thr change in the Hispanic population in the upper Rio Grande Valley in the southwestern US, and in the UK and France. No individuals with this pathogenic variant had the severe infantile form of NPC [Millat et al 1999].
  • More recently, the same group found that premature-termination-codon variants, variants involving the sterol-sensing domain, and p.Ala1054Thr in the cysteine-rich luminal loop of NPC1 are associated with early-onset disease and classic biochemical changes [Millat et al 2001b].
  • All mutated alleles that correlate with the biochemical "variant" phenotype are clustered in the cysteine-rich luminal loop [Millat et al 2001b].
  • A study of 40 unrelated individuals of Spanish descent suggested that those homozygous for the p.Gln775Pro pathogenic variant showed a severe infantile neurologic form and those homozygous for the p.Cys177Tyr pathogenic variant, a late-infantile clinical phenotype [Fernandez-Valero et al 2005].

NPC2. Of the five pathogenic variants identified by Millat et al [2001b], all but c.190+5G>A were associated with a severe phenotype, characterized by pulmonary infiltrates, respiratory failure, and death by age four years:


The older literature on NPC is bedeviled by the large number of terms used to describe individuals now known to have the disease. These include juvenile dystonic idiocy, juvenile dystonic lipidosis, juvenile NPC, neurovisceral lipidosis with vertical supranuclear gaze palsy, Neville-lake disease, sea-blue histiocytosis, lactosylceramidosis, and DAF (downgaze paralysis, ataxia, foam cells) syndrome.

The term Niemann-Pick disease type D describes a genetic isolate from Nova Scotia that is biochemically and clinically indistinguishable from NPC and that also results from mutation of NPC1.

The terms NPC1 and NPC2 are now preferred because they accurately describe the mutated genes responsible for the phenotype.


The prevalence of NPC has been estimated at 1:150,000 in western Europe. The incidence of NPC in France has been calculated at about 1:120,000, based on the number of postnatally diagnosed cases in a ten-year period versus the number of births during that same time period. When prenatal cases that did not result in a live-born infant were included, a slightly higher incidence of 1:100,000 was found [Vanier 2010]. The prevalence of NPC in early life is probably underestimated, owing to its nonspecific presentations. The overall prevalence is likely higher than the calculated incidence, owing to relatively prolonged survival in those with later-onset disease, although no comprehensive data are available.

Acadians in Nova Scotia, individuals of Hispanic descent in parts of Colorado and New Mexico, and a Bedouin group in Israel represent genetic isolates with a founder effect.

Differential Diagnosis

Neonatal and infantile presentations include biliary atresia, congenital infections, alpha-1-antitrypsin deficiency, tyrosinemia, malignancies (leukemia, lymphoma, histiocytosis), other storage diseases (e.g., Gaucher disease, Niemann-Pick disease type A, Niemann-Pick disease type B), and infections (e.g., TORCH). A study from Colorado found that 27% of infants initially diagnosed with idiopathic neonatal cholestasis and 8% of all infants with cholestasis had NPC [Yerushalmi et al 2002]. Although this cohort may have been enriched by a local Hispanic genetic isolate, the importance of Niemann-Pick disease type C (NPC) as a cause of jaundice in infants is appropriately emphasized.

Childhood presentations include pineal region or midbrain tumors causing dorsal midbrain syndrome, hydrocephalus, GM2 gangliosidosis, mitochondrial diseases, maple syrup urine disease, attention-deficit disorder, learning disabilities, absence seizures, other dementing illnesses, idiopathic torsion dystonia, dopa-responsive dystonia, Wilson disease, amino acidurias and organic acidopathies (e.g., glutaric aciduria type 1), pseudodementia (depressive disorder), neuronal ceroid-lipofuscinosis, subacute sclerosing panencephalitis (see Mitochondrial DNA-Associated Leigh Syndrome and NARP), HIV encephalopathy, sleep disorders, syncope, and periodic paralysis (see Hyperkalemic Periodic Paralysis Type 1, Hypokalemic Periodic Paralysis).

Adolescent and adult presentations include Alzheimer disease, Pick disease (an adult-onset disorder with dementia associated with characteristic neuronal inclusions called Pick bodies, not related to Niemann-Pick disease), frontotemporal dementias, Steele-Richardson-Olzewski syndrome (also known as progressive supranuclear palsy), late-onset lysosomal storage diseases, syphilis, HIV dementia, and primary psychiatric illnesses.


Clinical management guidelines for Niemann-Pick C have been published [Patterson et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Niemann-Pick disease type C (NPC), the following evaluations are recommended:

  • Assessment of ability to walk and transfer, manage secretions, and communicate (language, speech, and hearing)
  • For individuals with hepatosplenomegaly, complete blood count and tests of hepatic function
  • MRI of the head; usually performed in the course of the workup and usually normal until the disease is advanced
  • Consideration of EEG and sleep studies if the history suggests seizures or sleep disturbances
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No curative therapy for NPC exists.

Symptomatic therapy may be at least partially effective in the management of seizures, dystonia, and cataplexy.

If disordered sleep is identified, a nocturnal sedative may be indicated. In complex cases, formal evaluation by a sleep specialist should be considered.

Bronchoalveolar lavage has been described as effective in improving function in one child with pulmonary infiltrates [Palmeri et al 2005].

General supportive care, including respite for primary caregivers, is crucial to the maintenance of the family unit in the face of this devastating illness.

Prevention of Secondary Complications

Chest physical therapy with aggressive bronchodilation and antibiotic therapy for intercurrent infection appears beneficial, although no systematic study has been performed.

Individuals whose mobility is compromised should have a regular bowel program to prevent severe constipation, which may present as increased seizure frequency or increased spasticity in some impaired individuals with NPC.

Physical therapy is indicated to maintain mobility as long as possible.

Swallowing must be monitored to allow consideration of gastrostomy tube placement when aspiration or nutritional compromise is imminent.


General pediatric evaluations, with special attention to pulmonary function, swallowing, bowel habit, and mood (for occult depression), are appropriate at six-month intervals for most juvenile and adult affected individuals. Sleep disturbances are common in NPC; the affected individual or caregiver should be questioned regarding sleep hygiene as a part of regular evaluation.

Annual psychometric testing may be helpful in arranging appropriate school or work placement.

Teenagers and adults with motor or sensory impairments who are driving should be monitored at six- to 12-month intervals to ensure that they do not present a risk to themselves or others.

Agents/Circumstances to Avoid

Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with antiepileptic drugs should be avoided.

Alcohol as well as many drugs exacerbate ataxia and should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Inhibition of glycosphingolipid synthesis by n-butyldeoxynojirimycin has been shown to delay onset and prolong survival in both murine and feline models of NPC [Zervas et al 2001, Stein et al 2012]. A prospective trial of the same agent showed evidence of stabilization or benefit in some individuals [Patterson et al 2007]. Subsequent clinical studies have supported a role of miglustat in stabilizing NPC [Pineda et al 2009, Wraith & Imrie 2009, Patterson et al 2010, Pineda et al 2010, Wraith et al 2010, Fecarotta et al 2011, Di Rocco et al 2012, Héron et al 2012, Chien et al 2013]. The agent has been approved for the management of neurologic manifestations of NPC in several countries, not including the United States. A recent review of the published literature on miglustat, including clinical, biomarker, and imaging measures, supported the efficacy of this agent in ameliorating the course of Niemann-Pick disease, type C [Pineda et al 2018].

Laboratory studies of cellular and murine models of NPC have raised the possibility of small-molecule therapies to interdict pathways triggering apoptosis and related routes to cell death and dysfunction [Patterson & Platt 2004]; to date, these have not proceeded to clinical trials.

Preliminary studies of neurosteroid replacement therapy with allopregnanolone in NPC mice suggested similar improvements in survival to those seen with n-butyldeoxynojirimycin, provided that the steroid is administered early in postnatal life [Mellon & Griffin 2002]. Subsequent studies have shown that the active agent was the vehicle, hydroxypropyl beta cyclodextrin, which has shown dramatic effects in the murine model of NPC [Abi-Mosleh et al 2009, Davidson et al 2009, Ramirez et al 2010, Rosenbaum et al 2010, Ward et al 2010, Vance & Peake 2011, Peake & Vance 2012].

Studies in tissue culture have demonstrated that direct or indirect overexpression of the GTPase Rab 9 reverses the NPC phenotype [Choudhury et al 2002, Walter et al 2003]. Although not yet applicable in human trials, this finding suggests the existence of alternate pathways for mobilization of endosomal cargoes that are potential targets for small-molecule therapies.

Treatment of certain NPC fibroblast cell lines with an HDAC inhibitor produced marked reduction of cholesterol storage [Pipalia et al 2011]; a clinical trial is being considered.

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.


In the C57 murine model of NPC, all treatment modalities, including bone marrow transplantation, combined bone marrow and liver transplantation, and aggressive cholesterol-lowering therapy, have proven ineffective.

Although a trial of cholesterol-lowering agents showed that the amount of free cholesterol in the liver of individuals with NPC could be reduced by the administration of cholestyramine, lovastatin, and nicotinic acid [Patterson et al 1993], there is no evidence that this approach modifies the neurologic progression of NPC.

Liver transplantation in humans corrects hepatic dysfunction but does not ameliorate the neurologic disease.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Niemann-Pick disease type C (NPC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Parents of children with NPC are obligate heterozygotes.
  • Heterozygotes are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The phenotype usually runs true in families; that is, if the proband has early-onset disease, subsequent affected individuals will have a similar clinical course. In rare cases, a proband and subsequent offspring have had different clinical presentations.
  • Sibs younger than the proband may have the disease but be asymptomatic. Assuming that the phenotype runs true in the family, a proband's unaffected older sibs have a 2/3 risk of carrying one abnormal NPC allele.

Offspring of a proband. The offspring of an individual with NPC will inherit one abnormal NPC allele from the affected parent and are thus obligate heterozygotes.

Other family members of a proband. Each sib of a proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Biochemical testing is unreliable in defining the heterozygous state, owing to significant overlaps with findings seen in controls.

Molecular genetic analysis of NPC1 or NPC2 may be used for carrier testing if pathogenic variants in NPC1 or NPC2 have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

If both pathogenic variants have been identified in an affected family member [Vanier 2002], prenatal testing for a pregnancy at 25% risk and preimplantation genetic diagnosis for NPC are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Niemann-Pick Disease Type C: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Niemann-Pick Disease Type C (View All in OMIM)


Molecular Pathogenesis

The central defect in NPC is in intracellular trafficking of lipids, as opposed to the lysosomal hydrolase deficiency characteristic of the classic lysosomal storage diseases (LSDs). Notwithstanding, all LSDs are marked by the accumulation of multiple lipid species in the lysosomes, and secondary trafficking impairment occurs in disorders with primary hydrolase deficiencies. In NPC, cholesterol accumulates in great excess in the lysosomes and may lead to a deficiency in membrane cholesterol. Given the critical role of cholesterol in maintaining membrane order, this downstream deficiency could conceivably play a role in membrane dysfunction, and possibly in the triggering of apoptosis [Mukherjee & Maxfield 2004].

Glycosphingolipid accumulation is characteristic of the neuropathology of NPC; animal studies have demonstrated that GM2 accumulation is associated with ectopic dendritogenesis and meganeurite formation, which – together with the formation of neurofibrillary tangles (cholesterol dysregulation) and neuroaxonal dystrophy – are likely anatomic substrates for neurologic dysfunction [Walkley & Suzuki 2004].

Trafficking studies suggest that NPC2 binds cholesterol in the luminal space of the late-endosome/lysosome and transports it to the delimiting membrane. NPC resides in the membrane of the late endosomes and is shuttled between that compartment and the plasma membrane and other internal sites. It remains to be determined how these two molecules interact, how they sense the presence and concentration of lipids, and why NPC1 accompanies its vesicular cargo to its destination [Liscum & Sturley 2004]. One model proposes that initial sphongosone accumulation leads to lysosomal calcium deregulation, which triggers the cascade of secondary effects characteristic of NPC [Lloyd-Evans et al 2008, Tang et al 2010, Lloyd-Evans & Platt 2011].


Gene structure. NPC1 contains 25 exons, varying in size from 74 to 788 bp, spread over 47 kb [Morris et al 1999]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. More than 50 exon polymorphisms have been described; the most prevalent are listed in Table 2 [Millat et al 2005].

Pathogenic variants. Approximately 200 pathogenic variants have been described in NPC1 [Scott & Ioannou 2004, Fernandez-Valero et al 2005].

A study of 143 unrelated individuals with NPC identified 121 different pathogenic variants in 251 of 286 disease alleles, an overall detection rate of 88% [Park et al 2003]. Cases negative for pathogenic variants showed a high proportion of equivocal results in complementation studies, raising the possibilities of (1) a third complementation group for NPC or (2) nonspecificity of NPC biochemical testing. The region between amino acids 1038 and 1253 (which includes the Patched 1 domain) and the region in amino acids identical to the NPC1 homolog NPC1L1 were hot spots for mutation.

Most affected individuals are compound heterozygotes for single-nucleotide variants producing missense (~70% of pathogenic variants overall) [Millat et al 2005] and nonsense variants; deletions and splice site variants have also been reported.

A pathogenic variant leading to a p.Gly992Trp change has been identified in several individuals in the Acadian population of Nova Scotia [Greer et al 1998] and in Portugal; a p.Gly992Arg variant has been described in France [Fernandez-Valero et al 2005] (Table 2).

A Spanish report found that individuals homozygous for the p.Gln775Pro variant had a severe infantile neurologic illness, and those with the p.Cys177Tyr variant had a late-infantile clinical phenotype [Fernandez-Valero et al 2005].

The p.Ile1061Thr variant accounts for 15%-20% of mutated alleles in western Europe and the US, followed by p.Pro1007Ala [Millat et al 2005].

Table 2.

NPC1 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The NPC1 protein product is an integral membrane protein with 13 transmembrane domains, which appears to be localized to a late endosomal compartment. Its function is as yet imperfectly understood, but it clearly plays a central role in modulating intracellular sorting of cholesterol and glycosphingolipids [Neufeld et al 1999]. Wojtanik & Liscum [2003] have shown that in the cells of individuals with NPC1, LDL cholesterol traffics directly through endosomes to lysosomes, bypassing the plasma membrane, and is trapped there because of dysfunctional NPC1. NPC1 appears to serve this function, at least in part, by maintaining the small size of cholesterol-containing lipid droplets in the cell [Wiegand et al 2003]. Strauss et al [2002] have suggested that NPC1 may act cooperatively with NPC2 and MLN64 in an ordered sequence to effect intracellular sterol movement. Sterol storage in fibroblasts correlates with oxysterol levels; administration of oxysterols corrects the phenotype in cells with the p.Ile1061Thr pathogenic variant, suggesting that NPC1 and NPC2 regulate intracellular sterol homeostasis via oxysterols [Frolov et al 2003]. Domains 3-7 of the NPC1 protein have homology to the sterol-sensing domains of SCAP and HMG CoA reductase, and other domains are homologous to the Drosophila morphogen patched [Carstea et al 1997]. Studies in cultured fibroblasts have shown that specific single-nucleotide variants in the sterol-sensing domain can induce either loss of function (p.Pro692Ser) or gain of function (p.Asp787Asn, p.Leu657Phe) in trafficking to the plasma membrane and ER [Millard et al 2005]. The overrepresentation of pathogenic variants in these domains further emphasizes their key roles in the function of the protein (see NPC1, Pathogenic variants). NPC1 appears to mediate fatty acid transport in E coli; but this is not the case in human NPC fibroblasts, where fatty acid trafficking is normal [Passeggio & Liscum 2005].

Abnormal gene product. Deficiency of the NPC1 gene product leads to a complex pattern of intracellular lipid storage, including excess unesterified cholesterol, GM2 and GM3 gangliosides, lactosylceramide, glucosylceramide, and lysobisphosphatidic acid. The accumulation of these substrates is thought to reflect impaired intracellular trafficking mediated by the NPC1 and NPC2 proteins respectively [Watari et al 1999, Liscum & Sturley 2004, Mukherjee & Maxfield 2004].


Gene structure. NPC2 has five exons and a single transcript of 0.9 kb in all tissues. It has been mapped to 14q24.3 [Chikh et al 2004]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Two individuals were originally described with pathogenic variants in NPC2 [Naureckiene et al 2000]. One individual was homozygous for c.58G>T in exon 1, and the other was a compound heterozygote for c.58G>T and c.332delA. A comprehensive study of eight families with NPC2 found five pathogenic variants in the 16 mutated alleles identified (p.Glu20Ter, p.Glu118Ter, c.27delG, c.190_5G>A, p.Ser67Pro) [Millat et al 2001a]. Except for c.27delG, the variants were all homozygous. More recent studies have identified a total of 13 pathogenic variants, including five missense variants and six that code for a premature stop codon [Chikh et al 2005].

Table 3.

NPC2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions

Normal gene product. The NPC2 protein product is a 132-amino acid glycoprotein that is expressed in all tissues examined, with the highest concentrations being found in epididymal fluid as well as in testis, kidney, and liver. NPC2 protein is soluble, binds cholesterol, and is able to partially reverse the lipid accumulation in NPC2 fibroblasts when added to the medium in culture. Added NPC2 has no effect on NPC1 fibroblasts in culture [Naureckiene et al 2000]. Different isoforms varying from 19 to 23 kd are distributed in a tissue-specific fashion, reflecting variable glycosylation [Vanier & Millat 2004]. Only the Asn58 residue needs to be glycosylated to ensure accurate targeting. NPC2 protein binds the mannose-6-phosphate receptor, and, in contrast, is not dependent on the presence of cholesterol for lysosomal targeting. NPC2 mainly colocalizes with LAMP1 but is also distributed to LAMP1-negative organelles [Vanier & Millat 2004].


Literature Cited

  • Abi-Mosleh L, Infante RE, Radhakrishnan A, Goldstein JL, Brown MS. Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells. Proc Natl Acad Sci U S A. 2009;106:19316–21. [PMC free article: PMC2780767] [PubMed: 19884502]
  • Boustany RN, Kaye E, Alroy J. Ultrastructural findings in skin from patients with Niemann-Pick disease, type C. Pediatr Neurol. 1990;6:177–83. [PubMed: 2360958]
  • Brady RO, Filling-Katz MR, Barton NW, Pentchev PG. Niemann-Pick disease types C and D. Neurol Clin. 1989;7:75–88. [PubMed: 2646522]
  • Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF 3rd, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O'Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277:228–31. [PubMed: 9211849]
  • Chien YH, Peng SF, Yang CC, Lee NC, Tsai LK, Huang AC, Su SC, Tseng CC, Hwu WL. Long-term efficacy of miglustat in paediatric patients with Niemann-Pick disease type C. J Inherit Metab Dis. 2013;36:129–37. [PubMed: 22476655]
  • Chikh K, Rodriguez C, Vey S, Vanier MT, Millat G. Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. Hum Mutat. 2005;26:20–8. [PubMed: 15937921]
  • Chikh K, Vey S, Simonot C, Vanier MT, Millat G. Niemann-Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Mol Genet Metab. 2004;83:220–30. [PubMed: 15542393]
  • Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, Marks DL, Pagano RE. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest. 2002;109:1541–50. [PMC free article: PMC151017] [PubMed: 12070301]
  • Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PloS One. 2009;4:e6951. [PMC free article: PMC2736622] [PubMed: 19750228]
  • Di Rocco M, Dardis A, Madeo A, Barone R, Fiumara A. Early miglustat therapy in infantile Niemann-Pick disease type C. Pediatr Neurol. 2012;47:40–3. [PubMed: 22704015]
  • Fecarotta S, Amitrano M, Romano A, Della Casa R, Bruschini D, Astarita L, Parenti G, Andria G. The videofluoroscopic swallowing study shows a sustained improvement of dysphagia in children with Niemann-Pick disease type C after therapy with miglustat. Am J Med Genet A. 2011;155A:540–7. [PubMed: 21344635]
  • Fernandez-Valero EM, Ballart A, Iturriaga C, Lluch M, Macias J, Vanier MT, Pineda M, Coll MJ. Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet. 2005;68:245–54. [PubMed: 16098014]
  • Frolov A, Zielinski SE, Crowley JR, Dudley-Rucker N, Schaffer JE, Ory DS. NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. J Biol Chem. 2003;278:25517–25. [PubMed: 12719428]
  • Galanaud D, Tourbah A, Lehéricy S, Leveque N, Heron B, Billette de Villemeur T, Guffon N, Feillet F, Baumann N, Vanier MT, Sedel F. 24-month treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol Genet Metab. 2009;96:55–8. [PubMed: 19013089]
  • Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, Vanier MT, Walterfang M, Bolton S, Dawson C, Héron B, Stampfer M, Imrie J, Hendriksz C, Gissen P, Crushell E, Coll MJ, Nadjar Y, Klünemann H, Mengel E, Hrebicek M, Jones SA, Ory D, Bembi B, Patterson M, et al. Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis. 2018;13:50. [PMC free article: PMC5889539] [PubMed: 29625568]
  • Grau AJ, Brandt T, Weisbrod M, Niethammer R, Forsting M, Cantz M, Vanier MT, Harzer K. Adult Niemann-Pick disease type C mimicking features of multiple sclerosis. J Neurol Neurosurg Psychiatry. 1997;63:552. [PMC free article: PMC2169752] [PubMed: 9343150]
  • Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE. Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am J Hum Genet. 1999;65:1252–60. [PMC free article: PMC1288277] [PubMed: 10521290]
  • Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE. The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1. Am J Hum Genet. 1998;63:52–4. [PMC free article: PMC1377252] [PubMed: 9634529]
  • Héron B, Valayannopoulos V, Baruteau J, Chabrol B, Ogier H, Latour P, Dobbelaere D, Eyer D, Labarthe F, Maurey H, Cuisset JM, de Villemeur TB, Sedel F, Vanier MT. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis. 2012;7:36. [PMC free article: PMC3465012] [PubMed: 22676771]
  • Imrie J, Vijayaraghaven S, Whitehouse C, Harris S, Heptinstall L, Church H, Cooper A, Besley GT, Wraith JE. Niemann-Pick disease type C in adults. J Inherit Metab Dis. 2002;25:491–500. [PubMed: 12555942]
  • 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;52:1435–45. [PMC free article: PMC3122908] [PubMed: 21518695]
  • Josephs KA, Matsumoto JY, Lindor NM. Heterozygous Niemann-Pick disease type C presenting with tremor. Neurology. 2004;63:2189–90. [PubMed: 15596783]
  • Josephs KA, Van Gerpen MW, Van Gerpen JA. Adult onset Niemann-Pick disease type C presenting with psychosis. J Neurol Neurosurg Psychiatry. 2003;74:528–9. [PMC free article: PMC1738356] [PubMed: 12640083]
  • Kanbayashi T, Abe M, Fujimoto S, Miyachi T, Takahashi T, Yano T, Sawaishi Y, Arii J, Szilagyi G, Shimizu T. Hypocretin deficiency in niemann-pick type C with cataplexy. Neuropediatrics. 2003;34:52–3. [PubMed: 12690569]
  • Klünemann HH, Elleder M, Kaminski WE, Snow K, Peyser JM, O'Brien JF, Munoz D, Schmitz G, Klein HE, Pendlebury WW. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol. 2002;52:743–9. [PubMed: 12447927]
  • Liscum L, Sturley SL. Intracellular trafficking of Niemann-Pick C proteins 1 and 2: obligate components of subcellular lipid transport. Biochim Biophys Acta. 2004;1685:22–7. [PubMed: 15465423]
  • Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008;14:1247–55. [PubMed: 18953351]
  • Lloyd-Evans E, Platt FM. Lysosomal Ca(2+) homeostasis: role in pathogenesis of lysosomal storage diseases. Cell Calcium. 2011;50:200–5. [PubMed: 21724254]
  • Mellon SH, Griffin LD. Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab. 2002;13:35–43. [PubMed: 11750861]
  • Millard EE, Gale SE, Dudley N, Zhang J, Schaffer JE, Ory DS. The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol. J Biol Chem. 2005;280:28581–90. [PubMed: 15908696]
  • Millat G, Bailo N, Molinero S, Rodriguez C, Chikh K, Vanier MT. Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab. 2005;86:220–32. [PubMed: 16126423]
  • Millat G, Chikh K, Naureckiene S, Sleat DE, Fensom AH, Higaki K, Elleder M, Lobel P, Vanier MT. Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet. 2001a;69:1013–21. [PMC free article: PMC1274348] [PubMed: 11567215]
  • Millat G, Marcais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, Ohno K, Wenger DA, Vanier MT. Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet. 1999;65:1321–9. [PMC free article: PMC1288284] [PubMed: 10521297]
  • Millat G, Marcais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, Wenger DA, Ohno K, Vanier MT. Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am J Hum Genet. 2001b;68:1373–85. [PMC free article: PMC1226124] [PubMed: 11333381]
  • Morris JA, Zhang D, Coleman KG, Nagle J, Pentchev PG, Carstea ED. The genomic organization and polymorphism analysis of the human Niemann-Pick C1 gene. Biochem Biophys Res Commun. 1999;261:493–8. [PubMed: 10425213]
  • Mukherjee S, Maxfield FR. Lipid and cholesterol trafficking in NPC. Biochim Biophys Acta. 2004;1685:28–37. [PubMed: 15465424]
  • Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000;290:2298–301. [PubMed: 11125141]
  • Neufeld EB, Wastney M, Patel S, Suresh S, Cooney AM, Dwyer NK, Roff CF, Ohno K, Morris JA, Carstea ED, Incardona JP, Strauss JF 3rd, Vanier MT, Patterson MC, Brady RO, Pentchev PG, Blanchette-Mackie EJ. The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem. 1999;274:9627–35. [PubMed: 10092649]
  • Palmeri S, Tarugi P, Sicurelli F, Buccoliero R, Malandrini A, De Santi MM, Marciano G, Battisti C, Dotti MT, Calandra S, Federico A. Lung involvement in Niemann-Pick disease type C1: improvement with bronchoalveolar lavage. Neurol Sci. 2005;26:171–3. [PubMed: 16086131]
  • Park WD, O'Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS, Patterson MC, Snow K. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat. 2003;22:313–25. [PubMed: 12955717]
  • Passeggio J, Liscum L. Flux of fatty acids through NPC1 lysosomes. J Biol Chem. 2005;280:10333–9. [PubMed: 15632139]
  • Patterson MC, Di Bisceglie AM, Higgins JJ, Abel RB, Schiffmann R, Parker CC, Argoff CE, Grewal RP, Yu K, Pentchev PG. The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology. 1993;43:61–4. [PubMed: 8423912]
  • Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F., 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. [PubMed: 22572546]
  • Patterson MC, Platt F. Therapy of Niemann-Pick disease, type C. Biochim Biophys Acta. 2004;1685:77–82. [PubMed: 15465428]
  • Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007;6:765–72. [PubMed: 17689147]
  • Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, Wraith JE. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300–5. [PubMed: 19822772]
  • Peake KB, Vance JE. Normalization of cholesterol homeostasis by 2-hydroxypropyl-beta-cyclodextrin in neurons and glia from Niemann-Pick C1 (NPC1)-deficient mice. J Biol Chem. 2012;287:9290–8. [PMC free article: PMC3308731] [PubMed: 22277650]
  • Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S, Brady RO. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82:8247–51. [PMC free article: PMC391480] [PubMed: 3865225]
  • Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M, Bembi B, Walterfang M, Korenke GC, Marquardt T, Luzy C, Giorgino R, Patterson MC. Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab. 2009;98:243–9. [PubMed: 19656703]
  • Pineda M, Perez-Poyato MS, O'Callaghan M, Vilaseca MA, Pocovi M, Domingo R, Portal LR, Pérez AV, Temudo T, Gaspar A, Peñas JJ, Roldán S, Fumero LM, de la Barca OB, Silva MT, Macías-Vidal J, Coll MJ. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab. 2010;99:358–66. [PubMed: 20056559]
  • Pineda M, Walterfang M, Patterson MC. Miglustat in Niemann-Pick disease type C patients: a review. Orphanet J Rare Dis. 2018;13:140. [PMC free article: PMC6094874] [PubMed: 30111334]
  • Pipalia NH, Cosner CC, Huang A, Chatterjee A, Bourbon P, Farley N, Helquist P, Wiest O, Maxfield FR. Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts. Proc Natl Acad Sci U S A. 2011;108:5620–5. [PMC free article: PMC3078401] [PubMed: 21436030]
  • 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;2:56ra81. [PMC free article: PMC3170139] [PubMed: 21048217]
  • Ramirez CM, Liu B, Taylor AM, Repa JJ, Burns DK, Weinberg AG, Turley SD, Dietschy JM. Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life. Pediatr Res. 2010;68:309–15. [PMC free article: PMC3065173] [PubMed: 20581737]
  • Rosenbaum AI, Zhang G, Warren JD, Maxfield FR. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc Natl Acad Sci U S A. 2010;107:5477–82. [PMC free article: PMC2851804] [PubMed: 20212119]
  • Scott C, Ioannou YA. The NPC1 protein: structure implies function. Biochim Biophys Acta. 2004;1685:8–13. [PubMed: 15465421]
  • Stein VM, Crooks A, Ding W, Prociuk M, O'Donnell P, Bryan C, Sikora T, Dingemanse J, Vanier MT, Walkley SU, Vite CH. Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J Neuropathol Exp Neurol. 2012;71:434–48. [PMC free article: PMC3352323] [PubMed: 22487861]
  • Strauss JF 3rd, Liu P, Christenson LK, Watari H. Sterols and intracellular vesicular trafficking: lessons from the study of NPC1. Steroids. 2002;67:947–51. [PubMed: 12398991]
  • Sullivan D, Walterfang M, Velakoulis D. Bipolar disorder and Niemann-Pick disease type C. Am J Psychiatry. 2005;162:1021–2. [PubMed: 15863815]
  • Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O, Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet. 2001;68:1361. [PMC free article: PMC1226123] [PubMed: 11349231]
  • Tang Y, Li H, Liu JP. Niemann-Pick Disease Type C: from molecule to clinic. Clin Exp Pharmacol Physiol. 2010;37:132–40. [PubMed: 19566836]
  • Tedeschi G, Bonavita S, Barton NW, Betolino A, Frank JA, Patronas NJ, Alger JR, Schiffmann R. Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry. 1998;65:72–9. [PMC free article: PMC2170174] [PubMed: 9667565]
  • Vance JE, Peake KB. Function of the Niemann-Pick type C proteins and their bypass by cyclodextrin. Curr Opin Lipidol. 2011;22:204–9. [PubMed: 21412152]
  • Vanier MT. Phenotypic and genetic heterogeneity in Niemann-Pick disease type C: current knowledge and practical implications. Wien Klin Wochenschr. 1997;109:68–73. [PubMed: 9060145]
  • Vanier MT. Prenatal diagnosis of Niemann-Pick diseases types A, B and C. Prenat Diagn. 2002;22:630–2. [PubMed: 12124701]
  • Vanier MT, Millat G. Structure and function of the NPC2 protein. Biochim Biophys Acta. 2004;1685:14–21. [PubMed: 15465422]
  • Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16. [PMC free article: PMC2902432] [PubMed: 20525256]
  • Vankova J, Stepanova I, Jech R, Elleder M, Ling L, Mignot E, Nishino S, Nevsimalova S. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep. 2003;26:427–30. [PubMed: 12841368]
  • Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta. 2004;1685:48–62. [PubMed: 15465426]
  • Walter M, Davies JP, Ioannou YA. Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann-Pick C1 late endosomes. J Lipid Res. 2003;44:243–53. [PubMed: 12576506]
  • Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, Reutens D, Velakoulis D. Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables. AJNR Am J Neuroradiol. 2011;32:1340–6. [PubMed: 21596811]
  • Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, Adamson C, Kokkinos C, Fietz M, Velakoulis D. White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology. 2010;75:49–56. [PubMed: 20484681]
  • Walterfang M, Macfarlane MD, Looi JC, Abel L, Bowman E, Fahey MC, Desmond P, Velakoulis D. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol. 2012a;19:462–7. [PubMed: 22329857]
  • Walterfang M, Yu-Chien C, Imrie J, Rushton D, Schubiger D, Patterson MC. Dysphagia as a risk factor for mortality in Niemann-Pick disease type C:systematic literature review and evidence from studies with miglustat. Orphanet J Rare Dis. 2012b;7:76. [PMC free article: PMC3552828] [PubMed: 23039766]
  • Ward S, O'Donnell P, Fernandez S, Vite CH. 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res. 2010;68:52–6. [PMC free article: PMC2913583] [PubMed: 20357695]
  • Watari H, Blanchette-Mackie EJ, Dwyer NK, Glick JM, Patel S, Neufeld EB, Brady RO, Pentchev PG, Strauss JF 3rd. Niemann-Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization. Proc Natl Acad Sci USA. 1999;96:805–10. [PMC free article: PMC15306] [PubMed: 9927649]
  • Wiegand V, Chang TY, Strauss JF 3rd, Fahrenholz F, Gimpl G. Transport of plasma membrane-derived cholesterol and the function of Niemann-Pick C1 Protein. FASEB J. 2003;17:782–4. [PubMed: 12594172]
  • Wijburg FA, Sedel F, Pineda M, Hendriksz CJ, Fahey M, Walterfang M, Patterson MC, Wraith JE, Kolb SA. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology. 2012;78:1560–7. [PubMed: 22517094]
  • Wojtanik KM, Liscum L. The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem. 2003;278:14850–6. [PubMed: 12591922]
  • Wraith JE, Imrie J. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877–87. [PMC free article: PMC2781062] [PubMed: 19956552]
  • Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, Patterson MC. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010;99:351–7. [PubMed: 20045366]
  • Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, Akaboshi S, Watanabe Y, Takeshima T, Inui K, Okada S, Tanaka A, Sakuragawa N, Millat G, Vanier MT, Morris JA, Pentchev PG, Ohno K. NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C. Hum Genet. 1999;105:10–6. [PubMed: 10480349]
  • Yerushalmi B, Sokol RJ, Narkewicz MR, Smith D, Ashmead JW, Wenger DA. Niemann-pick disease type C in neonatal cholestasis at a North American Center. J Pediatr Gastroenterol Nutr. 2002;35:44–50. [PubMed: 12142809]
  • Zafeiriou DI, Triantafyllou P, Gombakis NP, Vargiami E, Tsantali C, Michelakaki E. Niemann-Pick type C disease associated with peripheral neuropathy. Pediatr Neurol. 2003;29:242–4. [PubMed: 14629910]
  • Zervas M, Somers KL, Thrall MA, Walkley SU. Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol. 2001;11:1283–7. [PubMed: 11525744]

Chapter Notes

Author Notes

At the time of original submission of this profile, the author's work was supported by the National Niemann-Pick Disease Foundation; and he was principal investigator in a trial of OGT 918 in Niemann-Pick disease type C, sponsored by Cell Tech (UK) and subsequently sponsored by Actelion Pharmaceuticals, Inc. The author currently serves as Chair of the Scientific Advisory Committee of a registry of Niemann-Pick disease, type C, supported by Actelion Pharmaceuticals. He also serves as a consultant for Shire HGT, Orphazyme, and Genzyme.

Revision History

  • 29 August 2019 (aa) Revision: Testing, Biochemical (assay of oxysterols); Therapies Under Investigation (miglustat)
  • 18 July 2013 (me) Comprehensive update posted live
  • 22 July 2008 (me) Comprehensive update posted live
  • 9 July 2007 (cd) Revision: prenatal diagnosis using biochemical testing no longer available clinically
  • 13 February 2006 (me) Comprehensive update posted live
  • 4 February 2004 (mp) Revision: testing
  • 18 December 2003 (me) Comprehensive update posted live
  • 10 September 2001 (mp) Revision
  • 26 January 2000 (me) Review posted live
  • 20 October 1999 (mp) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1296PMID: 20301473


Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...