Niemann-Pick Disease Type C

Tatiana Bremova-Ertl; Marc Patterson

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Niemann-Pick Disease Type C

Synonym: Niemann-Pick Type C Disease (NPCD)

Tatiana Bremova-Ertl, MD and Marc Patterson, MD.

Author Information and Affiliations

Initial Posting: January 26, 2000; Last Update: November 20, 2025.

Estimated reading time: 43 minutes

Summary

Clinical characteristics.

Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder in which the principal manifestations are age dependent.

Perinatal period and infancy: The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. Many infants succumb at this stage; however, of those who survive, some are hypotonic and have delayed psychomotor development, whereas others may have complete resolution of disease manifestations, only to present with neurologic disease many years later.

Mid- to late childhood onset: The initial presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and, in some individuals, epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent as progressive dementia. Death from aspiration pneumonia usually occurs in the late second or third decade.

Adolescent to adult onset: The initial presentation may be neurologic manifestations like those in childhood, but with a much slower rate of progression and longer life expectancy. In others, the initial presentation can be predominantly early-onset dementia or psychiatric manifestations.

Diagnosis/testing.

The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic variants in either NPC1 or NPC2 identified by molecular genetic testing.

Management.

Targeted therapies: Treatment for the neurologic manifestations of NPC can include miglustat (approved in several countries but not currently FDA approved for standalone treatment of NPC), arimoclomol (approved for use in combination with miglustat), and levacetylleucine (standalone treatment approved by FDA).

Supportive care: No curative therapy for NPC exists. Supportive therapy is provided by specialists from multiple disciplines including neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and clinical genetics.

Surveillance: Regularly scheduled follow up is recommended for multidisciplinary specialists to monitor disease progression, emergence of new disease manifestations, and response to supportive management including psychosocial support. For those on miglustat therapy, regularly scheduled follow up is recommended to monitor adherence, side effects, and conditions that would prompt discontinuation of therapy.

Agents/circumstances to avoid: Drugs that cause excessive salivation or may exacerbate seizures directly by interacting with anti-seizure medication; alcohol as well as many drugs that exacerbate ataxia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk sibs of an affected individual in order to identify as early as possible those who might benefit from targeted therapy for NPC.

Genetic counseling.

NPC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may manifest clinical and biochemical abnormalities. Once the NPC-causing pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

Consensus clinical management guidelines for Niemann-Pick disease type C (NPC) developed under the auspices of the International Niemann-Pick Disease Alliance [Geberhiwot et al 2018] include recommendations for clinical and laboratory diagnosis of NPC.

Suggestive Findings

NPC should be suspected in individuals with the following clinical findings [Patterson et al 2017] (full text) and preliminary laboratory findings.

Clinical findings

Typical findings. Presentations may be considered by age of onset, although this grouping is of necessity arbitrary and includes considerable overlap.
- Early infantile (age <2 years). Fetal ascites or neonatal liver disease, particularly when the latter is accompanied by prolonged cholestatic jaundice and pulmonary infiltrates.
- Late infantile (ages 2 to <6 years). Often presents with hypotonia and developmental delay. With time, vertical supranuclear saccadic palsy (VSSP; sometimes called vertical supranuclear saccadic paresis) becomes apparent. Children compensate for this deficit by blinking and vertical head and upper body movements / head thrusts [Bremova & Strupp 2017, Bremova-Ertl et al 2021]. Children later develop clumsiness that evolves into ataxia.
- Juvenile (ages 6 to <15 years). These children may present initially with clumsiness that evolves into ataxia, often with academic difficulties that may be misdiagnosed as attention-deficit disorder. With time, more global cognitive impairment and regression become evident. VSSP preceding the vertical supranuclear gaze palsy is almost invariably present in children with neurologic manifestations (and is often present before the emergence of other manifestations) [Bremova-Ertl et al 2021]. Some children develop seizures, gelastic cataplexy, dystonia, and/or spasticity.
- Adolescent/adult (age >15 years). May include all the neurologic manifestations, which are often overshadowed, at least initially, by cognitive impairment (early-onset dementia) or psychiatric manifestations (e.g., treatment-resistant depression, schizophreniform illness, apparent bipolar disease).
- Other. Some individuals present with isolated splenomegaly in childhood and may not develop neurologic manifestations for many years. Occasionally, adults have splenomegaly without obvious neurologic manifestations. Note: The absence of organomegaly never eliminates the diagnosis of NPC.
Suspicion index. The sensitivity of a quantitative scoring system [Wijburg et al 2012] that weighs the manifestations of NPC to assist clinicians in identifying individuals appropriate for further laboratory investigation was improved by separating children into two age groups: ≤4 years and >4 years [Pineda et al 2019].

Preliminary laboratory findings. Assay of oxysterols has largely replaced formerly used methods of diagnosis and is now regarded as both a robust screening test and a first-line diagnostic test for NPC [Porter et al 2010, Jiang et al 2011, Geberhiwot et al 2018].

Bile acids derived from 7-oxocholesterol and from cholestane-3β,5α,6β-triol are also elevated in NPC, and may be useful diagnostic markers in neonates in whom oxysterols may be less reliable, as well as in older individuals [Motamed-Gorji et al 2024].

Family history. Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in either NPC1 or NPC2 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of NPC1 or NPC2 variants of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of comprehensive genomic testing (exome sequencing, genome sequencing) and gene-targeted testing (multigene panel).Comprehensive genomic testing does not require that the clinician determine which gene(s) are likely involved (see Option 1) whereas gene-targeted testing does (see Option 2).

Note: Single-gene testing (sequence analysis of NPC1 and/or NPC2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Option 1

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of NPC1 and NPC2 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. Reports of intronic variants that may require genome sequencing for detection include Macías-Vidal et al [2011], Kılıç Yıldırım et al [2021], and Brown et al [2025].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NPC1 and NPC2) that cannot be detected by sequence analysis.

For an introduction to CMA click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

A multigene panel (including a neonatal cholestasis panel when relevant) that includes NPC1, NPC2, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Panels to consider include those for lysosomal disorders, treatable neurometabolic disorders, mendelian disorders with psychiatric symptoms, and metabolic nonimmune fetal hydrops. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Niemann-Pick Disease Type C: Molecular Genetic Testing

Gene ¹	Proportion of NPC Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ^2, 3 Identified by Method
Gene ¹	Proportion of NPC Attributed to Pathogenic Variants in Gene	Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵	Chromosomal microarray analysis⁶
NPC1	95%	76%	22%	2%
NPC2	5%	88%	12%	0%

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on variants detected in these genes.
3.: Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including NPC1 and NPC2) that cannot be detected by other methods of deletion/duplication analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 18q11.2 region that includes NPC1 and the 14q24.3 region that includes NPC2. CMA designs in current clinical use target these regions.

Clinical Characteristics

Clinical Description

Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and (in some individuals) epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have progressive dementia. Older teenagers and young adults may present predominantly with apparent early-onset dementia or psychiatric manifestations; however, detailed examination usually identifies typical neurologic signs.

Table 2.

Niemann-Pick Disease Type C: Comparison of Age-Related Phenotypes by Select Features

Feature	Phenotypes by Age of Onset
	Visceral neurodegenerative	Neurodegenerative		Psychiatric neurodegenerative
	Early infantile (age <2 yrs)	Late infantile (2 to <6 yrs)	Juvenile (6 to <15 yrs)	Adult (>15 yrs)
Hepatomegaly	●
Splenomegaly		●	●	(●)
Ataxia		●	●	●
Epilepsy		●	●	(●)
Cataplexy		(●)	●	●
Dementia			(●)	●
Psychiatric			(●)	●
Dystonia		(●)	●	●
VSSP	(●)	●	●	●
VSGP		(●)	●	●

: VSGP = vertical supranuclear gaze palsy; VSSP = vertical supranuclear saccadic palsy
: (●) = sometimes present; ● = usually present

Neonatal and Infantile Presentations

The presentation of NPC in early life is typically nonspecific and may go unrecognized by inexperienced clinicians. However, on occasion ultrasound examination in late pregnancy detects fetal ascites and newborns thus identified typically have severe neonatal liver disease with cholestatic jaundice, persistent ascites, and organomegaly.

López de Frutos et al [2021] reported five neonates with NPC who presented with neonatal cholestasis and organomegaly. Subsequently, in a retrospective study of 34 children with NPC and early liver involvement, Gardin et al [2023] found that all had hepatomegaly at initial evaluation, 33 had splenomegaly, and 30 had cholestasis. Serum alpha-fetoprotein was elevated in 17/21. Four children died by age six months; cholestasis regressed in all who survived after age six months.

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

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 disease manifestations, 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.

Another subgroup of children has minimal or absent hepatic or pulmonary dysfunction and presents primarily with hypotonia and delayed development. Children in this group might develop vertical supranuclear saccade palsy (VSSP) or even vertical supranuclear gaze palsy (VSGP), but this is only apparent if actively searched for by the clinician [Bremova & Strupp 2017, Bremova-Ertl et al 2021]. Children compensate for the oculomotor deficits with blinks and head / upper body movements that represent a diagnostic clue for this disease.

Childhood Presentations

The classic presentation of NPC is in mid- to late childhood, with clumsiness and gait disturbance that eventually become frank ataxia. Many observant parents are aware of impaired vertical saccades, which is an early manifestation. VSSP first manifests as decreased velocity of vertical saccades, gradually slowing down and eventually lost, resulting in restricted range of vertical eye movements, or VSGP. "Around-the-house" sign (i.e., rolling eye movements while performing vertical saccades) can occur [Eggink et al 2016]. In late stages of the illness, horizontal saccades are also impaired. These 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 above, many children develop dystonia, typically beginning as action dystonia in one limb that gradually spreads to involve all 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. Seizures usually improve if the child's survival is prolonged; this improvement presumably reflects 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 highly disabling in those children who experience daily multiple attacks, during which injuries may occur, and can progress into narcolepsy [Madan et al 2021, Leppmeier et al 2022].

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; prospective nerve conduction studies in a cohort of 41 affected individuals participating in a clinical trial of miglustat identified two individuals with peripheral neuropathy. One adult in the miglustat group had worsening of peripheral neuropathy, not considered to be treatment related; and one individual in the standard care group exhibited the neurophysiologic changes of peripheral neuropathy [Patterson et al 2007]. Subsequently, only a single instance of peripheral neuropathy in a 42-month-old girl with NPC with areflexia and abnormal nerve conduction studies has been reported; however, explicit biochemical and molecular data were not included [Barzegar et al 2022].

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 like that in childhood, albeit with a much slower rate of progression. One individual survived into the seventh decade, having first developed manifestations 25 years earlier [M Patterson, personal observation].

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 detailed examination.

An adult presented with bipolar disorder [Sullivan et al 2005].
Nineteen adults with NPC exhibited behavioral (15/17) and cognitive disorders (18/19) that included executive dysfunction (11/12), apathy (13/17), impaired social cognition (11/13), and stereotyped behaviors (5/10). Psychotic manifestations were often drug resistant (8/9); however, improvement in psychotic manifestations has been reported in individuals treated with miglustat [Morin et al 2023].
A 59-year-old man presenting with asymmetric parkinsonism and dementia was initially suspected to have corticobasal degeneration before proven to have NPC [Balázs et al 2019].
An individual presenting with features of progressive supranuclear palsy at age 61 years and another with parkinsonism at age 68 years were subsequently diagnosed with NPC [Wu et al 2020], as was a 67-year-old female with a five-year history of progressive walking and balance difficulties with near-fall episodes [Sousa et al 2024].

Other Studies

Imaging. MRI of the brain is usually normal until the late stages of the illness, when 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 be observed. In one adult, areas of confluent white matter signal hyperintensity mimicked multiple sclerosis [Grau et al 1997].

Quantitative MRI studies in adults 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-to-midbrain ratio correlates with oculomotor function and disease severity [Walterfang et al 2012a].

A study of 16 adults with NPC found that the choline (Cho)-to-N-acetylaspartate (NAA) ratio in the centrum ovale on proton magnetic resonance spectroscopy (H-MRS) correlated with disease progression, and that both responded in parallel to treatment with miglustat [Sedel et al 2016]. These findings were reinforced by a study of 12 juvenile and adult individuals with NPC in which H-MRS showed reduction in NAA-to-creatine (Cr) resonance intensity and an increase in the choline and lipid signals that correlated with signal hyperintensities in the white matter [Guo et al 2018].

In a case-control study in nine individuals with NPC, PET scanning utilizing a ligand-binding activated microglia suggested that neuroinflammation – particularly in white matter – was driving the neurodegenerative process [Walterfang et al 2020].

Heterozygotes

Josephs et al [2004] attributed tremor in an individual to presence of a heterozygous NPC1 pathogenic variant.

More recently, a study of 20 obligate heterozygotes for an NPC1 pathogenic variant found varying manifestations typically seen in compound heterozygotes (i.e., individuals with biallelic pathogenic variants), including hepatosplenomegaly, increased cholestane-3β,5α,6β-triol levels, hyposmia, REM sleep behavior disorder, and typical oculomotor abnormalities [Bremova-Ertl et al 2020].

In contrast, three large studies did not find an association between the frequency of a heterozygous NPC1 pathogenic variant in individuals with neurodegenerative disease that included Parkinson disease, frontotemporal lobar degeneration, progressive supranuclear palsy, REM sleep behavior disorder, and dementia with Lewy bodies [Zech et al 2013, Ouled Amar Bencheikh et al 2020, Somerville et al 2023].

Genotype-Phenotype Correlations

NPC1. The following phenotype correlations have been observed for homozygous pathogenic variants and the more common pathogenic variants in the compound heterozygous state:

No individuals with p.Ile1061Thr had early-infantile NPC in an international study that included the Hispanic population in the upper Rio Grande Valley of the southwestern United States, as well as the United Kingdom and France [Millat et al 1999].
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-infantile NPC [Millat et al 2001b].
In 40 unrelated individuals of Spanish descent homozygous for the p.Gln775Pro pathogenic variant had early-infantile NPC, and those homozygous for the p.Cys177Tyr pathogenic variant had late-infantile NPC [Fernandez-Valero et al 2005].

NPC2

Early-infantile NPC is associated with the variants p.Glu20Ter, p.Glu118Ter, c.27delG, and p.Ser67Pro [Millat et al 2001a].
Adult-onset disease with frontal lobe atrophy has been described in four individuals homozygous for the p.Val39Met pathogenic variant [Klünemann et al 2002, Park et al 2003, Chikh et al 2005].
Neonatal or infantile onset and death in early childhood were reported in children homozygous for p.Gln45Ter, p.Cys47Ter, and p.Cys99Arg pathogenic variants, whereas prolonged survival into mid-adulthood was reported in those homozygous for p.Val39Met [Chikh et al 2005].

Nomenclature

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 biallelic pathogenic variants in NPC1.

The terms Niemann-Pick disease type C1 (NPC1) and Niemann-Pick disease type C2 (NPC2) are now preferred because they correspond with the associated genes (NPC1 and NPC2).

Prevalence

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 individuals diagnosed postnatally in a ten-year period versus the number of births during the same period. When pregnancies 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 the United States was estimated at 2.9 in one million, based on assumption of underdiagnosis and misdiagnosis [Burton et al 2021].

A study in Quebec, Canda, reported a prevalence of 0.61 in 100,000 births [Labrecque et al 2021].

The prevalence of NPC in childhood is probably underestimated, owing to the nonspecific presentations in that age group. 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.

Genetic isolates with NPC1 founder variants include Acadians in Nova Scotia and a Bedouin group in Israel (see Table 9).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with germline pathogenic variants in NPC1 or NPC2.

Differential Diagnosis

The differential diagnosis of neonatal and infantile presentations of Niemann-Pick disease type C (NPC) includes:

Acquired conditions such as biliary atresia *
Congenital infections (e.g., TORCH)
Malignancies (leukemia, lymphoma, histiocytosis)
Other genetic disorders (See Table 3.)

* A study from Colorado found that 27% of infants initially diagnosed with idiopathic neonatal cholestasis (see Pediatric Genetic Cholestatic Liver Disease Overview) and 8% of all infants with cholestasis had NPC [Yerushalmi et al 2002].

Table 3.

Niemann-Pick Disease Type C (Neonatal and Infantile Presentations): Differential Diagnosis

Gene	Disorder	MOI	Clinical Characteristics
FAH	Tyrosinemia type I	AR	If untreated, usually presents either in young infants w/severe liver involvement or later in 1st yr of life w/liver dysfunction & significant renal involvement, growth failure, & rickets
SERPINA1	Alpha-1-antitrypsin deficiency	Autosomal codominant	May present w/hepatic dysfunction from infancy, or w/obstructive lung disease &/or bronchiectasis typically after age 30 yrs
GLB1	GM1 gangliosidosis (See GLB1-Related Disorders.)	AR	May present w/organomegaly. Children show coarsened features, edema, gum hypertrophy, dysostosis, & delayed development, followed by rapid regression & premature death in 2nd yr of life.
Storage diseases including:
GBA1 (GBA)	Gaucher disease type 2 (acute or infantile)	AR	CNS involvement, hepatomegaly, splenomegaly, cytopenia, pulmonary disease, & dermatologic changes
SMPD1	Niemann-Pick disease type A	AR	Hepatosplenomegaly is typically noted by age 3 mos; over time liver & spleen become massive.
SMPD1	Niemann-Pick disease type B	AR	Later onset & milder manifestations than NPD-A; hepatosplenomegaly w/progressive hypersplenism & stable liver dysfunction

: AR = autosomal recessive; MOI = mode of inheritance; NPD-A = Niemann-Pick disease type A

The differential diagnosis childhood presentations of NPC includes acquired conditions such as pineal region or midbrain tumors causing dorsal midbrain syndrome, hydrocephalus, attention-deficit disorder, learning disabilities, absence seizures, other dementing illnesses, pseudodementia (depressive disorder), HIV encephalopathy, sleep disorders, and syncope. Genetic disorders to consider include subacute necrotizing encephalomyelopathy (see Mitochondrial DNA-Associated Leigh Syndrome Spectrum and Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview), primary mitochondrial disorders, hereditary dystonias, and the conditions summarized in Table 4.

Table 4.

Niemann-Pick Disease Type C (Childhood Presentations): Differential Diagnosis

Gene	Disorder	MOI	Clinical Characteristics
ATP7B	Wilson disease	AR	Can present w/hepatic, neurologic, or psychiatric disturbances
BCKDHA BCKDHB DBT	Maple syrup urine disease	AR	Developmental delays later in infancy or childhood w/acute hyperleucinemia, ketonuria, & encephalopathy if stressed by fasting, dehydration, or infectious illness
HEXA	Juvenile (subacute) hexosaminidase A deficiency (See HEXA Disorders.)	AR	Variable neurologic findings incl progressive dystonia, spinocerebellar degeneration, & motor neuron disease
CLN3 CLN5 CLN6 CLN8 CTSD CTSF DNAJC5 GRN KCTD7 MFSD8 PPT1 TPP1	Neuronal ceroid lipofuscinoses	AR AD	Variable phenotype, ataxia, myoclonia, cognitive decline, visual disturbances, epilepsy
Amino acidurias & organic acidopathies including:
GCDH	Glutaric acidemia type 1	AR	Encephalopathic crises → acute bilateral striatal injury & subsequent complex movement disorders; insidious-onset basal ganglia injury may develop in absence of identified acute encephalopathic crisis.
Hereditary disorders w/periodic paralysis including:
CACNA1S SCN4A	Hypokalemic periodic paralysis	AD	Paralytic episodes w/concomitant hypokalemia ¹
SCN4A	Hyperkalemic periodic paralysis	AD	Attacks of flaccid limb weakness; may incl weakness of muscles of eyes, throat, & trunk

: AR = autosomal recessive; AD = autosomal dominant; MOI = mode of inheritance
1.: Serum potassium <3.5 mmol/L

The differential diagnosis adolescent and adult presentations of NPC includes the following:

Alzheimer disease, Pick disease (an adult-onset disorder with dementia associated with characteristic neuronal inclusions called Pick bodies, not related to Niemann-Pick disease), and frontotemporal dementias (FTD; e.g. CHMP2B-FTD, GRN-FTD, C9orf72 amyotrophic lateral sclerosis and FTD, MAPT-FTD).
Late-onset lysosomal storage diseases
Syphilis and HIV dementia
Primary psychiatric illnesses
Corticobasal degeneration

Management

Clinical management guidelines for Niemann-Pick disease type C (NPC) have been published [Geberhiwot et al 2018] (full text).

Note: Revised clinical management guidelines for NPC are being developed to incorporate the recently approved targeted therapies arimoclomol/miglustat and levacetylleucine.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NPC, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Niemann-Pick Disease Type C: Recommended Evaluations Following Initial Diagnosis

System/Concern	Evaluation	Comment
Physical exam	Document growth parameters & organomegaly.
Physical exam	Establish current level of disease severity.	Use NPC clinical severity score ¹ to document key features at diagnosis.
Neurologic exam	Assess for neurologic features incl spasticity, cataplexy, movement disorders, sleep disturbance, & seizures.	MRI if not already performed Consider sleep studies if history is suggestive. Consider EEG if history is suggestive.
Developmental assessment for children	Developmental assessment	Incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education
Cognitive assessment	Document baseline degree of cognitive impairment.
Bowel dysfunction	Medical history for signs/symptoms of constipation
Mobility / Activities of daily living	Assessment of mobility, balance, core stability, trunk control, spasticity, foot posture, & strength by suitably qualified PT	Assess modifications for safety & improved independence.
Speech & language	Comprehensive communication eval by speech-language therapist	Assess for need for speech therapy &/or augmentative & alternative communication.
Nutrition/ Feeding	Eval by nutritionist / gastroenterologist / feeding team	Clinical swallowing assessment in all affected persons VFSS may be useful in some. Assess need for dietary modification. Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Cognitive assessment	Eval by neuropsychologist	Document baseline degree of cognitive impairment.
Ophthalmology exam	Eval by neuro-ophthalmologist/neurologist	Document saccadic eye movement velocity & presence of vertical gaze palsy.
Hearing	Audiometry eval	To document presence of hearing loss
Neurobehavioral/psychiatric manifestations	Eval by psychiatrist or mental health professional	Assess for psychosis, behavioral disturbances, & depression.
Genetic counseling	By genetics professionals ²	To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of NPC to facilitate medical & personal decision making
Family support & resources	By providers at specialized care centers, family physician/pediatrician, & local palliative care services	Work closely w/affected persons & families/caregivers through life span incl: Advance care planning w/regular updating; Proper flow of communication & information for affected persons & families; & Designated point of contact for each stage in care pathway.

: MOI = mode of inheritance; PT = physical therapist; VFSS = videofluoroscopic swallowing study
1.: Geberhiwot et al [2018], Table 4
2.: Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

No curative therapy for NPC exists.

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Table 6.

Niemann-Pick Disease Type C: Targeted Therapies

Drug	Dosage	Consideration
Miglustat ¹		Approved for mgmt of neurologic manifestations of NPC in several countries; not currently FDA approved for standalone treatment of NPC in US.
Arimoclomol ¹	In persons w/actual body weight of: 8 kg to 15 kg, dosage is 47 mg 3x/day; >15 kg to 30 kg, dosage is 62 mg 3x/day; >30 kg to 55 kg, dosage is 93 mg 3x/day; >55 kg, dosage is 124 mg 3x/day. ²	Approved by FDA for use in combination w/miglustat for treatment of neurologic manifestations of NPC in persons age ≥2 yrs ³
Levacetylleucine ^1, 4	In persons w/body weight of: 15 kg to <25 kg, dosage is 1 g 2x/day; 25 kg to <35 kg, dosage is 1 g 3x/day; ≥35 kg, dosage is 2 g each morning, & 1 g in afternoon & evening ⁵	Approved by FDA for treatment of neurologic manifestations of NPC in adults & children weighing ≥15 kg ⁶

1.: Revised clinical management guidelines for NPC are being developed to incorporate arimoclomol/miglustat and levacetylleucine.
2.: See prescribing information.
3.: Keam [2025]
4.: Levacetylleucine is a modulator of tricarboxylic acid cycle and lysosomal-mitochondrial axis dysfunction through enhanced lysosomal biogenesis.
5.: See prescribing information.
6.: van Gool et al [2025]

Miglustat. Based on clinical studies that supported a role of miglustat in stabilizing mice with murine NPC, miglustat was approved for the management of neurologic manifestations of NPC in several countries [Patterson et al 2012] but not the United States. A literature review of the effect of miglustat on clinical, biomarker, and imaging measures supported its efficacy in ameliorating the course of NPC [Pineda et al 2018]. Analysis of data on long-term survival in NPC from several historical data sets as well as a prospective registry suggested that individuals treated with miglustat experienced a mean increase in survival of five years when measured from date of diagnosis or approximately ten years when measured from onset of neurologic manifestations [Patterson et al 2020]. This positive effect was supported by a three-year (median) prospective study of 50 individuals with NPC taking miglustat in whom swallowing function and the risk of aspiration stabilized [Solomon et al 2020]. Improvement in psychotic manifestations has also been reported in persons treated with miglustat [Morin et al 2023].

Thus, in countries where it is an approved therapy, individuals with a confirmed diagnosis of NPC should be considered for miglustat therapy, except individuals with NPC who:

Have advanced neurologic disease / dementia;
Have another life-threatening illness and an estimated life span <1 year;
Have only spleen/liver enlargement.

Note: Miglustat may produce loose stools and excessive flatus; these effects may be managed with dietary modification (by reduction or removal of lactose and other sugars). Physiologic tremor may be enhanced in some individuals.

Arimoclomol. Arimoclomol is an orally available small molecule that was studied as a potential therapy for NPC because of its ability to amplify the natural response to cellular stress by inducing the heat shock response and production of heat shock proteins to prevent protein misfolding [Kirkegaard et al 2016, Gray et al 2022]. A recent study found that concentrations of arimoclomol of 400 µm (but not lower concentrations) increased translocation of TFEB and TFE3 to the nucleus, with corresponding increased expression of CLEAR network genes [Shammas et al 2025]. It is not clear if such concentrations are attained in humans administered arimoclomol. In contrast, arimoclomol increased NPC1 protein concentrations in human NPC cell lines in a dose- and variant-dependent manner.

A randomized, double-blind, placebo-controlled multinational Phase II/III trial was conducted in persons ages two to 18 years (randomized two to one to receive arimoclomol vs placebo) stratified by miglustat use [Mengel et al 2021]. At month 12 of the study a statistically significant difference in favor of treatment with arimoclomol was observed. Fewer individuals had serious adverse effects with arimoclomol (14.7%) versus placebo (31.3%). Treatment-related serious adverse effects (n=2) included urticaria and angioedema. Arimoclomol was approved by the FDA for use in combination with miglustat for the treatment of neurologic manifestations of NPC in adults and children age two years and older in the US in September 2024 [van Gool et al 2025].

Levacetylleucine. Levacetylleucine is the L-enantiomer of acetylleucine, an orally available amino acid, which has been found to enhance lysosomal biogenesis and mitochondrial function in cell systems (pre-peer review; see bioRxiv), animal models [Kaya et al 2020], and human NPC fibroblasts (pre-peer review; see bioRxiv) through a mechanism involving modulation of the tricarboxylic acid cycle and translocation of transcription factor EB to the nucleus, thus enhancing lysosomal biogenesis with knock-on effects in redressing mitochondrial dysfunction.

N-acetyl-L-leucine (NALL; levacetylleucine) was studied in a double-blind, placebo-controlled, crossover trial in which individuals with NPC ages four years and older were randomly assigned to receive NALL for 12 weeks followed by placebo for 12 weeks or to receive placebo for 12 weeks followed by NALL for 12 weeks [Bremova-Ertl et al 2024]. The incidence of adverse events was similar with NALL and placebo and no treatment-related serious adverse events occurred. In a multinational, multicenter, open-label extension phase study of NALL involving 53 individuals with NPC, the improvements in neurologic manifestations demonstrated in the placebo-controlled trial on the primary Scale for Rating and Assessment of Ataxia (SARA) endpoint were sustained over long-term follow up. NALL was well tolerated, and no treatment-related adverse serious reactions occurred [Patterson et al 2025].

Levacetylleucine was approved by the FDA for the treatment of neurologic manifestations of NPC in adults and children weighing ≥15 kg in the US in September 2024 [van Gool et al 2025].

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 7).

Table 7.

Niemann-Pick Disease Type C: Supportive Care

Manifestation/Concern		Treatment	Considerations/Other
Developmental delay / Intellectual disability		See Developmental Delay / Intellectual Disability Management Issues.
Neurologic	Spasticity	PT	Anti-spasticity drugs; rarely, surgery
	Cataplexy	Modafinil, protriptyline, amitriptyline, venlafaxin	Usually effective & well tolerated
	Movement disorders	Trihexyphenidyl for dystonia	The effects of this agent may not be sustained.
	Sleep disturbance	A nocturnal sedative may be indicated; melatonin is often effective & well tolerated.	Consider formal eval by sleep specialist.
	Seizures	Appropriate antiseizure medications for seizure types; no special considerations for NPC	Treatment must be individualized based on seizure semiology & EEG findings.
Bowel dysfunction		Regular bowel program to prevent severe constipation	Constipation may manifest as ↑ seizure frequency &/or ↑ spasticity.
Mobility / Activities of daily living		PT to maintain mobility as long as possible Structured & personalized rehab program to prolong mobility & transfer ability.	Proactively seek strategies to maintain optimal mobility & ↓ falls such as providing appropriate walking/mobility aids, ankle-foot orthotics, & exercise programs.
Speech & language		Speech therapy	Consider eval for alternative means of communication (e.g., augmentative & alternative communication) for those w/expressive language difficulties.
Nutrition/Feeding		Thickened feeds & small boluses as tolerated	Consider gastrostomy tube placement when aspiration &/or nutritional compromise is a concern.
Eye movement disorder		No specific therapy, although changes may be slowed by treatment w/miglustat.
Hearing impairment		Occurs in course of illness Hearing aids may be helpful.	Use of amplification should be guided by clinical needs & recommendations of treating audiologist.
Psychosis, behavioral disturbances, depression		Appropriate psychotropic medications & supportive counseling	Psychiatric manifestations may be resistant to standard drug therapies.
Family/caregiver needs		Providers at specialized care centers, family physician/pediatrician, & local palliative care services should work closely w/affected persons & families/caregivers through life span, incl: Advance care planning w/regular updating; Proper flow of communication & information for affected persons & families; Designated point of contact for each stage in care pathway.	Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.

: PT = physical therapy

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 8 are recommended.

Table 8.

Niemann-Pick Disease Type C: Recommended Surveillance

System/Concern	Evaluation	Frequency
Interval medical history	Establish rate of disease progression.	Every 6 mos
For those on miglustat therapy	Monitor for: Adherence to therapy; Side effects from therapy; Conditions that would prompt discontinuation of therapy.	Review every 6 mos for indications, efficacy, & adverse effects.
Physical exam	Document growth parameters. Assess for neurologic features & organomegaly.	Every 6-12 mos
NPC clinical severity score ¹	Document progression & response to therapy of key disease features.	Every 6 mos
Mobility / Activities of daily living	Assessment of mobility, balance, core stability, trunk control, spasticity, foot posture, & strength by suitably qualified PT	Every 6 mos in children; every 12 mos in adults
Developmental or cognitive assessment	Monitor educational needs in children & cognitive abilities in adults.
Speech & language	Comprehensive communication eval by speech-language therapist
Ophthalmology assessment	Document progression of saccadic eye movement velocity & presence of gaze palsy as well as response to miglustat therapy.	At 6 & 12 mos; after starting treatment; frequency after 12 mos determined by clinical response
Hearing impairment	Audiometry for new-onset hearing loss or its progression	Every 12 mos
Nutrition/Feeding	Document nutritional status, presence/progression of dysphagia, & aspiration risk.	Every 6 mos in children; in adults, frequency could be ↓ to every 12 mos if asymptomatic & disease is stable
Psychosis, behavioral disturbances, & depression	By mental health care provider	In children, every 6 mos until age 18 yrs, then annually if stable or asymptomatic Frequency of eval should always be guided by individual clinical circumstances.
Sleep hygiene	Medical history for sleep disturbances	Review every 12 mos.
Driving	Monitor those who hold a driver's license for relevant motor &/or sensory impairments.	Every 12 mos
Family/caregiver needs	See Table 7, Family/caregiver needs. Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).	Every 6-12 mos

: PT = physical therapist
1.: Geberhiwot et al [2018], Table 4

Agents/Circumstances to Avoid

Avoid the following:

Drugs that cause excessive salivation or that may exacerbate seizures directly by interacting with anti-seizure medications
Alcohol as well as many drugs that exacerbate ataxia

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk sibs of an affected individual in order to identify as early as possible those who might benefit from targeted therapy for NPC (see Table 6).

Note: Sibs younger than the proband may have NPC but may not have apparent clinical manifestations of the disorder. Vertical supranuclear saccade palsy (VSSP), which may not be recognized without video-oculography, is often the first neurologic manifestation.

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

Therapies Under Investigation

Electroconvulsive therapy (ECT) has been effective in an adult [Foels et al 2020] and in an adolescent with NPC manifesting as drug-resistant catatonia [van Verseveld et al 2021]. ECT may be a preferred therapeutic option in such individuals with NPC who may be at increased risk of extrapyramidal manifestations (EPS), as described in a 28-year-old man with NPC and schizoaffective disorder, who experienced prolonged EPS after risperidone [Fuchs et al 2019].

Intrathecal 2-hydroxypropyl-beta-cyclodextrin. Based on results of studies of hydroxypropyl-beta-cyclodextrin in the murine model of NPC [Abi-Mosleh et al 2009, Davidson et al 2009], uncontrolled clinical studies of intrathecal 2-hydroxypropyl-β-cyclodextrin suggested amelioration of disease progression [Ory et al 2017, Berry-Kravis et al 2018]. However, a controlled clinical trial of this therapy failed to show a difference between controls and the intervention group (NCT02534844). In another study, five individuals with NPC – two with infantile onset, one with onset at age five years, and two with onset at age 20 years – were treated with open-label intrathecal cyclodextrin in doses ranging from 200 mg twice a week to 900 mg every other week. All individuals showed rapid progression despite miglustat therapy. By final follow up (range: 5-11 years), all study participants had stabilized, although further progression had occurred during the course of therapy. Three individuals had mild-to-moderate hearing loss [Matsuo et al 2024].

Intravenous hydroxypropyl-beta-cyclodextrin. A prospective, randomized, double-blind, placebo-controlled trial of intravenous hydroxypropyl-beta-cyclodextrin is currently in progress (NCT04860960). In a preceding Phase I/II study in which participants received intravenous hydroxypropyl-beta-cyclodextrin, seven of nine individuals who completed the study were reported to be improved to some degree and two were stable [Sharma et al 2023].

Search ClinicalTrials.gov 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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

The parents of an individual with NPC are presumed to be heterozygous for an NPC1 or NPC2 pathogenic variant.
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an NPC-related pathogenic variant and to allow reliable recurrence risk assessment.
If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband [Jónsson et al 2017] or as a postzygotic de novo event in a mosaic parent [Cervera-Gaviria et al 2016]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
- A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
- Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
Heterozygotes may manifest clinical and biochemical abnormalities (see Clinical Description, Heterozygotes).

Sibs of a proband

If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
The NPC phenotype usually runs true in families; that is, if the proband has early-onset disease, sibs who inherit biallelic pathogenic variants will have a similar clinical course. In rare cases, a proband and the proband's affected sibs have had different clinical presentations.
Heterozygotes may manifest clinical and biochemical abnormalities (see Clinical Description, Heterozygotes).

Offspring of a proband. The offspring of an individual with NPC are obligate heterozygotes for an NPC-related pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an NPC-related pathogenic variant.

Heterozygote Detection

Molecular genetic heterozygote testing for at-risk relatives requires prior identification of the NPC1 or NPC2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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 heterozygous, or are at risk of being heterozygous.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with NPC, particularly if both partners are of the same ancestry. Founder variants have been identified in the Acadian and Bedouin populations (see Table 9).

Prenatal Testing and Preimplantation Genetic Testing

Once the NPC-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

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.

Ara Parseghian Medical Research Foundation
parseghian.org
International Niemann–Pick Disease Alliance (INPDA)
Phone: 44 (0)191 4150693
Email: info@inpda.org
inpda.org
MedlinePlus
Niemann-Pick disease
National Niemann-Pick Disease Foundation (NNPDF)
Phone: 877-287-3672
Email: nnpdf@nnpdf.org
nnpdf.org
NCBI Genes and Disease
Niemann-Pick disease
Niemann-Pick UK
United Kingdom
Phone: +44-0191-415-0693
Email: info@npuk.org
npuk.org
Canadian MPS Society for Mucopolysaccharidoses and Related Diseases
Canada
Phone: 800-667-1846
Email: info@mpssociety.ca
mpssociety.ca
International Niemann-Pick Disease Registry
INPDR
RDCRN Contact Registry
RDCRN Contact Registry | Rare Diseases Clinical Research Network

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

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
NPC1	18q11.2	NPC intracellular cholesterol transporter 1	NPC1 database	NPC1	NPC1
NPC2	14q24.3	NPC intracellular cholesterol transporter 2	NPC2 database	NPC2	NPC2

: 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)

257220	NIEMANN-PICK DISEASE, TYPE C1; NPC1
601015	NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 2; NPC2
607623	NPC INTRACELLULAR CHOLESTEROL TRANSPORTER 1; NPC1
607625	NIEMANN-PICK DISEASE, TYPE C2; NPC2

Molecular Pathogenesis

Pathogenic variants described throughout NPC1 and NPC2 lead to either dysfunction or complete loss of the proteins NPC1 or NPC2, the deficiency of which leads to accumulation in the lysosomes of multiple lipid cargoes including unesterified cholesterol, glucosylceramide, and gangliosides. The consequent lysosomal dysfunction leads to a cascade of downstream effects, including an inflammatory response and triggering of apoptosis.

Mechanism of disease causation. Loss of function; supported by in vitro studies [Shammas et al 2019].

Table 9.

NPC1 and NPC2 Pathogenic Variants Referenced in This GeneReview

Gene	Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
NPC1	NM_000271.3 NP_000262.1	c.3182T>C	p.Ile1061Thr	No persons w/this variant had early-infantile NPC [Millat et al 1999].
		c.530G>A	p.Cys177Tyr	Homozygotes have late-infantile NPC [Fernandez-Valero et al 2005].
		c.1211G > A	p.Arg404Gln	Founder variant in Bedouin population in Israel. Assoc in homozygous state w/early-onset pulmonary disease [Staretz-Chacham et al 2018].
		c.2324A>C	p.Gln775Pro	Homozygotes have early-infantile NPC [Fernandez-Valero et al 2005].
		c.2974G>T	p.Gly992Trp	Founder variant in Acadian population (Yarmouth County) of Nova Scotia [Winsor & Welch 1978, Greer et al 1998]
		c.3160G>A	p.Ala1054Thr	Assoc w/early-infantile NPC [Millat et al 2001b]
NPC2	NM_006432.3 NP_006423.1	c.115G>A	p.Val39Met	Adult-onset disease w/frontal lobe atrophy [Klünemann et al 2002, Chikh et al 2005]
		c.133C>T	p.Gln45Ter	Homozygotes have neonatal or infantile onset & die in early childhood [Chikh et al 2005].
		c.141C>A	p.Cys47Ter
		c.199T>C	p.Ser67Pro	Assoc w/early infantile NPC [Millat et al 2001a].
		c.295T>C	p.Cys99Arg	Homozygotes have neonatal or infantile onset & die in early childhood [Chikh et al 2005].
		c.58G>T	p.Glu20Ter	Assoc w/early infantile NPC [Millat et al 2001a]
		c.352G>T	p.Glu118Ter
		c.27delG	p.Leu10SerfsTer25

: 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.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Prior to his retirement from clinical practice in December 2024, Marc Patterson's work was supported by the Peggy Furth Fund at Mayo Clinic and research grants from NINDS, Amicus, Cerecor, Glycomine, Idorsia, Orphazyme/Zevra, and Shire-Takeda. Until retirement, the author served as Chair of the Scientific Advisory Committee of the International Niemann-Pick Disease Registry. He also served as a consultant for IntraBio and Orphazyme, and holds stock in IntraBio.

Marc Patterson's website

Revision History

20 November 2025 (bp) Comprehensive update posted live
10 December 2020 (bp) Comprehensive update posted live
18 July 2013 (me) Comprehensive update posted live
22 July 2008 (me) Comprehensive update posted live
13 February 2006 (me) Comprehensive update posted live
18 December 2003 (me) Comprehensive update posted live
26 January 2000 (me) Review posted live
20 October 1999 (mp) Original submission

References

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Bremova-Ertl T, Patterson M. Niemann-Pick Disease Type C. 2000 Jan 26 [Updated 2025 Nov 20]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.
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Niemann-Pick Disease Type C

Summary

Clinical characteristics.

Diagnosis/testing.

Management.

Genetic counseling.

Diagnosis

Suggestive Findings

Establishing the Diagnosis

Option 1

Option 2

Table 1.

Clinical Characteristics

Clinical Description

Table 2.

Neonatal and Infantile Presentations

Childhood Presentations

Adolescent and Adult Presentations

Other Studies

Heterozygotes

Genotype-Phenotype Correlations

Nomenclature

Prevalence

Genetically Related (Allelic) Disorders

Differential Diagnosis

Table 3.

Table 4.

Management

Evaluations Following Initial Diagnosis

Table 5.

Treatment of Manifestations

Targeted Therapies

Table 6.

Supportive Care

Table 7.

Developmental Delay / Intellectual Disability Management Issues

Surveillance

Table 8.

Agents/Circumstances to Avoid

Evaluation of Relatives at Risk

Therapies Under Investigation

Genetic Counseling

Mode of Inheritance

Risk to Family Members

Heterozygote Detection

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Resources

Molecular Genetics

Table A.

Table B.

Molecular Pathogenesis

Table 9.

Chapter Notes

Author Notes

Revision History

References

Literature Cited

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