Niemann-Pick Disease Type C - Disorder Mechanisms

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Inheritance

1

Autosomal Recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"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..."

GeneReviews confirms autosomal recessive inheritance with standard Mendelian ratios.

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Subtypes

2

NPC1 MONDO:0009757

Caused by mutations in the NPC1 gene. Accounts for approximately 95% of NPC cases. The NPC1 protein is a large transmembrane protein in late endosomes/lysosomes involved in intracellular cholesterol trafficking.

Show evidence (1 reference)

PMID:22572546 SUPPORT Human Clinical

"Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the..."

Patterson guidelines confirm NPC1 accounts for 95% of NPC cases.

NPC2 MONDO:0011873

Caused by mutations in the NPC2 gene. Accounts for approximately 5% of cases. NPC2 is a small soluble lysosomal protein that binds cholesterol and works cooperatively with NPC1 for cholesterol egress from lysosomes.

Show evidence (1 reference)

PMID:22572546 SUPPORT Human Clinical

"Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the..."

Patterson guidelines confirm NPC2 accounts for approximately 5% of cases.

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Pathophysiology

9

NPC1/NPC2-Mediated Cholesterol Egress Failure

Mutations in NPC1 or NPC2 impair export of cholesterol from late endosomes and lysosomes.

Hepatocyte link Neuron link

NPC1 link NPC2 link

Intracellular Cholesterol Transport link Lipid Transport link

cholesterol transfer activity link

Show evidence (2 references)

PMID:33445799 SUPPORT Human Clinical

"Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY)."

This review directly identifies NPC1 and NPC2 as the proteins required for lysosomal cholesterol egress.

PMID:9211849 SUPPORT In Vitro

"Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking."

NPC1 cDNA rescues the cholesterol trafficking defect in patient fibroblasts.

Lysosomal Unesterified Cholesterol Accumulation

Unesterified cholesterol accumulates in late endosomes and lysosomes as a defining storage abnormality in NPC.

Hepatocyte link Neuron link

Show evidence (1 reference)

PMID:9211849 SUPPORT Human Clinical

"Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol."

The landmark NPC1 paper establishes lysosomal cholesterol accumulation as a defining disease abnormality.

Glycosphingolipid and Ganglioside Accumulation in Brain

While cholesterol accumulates in peripheral tissues, the brain prominently accumulates glycosphingolipids including gangliosides GM2 and GM3. This ganglioside storage disrupts endosomal transport and is a major driver of neurodegeneration in NPC.

Purkinje Cell link Neuron link

Glycosphingolipid Catabolic Process link Sphingolipid Catabolic Process link

Show evidence (2 references)

PMID:20525256 SUPPORT Human Clinical

"NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides."

Vanier review confirms that gangliosides rather than cholesterol are the predominant storage material in the NPC brain.

PMID:15078881 SUPPORT Model Organism

"High pressure liquid chromatography and mass spectrometric analysis of NPC1(-/-) mouse brain revealed large increases in GSL."

Mass spectrometry of NPC1-null mouse brain confirms glycosphingolipid accumulation.

Cerebellar Purkinje Cell Degeneration

Progressive loss of cerebellar Purkinje cells is a hallmark neuropathological feature of NPC. Purkinje cells are particularly vulnerable to lipid accumulation and are among the earliest neuronal populations to degenerate.

Purkinje Cell link

Show evidence (1 reference)

PMID:28803710 SUPPORT Model Organism

"In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1."

Animal model data confirms that Purkinje cell loss is a central feature of NPC1 pathology that can be delayed with cyclodextrin treatment.

Sphingosine Storage as Initiating Factor

Sphingosine accumulates in the acidic compartment of NPC1-mutant cells almost immediately upon NPC1 dysfunction, preceding cholesterol and other lipid storage. This sphingosine accumulation is proposed as an initiating factor in NPC pathogenesis that triggers secondary lipid storage.

Neuron link

Sphingolipid Catabolic Process link

Show evidence (1 reference)

PMID:18953351 SUPPORT In Vitro

"Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol."

Lloyd-Evans et al. demonstrate that sphingosine accumulation in lysosomes is the initiating event driving secondary lipid storage in NPC.

Lysosomal Calcium Dysregulation

NPC1-mutant cells have significantly reduced lysosomal calcium stores. This calcium depletion downstream of sphingosine accumulation causes secondary accumulation of cholesterol, sphingomyelin, and glycosphingolipids, linking calcium dysregulation to the broad lipid storage phenotype.

Neuron link

Intracellular Calcium Ion Homeostasis link

Show evidence (1 reference)

PMID:18953351 SUPPORT In Vitro

"NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells."

Lysosomal calcium stores are significantly reduced in NPC1-mutant cells, linking calcium dysregulation to lipid storage.

Defective Cellular Autophagy

Impaired autophagic handling is an additional downstream mechanism in NPC that likely contributes to cellular dysfunction and disease progression.

Neuron link

autophagy link ↕ DYSREGULATED

Show evidence (1 reference)

PMID:26014711 SUPPORT Human Clinical

"Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all..."

This review supports defective cellular autophagy as a secondary pathophysiologic mechanism in NPC downstream of the core cholesterol trafficking defect.

Progressive Neurological Dysfunction

NPC neurological disease produces a broad syndrome of progressive brain dysfunction with bulbar, oculomotor, seizure, and cognitive manifestations.

Show evidence (1 reference)

PMID:33924575 SUPPORT Human Clinical

"Affected patients are mainly characterized by neurological dysfunction and liver damage."

This review supports progressive neurological dysfunction as a major component of NPC disease biology.

Tau Hyperphosphorylation and Neurofibrillary Tangles

NPC shares neuropathological features with Alzheimer disease including neurofibrillary tangle (NFT) formation from hyperphosphorylated tau protein. Plasma phosphorylated-tau217 is elevated in NPC and correlates with disease progression, suggesting tau pathology is an active disease marker.

Neuron link

Protein Phosphorylation link

Show evidence (2 references)

PMID:39502943 SUPPORT Human Clinical

"plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset"

Elevated p-tau217 in NPC patients demonstrates active tau pathology paralleling Alzheimer-like neurodegeneration.

PMID:39502943 SUPPORT Human Clinical

"Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology."

Confirms shared NFT pathology between NPC and Alzheimer disease.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Cardiovascular 1

Hepatosplenomegaly VERY_FREQUENT Hepatosplenomegaly (HP:0001433)

Often presenting sign in infancy; may resolve but precedes neurological disease

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates."

GeneReviews confirms hepatosplenomegaly as a presenting feature in perinatal/infantile NPC.

Digestive 2

Dysphagia VERY_FREQUENT Dysphagia (HP:0002015)

Often leads to aspiration pneumonia, a major cause of death

Show evidence (2 references)

PMID:20525256 SUPPORT Human Clinical

"The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."

Vanier review lists dysphagia as a core neurological feature of NPC.

PMID:20301473 SUPPORT Human Clinical

"Death from aspiration pneumonia usually occurs in the late second or third decade."

GeneReviews confirms aspiration pneumonia from dysphagia as a major cause of death.

Neonatal Cholestasis FREQUENT Neonatal cholestatic liver disease (HP:0006566)

Present in perinatal/infantile onset; may resolve spontaneously

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates."

Cholestatic jaundice is a key early visceral manifestation of NPC.

Eye 1

Vertical Supranuclear Gaze Palsy VERY_FREQUENT Vertical supranuclear gaze palsy (HP:0000511)

Most characteristic neurological sign of NPC

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"The most characteristic sign is vertical supranuclear gaze palsy."

Vanier review identifies VSGP as the single most characteristic sign of NPC.

Nervous System 8

Cerebellar Ataxia VERY_FREQUENT Progressive cerebellar ataxia (HP:0002073)

Progressive gait and limb ataxia, often presenting feature in childhood

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."

Cerebellar ataxia is listed as one of the main neurological manifestations.

Dysarthria VERY_FREQUENT Dysarthria (HP:0001260)

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."

Dysarthria is a core neurological feature of NPC.

Progressive Dementia VERY_FREQUENT Dementia (HP:0000726)

Cognitive decline progresses to severe dementia

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."

Progressive dementia is a core neurological feature of NPC.

Dystonia FREQUENT Dystonia (HP:0001332)

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"Cataplexy, seizures and dystonia are other common features."

Dystonia is identified as a common neurological feature of NPC.

Seizures FREQUENT Seizure (HP:0001250)

Epileptic seizures, more common in juvenile onset

Show evidence (1 reference)

PMID:22572546 SUPPORT Human Clinical

"Epileptic seizures are also common in affected patients."

Patterson et al. guideline update confirms seizures are common in NPC.

Gelastic Cataplexy FREQUENT Cataplexy (HP:0002524)

Sudden loss of muscle tone triggered by laughter; highly suggestive of NPC

Show evidence (1 reference)

PMID:22572546 SUPPORT Human Clinical

"Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy."

Patterson et al. guideline identifies gelastic cataplexy as a characteristic NPC manifestation.

Psychiatric Manifestations FREQUENT Psychosis (HP:0000709)

More common in adolescent/adult-onset NPC; may be the initial presentation

Show evidence (2 references)

PMID:22572546 SUPPORT Human Clinical

"an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations."

Patterson guidelines confirm psychiatric manifestations as a presentation in adult-onset NPC.

PMID:20525256 SUPPORT Human Clinical

"ataxia not unfrequently following initial psychiatric disturbances (adult form)."

Vanier review identifies psychiatric disturbances as a common initial presentation in adult-onset NPC.

Neurofibrillary Tangles VERY_FREQUENT Neurofibrillary tangles (HP:0002185)

Alzheimer-like tau pathology; shared between NPC and Alzheimer disease

Show evidence (1 reference)

PMID:39502943 SUPPORT Human Clinical

"Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology."

NFT pathology is a confirmed shared neuropathological feature of NPC.

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Genetic Associations

2

NPC1 (Causative)

Show evidence (2 references)

PMID:9211849 SUPPORT Human Clinical

"By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients."

Landmark paper identifying NPC1 as the causative gene by positional cloning.

PMID:22572546 SUPPORT Human Clinical

"Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the..."

Patterson guidelines confirm NPC1 accounts for 95% and NPC2 for 5% of cases.

NPC2 (Causative)

Show evidence (1 reference)

PMID:22572546 SUPPORT Human Clinical

"Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the..."

Patterson guidelines confirm NPC2 accounts for approximately 5% of NPC cases.

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Treatments

6

Miglustat

Action: miglustat therapy Ontology label: pharmacotherapy MAXO:0000058

Substrate reduction therapy approved in Europe and several other countries for treatment of neurological manifestations. Inhibits glucosylceramide synthase to reduce glycosphingolipid accumulation.

Show evidence (1 reference)

PMID:20525256 SUPPORT Human Clinical

"A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations."

Vanier review confirms miglustat authorization for NPC neurological manifestations.

Intrathecal 2-Hydroxypropyl-Beta-Cyclodextrin

Action: intrathecal cyclodextrin therapy Ontology label: pharmacotherapy MAXO:0000058

HPbCD given by lumbar intrathecal injection mobilizes cholesterol from lysosomes. Phase 1-2 trial showed slowed neurological disease progression compared to natural history.

Show evidence (1 reference)

PMID:28803710 SUPPORT Human Clinical

"Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile."

Phase 1-2 trial demonstrates intrathecal HPbCD slows neurological progression in NPC1.

Levacetylleucine

Action: levacetylleucine therapy Ontology label: pharmacotherapy MAXO:0000058

FDA-approved standalone treatment for NPC.

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"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)."

GeneReviews confirms FDA approval of levacetylleucine as standalone therapy for NPC.

Arimoclomol

Action: arimoclomol therapy Ontology label: pharmacotherapy MAXO:0000058

Co-inducer of heat shock proteins, approved for use in combination with miglustat for NPC. Enhances cellular stress response and may improve protein folding and lysosomal function.

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"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)."

GeneReviews confirms arimoclomol is approved for NPC in combination with miglustat.

Supportive Care

Action: supportive care MAXO:0000950

Multidisciplinary management including neurology, physical therapy, occupational therapy, speech therapy, nutrition support, and seizure management.

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"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."

GeneReviews outlines the multidisciplinary supportive care approach for NPC.

Genetic Counseling

Action: genetic counseling MAXO:0000079

Family screening, carrier testing, and prenatal/preimplantation genetic testing for at-risk relatives.

Show evidence (1 reference)

PMID:20301473 SUPPORT Human Clinical

"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."

GeneReviews confirms genetic testing for at-risk relatives is recommended.

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Biochemical Markers

4

Unesterified Cholesterol Accumulation (Elevated)

Context: Filipin staining of skin fibroblasts shows accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes). Pronounced abnormalities in approximately 80% of cases.

Show evidence (1 reference)

PMID:20525256 SUPPORT In Vitro

"The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin."

Filipin staining of fibroblasts is the classic diagnostic test demonstrating cholesterol accumulation.

Plasma 24(S)-Hydroxycholesterol (Elevated)

Context: Plasma 24(S)-hydroxycholesterol serves as a pharmacodynamic biomarker reflecting neuronal cholesterol homeostasis in NPC clinical trials.

Show evidence (1 reference)

PMID:28803710 SUPPORT Human Clinical

"Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037)."

24(S)-HC serves as a validated biomarker of neuronal cholesterol homeostasis in NPC clinical trials.

Sphingosine Accumulation (Elevated)

Context: Sphingosine accumulates in the lysosomal compartment of NPC cells almost immediately upon NPC1 dysfunction, preceding cholesterol and other lipid storage. Proposed as an initiating factor in NPC pathogenesis.

Show evidence (1 reference)

PMID:18953351 SUPPORT In Vitro

"sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate"

Multiple lipid species including sphingosine accumulate in NPC1-mutant cells.

Plasma Phosphorylated-Tau217 (Elevated)

Context: Plasma p-tau217 is elevated in NPC patients compared to controls and correlates with disease severity and rate of progression. Represents a potential blood-based biomarker for monitoring NPC.

Show evidence (1 reference)

PMID:39502943 SUPPORT Human Clinical

"plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset"

Plasma p-tau217 is significantly elevated in NPC and tracks disease severity.

{ }

Source YAML

click to show

name: Niemann-Pick Disease Type C
creation_date: '2026-03-14T00:00:00Z'
updated_date: '2026-04-06T22:37:07Z'
category: Genetic
parents:
- Lysosomal Storage Disorder
- Sphingolipidosis
- Neurodegeneration
disease_term:
  preferred_term: Niemann-Pick disease type C
  term:
    id: MONDO:0018982
    label: Niemann-Pick disease type C
prevalence:
- population: Global
  percentage: Rare
  notes: >
    Estimated incidence of approximately 1 in 100,000 live births.
    Likely underdiagnosed due to phenotypic heterogeneity and delayed diagnosis.
  evidence:
  - reference: PMID:29625568
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care."
    explanation: Consensus guidelines estimate NPC incidence at approximately 1 in 100,000.
progression:
- phase: Perinatal/Infantile
  age_range: 0-2 years
  notes: >
    Initial presentation predominantly visceral with hepatosplenomegaly
    and cholestatic jaundice. Many succumb at this stage; survivors may
    have complete resolution before neurological disease emerges.
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates."
    explanation: GeneReviews describes the perinatal/infantile presentation as predominantly visceral.
- phase: Late Infantile/Juvenile
  age_range: 2-15 years
  notes: >
    Neurological manifestations dominate. Ataxia, dysarthria, dysphagia,
    seizures, dystonia, and gelastic cataplexy emerge. Cognitive decline
    progresses to dementia. Death typically in late second or third decade.
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death from aspiration pneumonia usually occurs in the late second or third decade."
    explanation: GeneReviews confirms typical death in second or third decade for childhood-onset NPC.
- phase: Adolescent/Adult
  age_range: 15+ years
  notes: >
    Slower neurological progression and longer life expectancy. May present
    with psychiatric manifestations or early-onset dementia.
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ataxia not unfrequently following initial psychiatric disturbances (adult form)."
    explanation: Vanier review confirms adult-onset NPC often presents with psychiatric features.
has_subtypes:
- name: NPC1
  description: >
    Caused by mutations in the NPC1 gene. Accounts for approximately 95% of NPC cases.
    The NPC1 protein is a large transmembrane protein in late endosomes/lysosomes
    involved in intracellular cholesterol trafficking.
  subtype_term:
    preferred_term: Niemann-Pick disease, type C1
    term:
      id: MONDO:0009757
      label: Niemann-Pick disease, type C1
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues."
    explanation: Patterson guidelines confirm NPC1 accounts for 95% of NPC cases.
- name: NPC2
  description: >
    Caused by mutations in the NPC2 gene. Accounts for approximately 5% of cases.
    NPC2 is a small soluble lysosomal protein that binds cholesterol and works
    cooperatively with NPC1 for cholesterol egress from lysosomes.
  subtype_term:
    preferred_term: Niemann-Pick disease, type C2
    term:
      id: MONDO:0011873
      label: Niemann-Pick disease, type C2
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues."
    explanation: Patterson guidelines confirm NPC2 accounts for approximately 5% of cases.
pathophysiology:
- name: NPC1/NPC2-Mediated Cholesterol Egress Failure
  description: >
    Mutations in NPC1 or NPC2 impair export of cholesterol from late
    endosomes and lysosomes.
  genes:
  - preferred_term: NPC1
    term:
      id: hgnc:7897
      label: NPC1
  - preferred_term: NPC2
    term:
      id: hgnc:7898
      label: NPC2
  molecular_functions:
  - preferred_term: cholesterol transfer activity
    term:
      id: GO:0120020
      label: cholesterol transfer activity
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Intracellular Cholesterol Transport
    term:
      id: GO:0032367
      label: intracellular cholesterol transport
  - preferred_term: Lipid Transport
    term:
      id: GO:0006869
      label: lipid transport
  downstream:
  - target: Lysosomal Unesterified Cholesterol Accumulation
    description: Failed cholesterol egress leads directly to lysosomal cholesterol storage.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33445799
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark."
      explanation: This review directly links NPC1/NPC2 cholesterol-export failure to lysosomal unesterified cholesterol accumulation.
  - target: Glycosphingolipid and Ganglioside Accumulation in Brain
    description: NPC1/NPC2 transport failure also leads to secondary glycosphingolipid accumulation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33445799
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY). Consequently, mutations in one of the two proteins lead to the accumulation of unesterified cholesterol and glycosphingolipids in LE/LY, displaying a disease hallmark."
      explanation: This review directly supports secondary glycosphingolipid accumulation downstream of NPC1/NPC2 transport failure.
  - target: Defective Cellular Autophagy
    description: Core cholesterol-trafficking failure is linked to defective cellular autophagy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26014711
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes."
      explanation: This review supports defective autophagy as a downstream consequence of the core NPC trafficking defect.
  evidence:
  - reference: PMID:33445799
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both NPC1 and NPC2 are proteins responsible for the exit of cholesterol from late endosomes and lysosomes (LE/LY)."
    explanation: This review directly identifies NPC1 and NPC2 as the proteins required for lysosomal cholesterol egress.
  - reference: PMID:9211849
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking."
    explanation: NPC1 cDNA rescues the cholesterol trafficking defect in patient fibroblasts.
- name: Lysosomal Unesterified Cholesterol Accumulation
  description: >
    Unesterified cholesterol accumulates in late endosomes and lysosomes as a
    defining storage abnormality in NPC.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:9211849
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol."
    explanation: The landmark NPC1 paper establishes lysosomal cholesterol accumulation as a defining disease abnormality.
- name: Glycosphingolipid and Ganglioside Accumulation in Brain
  description: >
    While cholesterol accumulates in peripheral tissues, the brain prominently
    accumulates glycosphingolipids including gangliosides GM2 and GM3. This
    ganglioside storage disrupts endosomal transport and is a major driver
    of neurodegeneration in NPC.
  cell_types:
  - preferred_term: Purkinje Cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Glycosphingolipid Catabolic Process
    term:
      id: GO:0046479
      label: glycosphingolipid catabolic process
  - preferred_term: Sphingolipid Catabolic Process
    term:
      id: GO:0030149
      label: sphingolipid catabolic process
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides."
    explanation: Vanier review confirms that gangliosides rather than cholesterol are the predominant storage material in the NPC brain.
  - reference: PMID:15078881
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "High pressure liquid chromatography and mass spectrometric analysis of NPC1(-/-) mouse brain revealed large increases in GSL."
    explanation: Mass spectrometry of NPC1-null mouse brain confirms glycosphingolipid accumulation.
- name: Cerebellar Purkinje Cell Degeneration
  description: >
    Progressive loss of cerebellar Purkinje cells is a hallmark neuropathological
    feature of NPC. Purkinje cells are particularly vulnerable to lipid
    accumulation and are among the earliest neuronal populations to degenerate.
  cell_types:
  - preferred_term: Purkinje Cell
    term:
      id: CL:0000121
      label: Purkinje cell
  evidence:
  - reference: PMID:28803710
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In preclinical testing, 2-hydroxypropyl-β-cyclodextrins (HPβCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1."
    explanation: Animal model data confirms that Purkinje cell loss is a central feature of NPC1 pathology that can be delayed with cyclodextrin treatment.
- name: Sphingosine Storage as Initiating Factor
  description: >
    Sphingosine accumulates in the acidic compartment of NPC1-mutant cells
    almost immediately upon NPC1 dysfunction, preceding cholesterol and other
    lipid storage. This sphingosine accumulation is proposed as an initiating
    factor in NPC pathogenesis that triggers secondary lipid storage.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Sphingolipid Catabolic Process
    term:
      id: GO:0030149
      label: sphingolipid catabolic process
  downstream:
  - target: Lysosomal Calcium Dysregulation
    description: Sphingosine storage depletes lysosomal calcium stores and perturbs calcium homeostasis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18953351
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol."
      explanation: This study directly links sphingosine accumulation to altered calcium homeostasis.
  evidence:
  - reference: PMID:18953351
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol."
    explanation: Lloyd-Evans et al. demonstrate that sphingosine accumulation in lysosomes is the initiating event driving secondary lipid storage in NPC.
- name: Lysosomal Calcium Dysregulation
  description: >
    NPC1-mutant cells have significantly reduced lysosomal calcium stores.
    This calcium depletion downstream of sphingosine accumulation causes
    secondary accumulation of cholesterol, sphingomyelin, and glycosphingolipids,
    linking calcium dysregulation to the broad lipid storage phenotype.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Intracellular Calcium Ion Homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
  evidence:
  - reference: PMID:18953351
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells."
    explanation: Lysosomal calcium stores are significantly reduced in NPC1-mutant cells, linking calcium dysregulation to lipid storage.
- name: Defective Cellular Autophagy
  description: >
    Impaired autophagic handling is an additional downstream mechanism in NPC
    that likely contributes to cellular dysfunction and disease progression.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: autophagy
    modifier: DYSREGULATED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:26014711
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Impaired cholesterol trafficking and unesterified cholesterol accumulation in the late endosomes and lysosomals, as a results of mutations in NPC1 or NPC2 genes, are initial for the disease, and defective cellular autophagy, defective lysosomal calcium homeostasis and oxidative stress may all play roles in the physiological processes."
    explanation: This review supports defective cellular autophagy as a secondary pathophysiologic mechanism in NPC downstream of the core cholesterol trafficking defect.
- name: Progressive Neurological Dysfunction
  description: >
    NPC neurological disease produces a broad syndrome of progressive brain
    dysfunction with bulbar, oculomotor, seizure, and cognitive manifestations.
  downstream:
  - target: Dysphagia
    description: Neurological dysfunction in NPC contributes directly to dysphagia and swallowing difficulty.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33924575
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected patients are mainly characterized by neurological dysfunction and liver damage. Neurological dysfunction causes many identifiable symptoms, including vertical supranuclear ophthalmoplegia, cataplexy, dysarthria, dysphagia, seizures, speaking and swallowing difficulty, and dementia."
      explanation: This review directly attributes dysphagia to NPC-related neurological dysfunction.
  - target: Seizures
    description: Progressive neurological dysfunction in NPC contributes directly to seizures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33924575
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected patients are mainly characterized by neurological dysfunction and liver damage. Neurological dysfunction causes many identifiable symptoms, including vertical supranuclear ophthalmoplegia, cataplexy, dysarthria, dysphagia, seizures, speaking and swallowing difficulty, and dementia."
      explanation: This review directly attributes seizures to NPC-related neurological dysfunction.
  - target: Progressive Dementia
    description: Ongoing neurological dysfunction contributes to progressive dementia in NPC.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33924575
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Affected patients are mainly characterized by neurological dysfunction and liver damage. Neurological dysfunction causes many identifiable symptoms, including vertical supranuclear ophthalmoplegia, cataplexy, dysarthria, dysphagia, seizures, speaking and swallowing difficulty, and dementia."
      explanation: This review directly attributes dementia to NPC-related neurological dysfunction.
  evidence:
  - reference: PMID:33924575
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected patients are mainly characterized by neurological dysfunction and liver damage."
    explanation: This review supports progressive neurological dysfunction as a major component of NPC disease biology.
- name: Tau Hyperphosphorylation and Neurofibrillary Tangles
  description: >
    NPC shares neuropathological features with Alzheimer disease including
    neurofibrillary tangle (NFT) formation from hyperphosphorylated tau protein.
    Plasma phosphorylated-tau217 is elevated in NPC and correlates with disease
    progression, suggesting tau pathology is an active disease marker.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Protein Phosphorylation
    term:
      id: GO:0006468
      label: protein phosphorylation
  evidence:
  - reference: PMID:39502943
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset"
    explanation: Elevated p-tau217 in NPC patients demonstrates active tau pathology paralleling Alzheimer-like neurodegeneration.
  - reference: PMID:39502943
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology."
    explanation: Confirms shared NFT pathology between NPC and Alzheimer disease.
phenotypes:
- name: Vertical Supranuclear Gaze Palsy
  category: Neurological
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Most characteristic neurological sign of NPC
  phenotype_term:
    preferred_term: Vertical supranuclear gaze palsy
    term:
      id: HP:0000511
      label: Vertical supranuclear gaze palsy
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most characteristic sign is vertical supranuclear gaze palsy."
    explanation: Vanier review identifies VSGP as the single most characteristic sign of NPC.
- name: Cerebellar Ataxia
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Progressive gait and limb ataxia, often presenting feature in childhood
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."
    explanation: Cerebellar ataxia is listed as one of the main neurological manifestations.
- name: Dysarthria
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."
    explanation: Dysarthria is a core neurological feature of NPC.
- name: Dysphagia
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Often leads to aspiration pneumonia, a major cause of death
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."
    explanation: Vanier review lists dysphagia as a core neurological feature of NPC.
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death from aspiration pneumonia usually occurs in the late second or third decade."
    explanation: GeneReviews confirms aspiration pneumonia from dysphagia as a major cause of death.
- name: Progressive Dementia
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Cognitive decline progresses to severe dementia
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."
    explanation: Progressive dementia is a core neurological feature of NPC.
- name: Dystonia
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cataplexy, seizures and dystonia are other common features."
    explanation: Dystonia is identified as a common neurological feature of NPC.
- name: Seizures
  category: Neurological
  frequency: FREQUENT
  notes: Epileptic seizures, more common in juvenile onset
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epileptic seizures are also common in affected patients."
    explanation: Patterson et al. guideline update confirms seizures are common in NPC.
- name: Gelastic Cataplexy
  category: Neurological
  frequency: FREQUENT
  diagnostic: true
  notes: Sudden loss of muscle tone triggered by laughter; highly suggestive of NPC
  phenotype_term:
    preferred_term: Gelastic cataplexy
    term:
      id: HP:0002524
      label: Cataplexy
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic neurological manifestations of NP-C include saccadic eye movement (SEM) abnormalities or vertical supranuclear gaze palsy (VSGP), cerebellar signs (ataxia, dystonia/dysmetria, dysarthria and dysphagia) and gelastic cataplexy."
    explanation: Patterson et al. guideline identifies gelastic cataplexy as a characteristic NPC manifestation.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  notes: Often presenting sign in infancy; may resolve but precedes neurological disease
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates."
    explanation: GeneReviews confirms hepatosplenomegaly as a presenting feature in perinatal/infantile NPC.
- name: Neonatal Cholestasis
  category: Gastrointestinal
  frequency: FREQUENT
  notes: Present in perinatal/infantile onset; may resolve spontaneously
  phenotype_term:
    preferred_term: Neonatal cholestatic liver disease
    term:
      id: HP:0006566
      label: Neonatal cholestatic liver disease
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates."
    explanation: Cholestatic jaundice is a key early visceral manifestation of NPC.
- name: Psychiatric Manifestations
  category: Psychiatric
  frequency: FREQUENT
  notes: More common in adolescent/adult-onset NPC; may be the initial presentation
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an increasing number of cases are being detected and diagnosed during adulthood based on late-onset neurological signs and psychiatric manifestations."
    explanation: Patterson guidelines confirm psychiatric manifestations as a presentation in adult-onset NPC.
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ataxia not unfrequently following initial psychiatric disturbances (adult form)."
    explanation: Vanier review identifies psychiatric disturbances as a common initial presentation in adult-onset NPC.
- name: Neurofibrillary Tangles
  category: Neuropathological
  frequency: VERY_FREQUENT
  notes: Alzheimer-like tau pathology; shared between NPC and Alzheimer disease
  phenotype_term:
    preferred_term: Neurofibrillary tangles
    term:
      id: HP:0002185
      label: Neurofibrillary tangles
  evidence:
  - reference: PMID:39502943
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology."
    explanation: NFT pathology is a confirmed shared neuropathological feature of NPC.
biochemical:
- name: Unesterified Cholesterol Accumulation
  presence: Elevated
  context: >
    Filipin staining of skin fibroblasts shows accumulation of unesterified
    cholesterol in perinuclear vesicles (lysosomes). Pronounced abnormalities
    in approximately 80% of cases.
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin."
    explanation: Filipin staining of fibroblasts is the classic diagnostic test demonstrating cholesterol accumulation.
- name: Plasma 24(S)-Hydroxycholesterol
  presence: Elevated
  context: >
    Plasma 24(S)-hydroxycholesterol serves as a pharmacodynamic biomarker
    reflecting neuronal cholesterol homeostasis in NPC clinical trials.
  evidence:
  - reference: PMID:28803710
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0·0063) and 1200 mg (p=0·0037)."
    explanation: 24(S)-HC serves as a validated biomarker of neuronal cholesterol homeostasis in NPC clinical trials.
- name: Sphingosine Accumulation
  presence: Elevated
  context: >
    Sphingosine accumulates in the lysosomal compartment of NPC cells almost
    immediately upon NPC1 dysfunction, preceding cholesterol and other lipid
    storage. Proposed as an initiating factor in NPC pathogenesis.
  evidence:
  - reference: PMID:18953351
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate"
    explanation: Multiple lipid species including sphingosine accumulate in NPC1-mutant cells.
- name: Plasma Phosphorylated-Tau217
  presence: Elevated
  context: >
    Plasma p-tau217 is elevated in NPC patients compared to controls and
    correlates with disease severity and rate of progression. Represents a
    potential blood-based biomarker for monitoring NPC.
  evidence:
  - reference: PMID:39502943
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset"
    explanation: Plasma p-tau217 is significantly elevated in NPC and tracks disease severity.
genetic:
- name: NPC1
  association: Causative
  gene_term:
    preferred_term: NPC1
    term:
      id: hgnc:7897
      label: NPC1
  notes: >
    Autosomal recessive. Accounts for 95% of NPC cases. Located on chromosome 18q11.
    Encodes a 1278-amino acid transmembrane protein with a sterol-sensing domain.
    The protein contains homology to PATCHED and SCAP.
  evidence:
  - reference: PMID:9211849
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients."
    explanation: Landmark paper identifying NPC1 as the causative gene by positional cloning.
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues."
    explanation: Patterson guidelines confirm NPC1 accounts for 95% and NPC2 for 5% of cases.
- name: NPC2
  association: Causative
  gene_term:
    preferred_term: NPC2
    term:
      id: hgnc:7898
      label: NPC2
  notes: >
    Autosomal recessive. Accounts for approximately 5% of cases. Encodes a small
    soluble lysosomal protein that binds cholesterol and works cooperatively
    with NPC1.
  evidence:
  - reference: PMID:22572546
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene (in around 5% of cases), which lead to impaired intracellular lipid trafficking and accumulation of cholesterol and glycosphingolipids in the brain and other tissues."
    explanation: Patterson guidelines confirm NPC2 accounts for approximately 5% of NPC cases.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews confirms autosomal recessive inheritance with standard Mendelian ratios.
treatments:
- name: Miglustat
  description: >
    Substrate reduction therapy approved in Europe and several other countries
    for treatment of neurological manifestations. Inhibits glucosylceramide
    synthase to reduce glycosphingolipid accumulation.
  treatment_term:
    preferred_term: miglustat therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:20525256
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations."
    explanation: Vanier review confirms miglustat authorization for NPC neurological manifestations.
- name: Intrathecal 2-Hydroxypropyl-Beta-Cyclodextrin
  description: >
    HPbCD given by lumbar intrathecal injection mobilizes cholesterol from
    lysosomes. Phase 1-2 trial showed slowed neurological disease progression
    compared to natural history.
  treatment_term:
    preferred_term: intrathecal cyclodextrin therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:28803710
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with NPC1 treated with intrathecal HPβCD had slowed disease progression with an acceptable safety profile."
    explanation: Phase 1-2 trial demonstrates intrathecal HPbCD slows neurological progression in NPC1.
- name: Levacetylleucine
  description: >
    FDA-approved standalone treatment for NPC.
  treatment_term:
    preferred_term: levacetylleucine therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews confirms FDA approval of levacetylleucine as standalone therapy for NPC.
- name: Arimoclomol
  description: >
    Co-inducer of heat shock proteins, approved for use in combination with
    miglustat for NPC. Enhances cellular stress response and may improve
    protein folding and lysosomal function.
  treatment_term:
    preferred_term: arimoclomol therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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)."
    explanation: GeneReviews confirms arimoclomol is approved for NPC in combination with miglustat.
- name: Supportive Care
  description: >
    Multidisciplinary management including neurology, physical therapy,
    occupational therapy, speech therapy, nutrition support, and seizure
    management.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews outlines the multidisciplinary supportive care approach for NPC.
- name: Genetic Counseling
  description: >
    Family screening, carrier testing, and prenatal/preimplantation genetic
    testing for at-risk relatives.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:20301473
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: GeneReviews confirms genetic testing for at-risk relatives is recommended.
datasets: []