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Inheritance

1

Autosomal Recessive HP:0000007

Autosomal recessive inheritance

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"Autosomal recessive"

Orphanet confirms autosomal recessive inheritance for NPC.

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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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Mechanistic Hypotheses

1

Canonical NPC1/NPC2 Cholesterol & Lipid Lysosomal Trafficking Model

canonical_npc1_npc2_cholesterol_lysosomal_trafficking_model CANONICAL

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal cholesterol-trafficking disorder caused by loss-of-function variants in NPC1 (~95%) or NPC2 (~5%) encoding complementary late-endosomal / lysosomal membrane proteins that mediate egress of unesterified cholesterol from the lysosome. Loss of NPC1/NPC2 function produces lysosomal accumulation of unesterified cholesterol, sphingomyelin, glycosphingolipids, and sphingosine, dysregulating endolysosomal homeostasis, autophagy, calcium signaling, and synaptic function. The resulting phenotype is highly heterogeneous, including neonatal cholestatic hepatosplenomegaly, progressive neurologic regression (vertical supranuclear gaze palsy, cerebellar ataxia, dystonia, seizures, dementia), and psychiatric features. Miglustat (substrate reduction, EU/UK approved), arimoclomol, 2-hydroxypropyl-β- cyclodextrin (intrathecal), and acetyl-DL-leucine (Aqneursa, FDA-approved 2024) corroborate the cholesterol/sphingolipid-trafficking axis as the canonical pathogenic mechanism.

Retained as CANONICAL with important scope qualifiers. The 2026 falcon hypothesis-search report (kb/hypotheses/Niemann_Pick_Disease_Type_C/canonical_npc1_npc2_cholesterol_lysosomal_trafficking_model; openscientist timed out at 3600s) finds SUPPORTED. The canonical NPC1 (lysosomal membrane) / NPC2 (lysosomal lumen) chain → blocked LDL-derived cholesterol egress → lysosomal cholesterol/sphingolipid storage → multisystem dysfunction is strongly validated. Recent extensions: (1) NPC1 directly interacts with and mediates SPHINGOSINE export in addition to cholesterol, indicating multi-lipid export biology; (2) more explicit downstream causal links to neurodegeneration via organelle contact-site dysfunction, Ca²⁺ dysregulation, and cell-type-specific neuron/microglia vulnerabilities. Three caveats: (1) some downstream steps (autophagy impairment, Ca²⁺ defects, neuroinflammation) remain incompletely ordered causally in humans; (2) therapy-linked biomarker changes (cholesterol mobilization with 2-hydroxypropyl-β-cyclodextrin, miglustat) show target engagement but inconsistent linkage to neuronal-injury markers across small cohorts; (3) tissue specificity is substantial — e.g., lung-restricted cholesterol accumulation from TMEM241 perturbation — indicating modifiers/upstream dependencies beyond NPC1/NPC2 genotype alone. Acetyl-DL-leucine (Aqneursa, FDA 2024) and arimoclomol further validate the lipid-trafficking axis.

Deep research

Falcon citations 40 citations 2026-05-25T12:34:44.444489

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 accum"

Existing canonical mechanism citation in the dismech knowledge base, used as the seed for the hypothesis-search deep-research run.

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Pathophysiology

10

NPC1/NPC2-Mediated Cholesterol Egress Failure

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

Hepatocyte CL:0000182 Neuron CL:0000540

NPC1 hgnc:7897 NPC2 hgnc:14537

Intracellular Cholesterol Transport GO:0032367 Lipid Transport GO:0006869

cholesterol transfer activity GO:0120020

Downstream

Lysosomal Unesterified Cholesterol Accumulation Failed cholesterol egress leads directly to lysosomal cholesterol storage.

Glycosphingolipid and Ganglioside Accumulation in Brain NPC1/NPC2 transport failure also leads to secondary glycosphingolipid accumulation.

Defective Cellular Autophagy Core cholesterol-trafficking failure is linked to defective cellular autophagy.

Sphingosine Storage as Initiating Factor NPC1/NPC2 trafficking failure is modeled upstream of early lysosomal sphingosine storage.

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 CL:0000182 Neuron CL:0000540

Downstream

Unesterified Cholesterol Accumulation

Low Cholesterol Esterification Rate Cholesterol trapped in lysosomes is unavailable for normal esterification in NPC fibroblasts.

Plasma 24(S)-Hydroxycholesterol Disturbed neuronal cholesterol handling is reflected by oxysterol biomarker changes.

Hepatosplenomegaly Visceral cholesterol and lipid storage contribute to liver and spleen enlargement.

Hepatomegaly

Splenomegaly

Neonatal Cholestasis Infantile hepatic storage disease produces cholestatic liver involvement.

Jaundice Neonatal cholestasis manifests clinically as prolonged jaundice.

Bone-Marrow Foam Cells Stored lipids in tissue macrophages produce foam cells and sea-blue histiocytes.

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 CL:0000121 Neuron CL:0000540

Glycosphingolipid Catabolic Process GO:0046479 Sphingolipid Catabolic Process GO:0030149

Downstream

Cerebellar Purkinje Cell Degeneration Ganglioside and glycosphingolipid storage contributes to selective neuronal vulnerability in the cerebellum.

Progressive Neurological Dysfunction Brain lipid storage drives the progressive neurologic syndrome in NPC.

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 CL:0000121

Downstream

Cerebellar Ataxia

Gait Disturbance Purkinje cell loss produces cerebellar gait and coordination impairment.

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 CL:0000540

Sphingolipid Catabolic Process GO:0030149

Downstream

Lysosomal Calcium Dysregulation Sphingosine storage depletes lysosomal calcium stores and perturbs calcium homeostasis.

Sphingosine Accumulation

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 CL:0000540

Intracellular Calcium Ion Homeostasis GO:0006874

Downstream

Lysosomal Unesterified Cholesterol Accumulation Altered lysosomal calcium homeostasis contributes to secondary cholesterol storage.

Glycosphingolipid and Ganglioside Accumulation in Brain Altered lysosomal calcium homeostasis contributes to secondary sphingolipid and ganglioside storage.

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 CL:0000540

autophagy GO:0006914 ↕ DYSREGULATED

Downstream

Progressive Neurological Dysfunction Defective lysosomal autophagy contributes to neuronal dysfunction and disease progression.

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.

Downstream

Dysphagia Neurological dysfunction in NPC contributes directly to dysphagia and swallowing difficulty.

Seizures Progressive neurological dysfunction in NPC contributes directly to seizures.

Progressive Mental Deterioration Ongoing neurological dysfunction contributes to progressive dementia and mental deterioration in NPC.

Vertical Supranuclear Gaze Palsy

Dysarthria

Dystonia

Gelastic Cataplexy

Psychiatric Manifestations Adult-onset NPC can present with psychiatric manifestations before or alongside neurologic decline.

Hearing Impairment Hearing impairment is a recurrent neurologic/sensory manifestation, but the proximal path in this graph is not separated.

Progressive Neurologic Deterioration

Cognitive Impairment

Dysphonia Bulbar neurologic dysfunction contributes to voice impairment.

Feeding Difficulties Bulbar dysfunction and dysphagia contribute to feeding problems.

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

NPC neurons develop hyperphosphorylated tau protein, paralleling Alzheimer-like tau pathology. Plasma phosphorylated-tau217 is elevated in NPC and inversely correlates with age at disease onset, indicating active tau phosphorylation as a disease process.

Neuron CL:0000540

Protein Phosphorylation GO:0006468 ↑ INCREASED

Downstream

Neurofibrillary Tangle Formation Hyperphosphorylated tau aggregates into insoluble neurofibrillary tangles.

Plasma Phosphorylated-Tau217 Plasma p-tau217 is modeled as a blood biomarker reflecting tau pathology, not as a causal downstream disease mechanism.

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"

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

Neurofibrillary Tangle Formation

Hyperphosphorylated tau aggregates into insoluble intraneuronal neurofibrillary tangles, a neuropathological lesion that NPC shares with Alzheimer disease.

Neuron CL:0000540

neurofibrillary tangle assembly GO:1902988 ↑ INCREASED

Downstream

Neurofibrillary Tangles

Progressive Mental Deterioration Tau pathology is modeled as one contributor to cognitive decline in NPC.

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."

Confirms shared NFT pathology between NPC and Alzheimer disease.

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Pathograph

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Phenotypes

22

Cardiovascular 2

Hepatosplenomegaly OCCASIONAL Hepatosplenomegaly HP:0001433

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

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"HP:0001433 | Hepatosplenomegaly | Occasional (29-5%)"

Orphanet reports hepatosplenomegaly as occasional (29-5%) in NPC; hepatomegaly alone (HP:0002240) is rated very frequent.

Splenomegaly FREQUENT Splenomegaly HP:0001744

Isolated splenomegaly may be presenting sign; Orphanet definition notes isolated unexplained splenomegaly

Show evidence (2 references)

ORPHA:646 SUPPORT Human Clinical

"HP:0001744 | Splenomegaly | Frequent (79-30%)"

Orphanet reports splenomegaly as frequent (79-30%) in NPC.

ORPHA:646 SUPPORT Human Clinical

"isolated unexplained splenomegaly"

Orphanet definition notes isolated unexplained splenomegaly as a characteristic clinical sign.

Digestive 5

Dysphagia VERY_FREQUENT Dysphagia HP:0002015

Often leads to aspiration pneumonia, a major cause of death

Show evidence (3 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.

ORPHA:646 SUPPORT Human Clinical

"HP:0002015 | Dysphagia | Very frequent (99-80%)"

Orphanet reports dysphagia as very frequent (99-80%) in NPC.

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.

Hepatomegaly VERY_FREQUENT Hepatomegaly HP:0002240

Isolated hepatomegaly more common than combined hepatosplenomegaly across all age groups

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0002240 | Hepatomegaly | Very frequent (99-80%)"

Orphanet reports hepatomegaly as very frequent (99-80%) in NPC.

Jaundice VERY_FREQUENT Jaundice HP:0000952

Neonatal jaundice frequently presenting sign; overlaps with neonatal cholestasis

Show evidence (2 references)

ORPHA:646 SUPPORT Human Clinical

"HP:0000952 | Jaundice | Very frequent (99-80%)"

Orphanet reports jaundice as very frequent (99-80%) in NPC.

ORPHA:646 SUPPORT Human Clinical

"prolonged unexplained neonatal jaundice or cholestasis"

Orphanet definition highlights prolonged neonatal jaundice as a characteristic sign.

Feeding Difficulties FREQUENT Feeding difficulties HP:0011968

Includes poor feeding in infancy and progressive swallowing difficulty

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0011968 | Feeding difficulties | Frequent (79-30%)"

Orphanet reports feeding difficulties as frequent (79-30%) in NPC.

Ear 1

Hearing Impairment FREQUENT Hearing impairment HP:0000365

Sensorineural hearing loss reported in NPC patients

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0000365 | Hearing impairment | Frequent (79-30%)"

Orphanet reports hearing impairment as frequent (79-30%) in NPC.

Eye 1

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

Most characteristic neurological sign of NPC

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"HP:0000511 | Vertical supranuclear gaze palsy | Very frequent (99-80%)"

Orphanet confirms VSGP as very frequent (99-80%) in NPC.

Nervous System 11

Cerebellar Ataxia FREQUENT Progressive cerebellar ataxia HP:0002073

Progressive gait and limb ataxia, often presenting feature in childhood

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"HP:0001251 | Ataxia | Frequent (79-30%)"

Orphanet reports ataxia as frequent (79-30%) in NPC.

Dysarthria FREQUENT Dysarthria HP:0001260

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"HP:0001260 | Dysarthria | Frequent (79-30%)"

Orphanet reports dysarthria as frequent (79-30%) in NPC.

Progressive Mental Deterioration VERY_FREQUENT Mental deterioration HP:0001268

Progressive cognitive decline is a hallmark of NPC

Show evidence (2 references)

PMID:20525256 SUPPORT Human Clinical

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

Progressive cognitive decline is a core neurological feature of NPC.

ORPHA:646 SUPPORT Human Clinical

"HP:0001268 | Mental deterioration | Very frequent (99-80%)"

Orphanet reports mental deterioration as very frequent (99-80%) in NPC.

Dystonia FREQUENT Dystonia HP:0001332

Show evidence (2 references)

PMID:20525256 SUPPORT Human Clinical

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

Dystonia is identified as a common neurological feature of NPC.

ORPHA:646 SUPPORT Human Clinical

"HP:0001332 | Dystonia | Frequent (79-30%)"

Orphanet reports dystonia as frequent (79-30%) in NPC.

Seizures FREQUENT Seizure HP:0001250

Epileptic seizures, more common in juvenile onset

Show evidence (2 references)

PMID:22572546 SUPPORT Human Clinical

"Epileptic seizures are also common in affected patients."

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

ORPHA:646 SUPPORT Human Clinical

"HP:0001250 | Seizure | Frequent (79-30%)"

Orphanet reports seizures as frequent (79-30%) in NPC.

Gelastic Cataplexy OCCASIONAL Cataplexy HP:0002524

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

Show evidence (2 references)

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.

ORPHA:646 SUPPORT Human Clinical

"HP:0002524 | Cataplexy | Occasional (29-5%)"

Orphanet reports cataplexy as occasional (29-5%) in NPC.

Psychiatric Manifestations OCCASIONAL Psychosis HP:0000709

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

Show evidence (3 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.

ORPHA:646 SUPPORT Human Clinical

"HP:0000709 | Psychosis | Occasional (29-5%)"

Orphanet reports psychosis as occasional (29-5%) in 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.

Gait Disturbance VERY_FREQUENT Gait disturbance HP:0001288

Progressive gait abnormality related to cerebellar and extrapyramidal dysfunction

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0001288 | Gait disturbance | Very frequent (99-80%)"

Orphanet reports gait disturbance as very frequent (99-80%) in NPC.

Progressive Neurologic Deterioration VERY_FREQUENT Progressive neurologic deterioration HP:0002344

Hallmark of NPC; rate depends on age of onset

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0002344 | Progressive neurologic deterioration | Very frequent (99-80%)"

Orphanet reports progressive neurologic deterioration as very frequent (99-80%) in NPC.

Cognitive Impairment FREQUENT Cognitive impairment HP:0100543

Ranges from learning difficulties to frank dementia depending on age of onset

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0100543 | Cognitive impairment | Frequent (79-30%)"

Orphanet reports cognitive impairment as frequent (79-30%) in NPC.

Other 2

Bone-Marrow Foam Cells FREQUENT Bone-marrow foam cells HP:0004333

Sea-blue histiocytes / foam cells in bone marrow; diagnostically suggestive

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0004333 | Bone-marrow foam cells | Frequent (79-30%)"

Orphanet reports bone-marrow foam cells as frequent (79-30%) in NPC.

Dysphonia FREQUENT Dysphonia HP:0001618

Voice abnormality from bulbar dysfunction

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0001618 | Dysphonia | Frequent (79-30%)"

Orphanet reports dysphonia as frequent (79-30%) in NPC.

🧬

Genetic Associations

2

NPC1 (Causative)

Gene: NPC1 hgnc:7897

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)

Gene: NPC2 hgnc:14537

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.

💊

Medical Actions

6

Miglustat

Action: miglustat therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: miglustat CHEBI:50381

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

Mechanism Target:

INHIBITS Glycosphingolipid and Ganglioside Accumulation in Brain — Miglustat inhibits glucosylceramide synthase to reduce glycosphingolipid substrate 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 NCIT:C15986

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

Mechanism Target:

MODULATES Lysosomal Unesterified Cholesterol Accumulation — Intrathecal HPbCD mobilizes cholesterol from lysosomes and modifies the core storage abnormality.

MODULATES Progressive Neurological Dysfunction — Clinical trial evidence supports slowed neurologic disease progression.

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 NCIT:C15986

Agent: levacetylleucine CHEBI:17786

FDA-approved standalone treatment for NPC.

Mechanism Target:

MODULATES Progressive Neurological Dysfunction — Levacetylleucine is modeled as symptomatic neurologic therapy rather than correction of lysosomal lipid trafficking.

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 NCIT:C15986

Agent: arimoclomol CHEBI:747211

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.

Mechanism Target:

MODULATES Progressive Neurological Dysfunction — Arimoclomol is approved for neurologic manifestations in combination with miglustat.

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.

🔬

Biochemical Markers

5

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.

Low Cholesterol Esterification Rate (Abnormal)

Context: Impaired esterification of LDL-derived cholesterol is a hallmark biochemical abnormality in NPC fibroblasts, reflecting the underlying cholesterol trafficking defect. Used as a diagnostic marker.

Show evidence (1 reference)

ORPHA:646 SUPPORT Human Clinical

"HP:0003349 | Low cholesterol esterification rate | Very frequent (99-80%)"

Orphanet reports low cholesterol esterification rate as very frequent (99-80%) in NPC.

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

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name: Niemann-Pick Disease Type C
creation_date: '2026-03-14T00:00:00Z'
updated_date: '2026-05-06T23:30:45Z'
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
    reference_title: Consensus clinical management guidelines for Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1-9 / 1 000 000 | Australia | Prevalence at birth | PMID:9918480"
    explanation: Orphanet epidemiology confirms prevalence at birth of 1-9 per million in Australia.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1-9 / 1 000 000 | France | Prevalence at birth | PMID:20525256,PMID:12974729,EXPERT"
    explanation: Orphanet epidemiology confirms prevalence at birth of 1-9 per million in France.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1-9 / 100 000 | Portugal | Prevalence at birth | PMID:14685153"
    explanation: Orphanet epidemiology indicates higher prevalence at birth of 1-9 per 100,000 in Portugal.
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
    reference_title: Niemann-Pick Disease Type C.
    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
    reference_title: Niemann-Pick Disease Type C.
    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
    reference_title: Niemann-Pick disease type C.
    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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_npc1_npc2_cholesterol_lysosomal_trafficking_model
  hypothesis_label: Canonical NPC1/NPC2 Cholesterol & Lipid Lysosomal Trafficking Model
  status: CANONICAL
  description: >-
    Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal cholesterol-trafficking
    disorder caused by loss-of-function variants in NPC1 (~95%) or NPC2 (~5%) encoding complementary
    late-endosomal / lysosomal membrane proteins that mediate egress of unesterified cholesterol from
    the lysosome. Loss of NPC1/NPC2 function produces lysosomal accumulation of unesterified
    cholesterol, sphingomyelin, glycosphingolipids, and sphingosine, dysregulating endolysosomal
    homeostasis, autophagy, calcium signaling, and synaptic function. The resulting phenotype is highly
    heterogeneous, including neonatal cholestatic hepatosplenomegaly, progressive neurologic regression
    (vertical supranuclear gaze palsy, cerebellar ataxia, dystonia, seizures, dementia), and psychiatric
    features. Miglustat (substrate reduction, EU/UK approved), arimoclomol, 2-hydroxypropyl-β-
    cyclodextrin (intrathecal), and acetyl-DL-leucine (Aqneursa, FDA-approved 2024) corroborate the
    cholesterol/sphingolipid-trafficking axis as the canonical pathogenic mechanism.
  notes: >-
    Retained as CANONICAL with important scope
    qualifiers. The 2026 falcon hypothesis-search report
    (kb/hypotheses/Niemann_Pick_Disease_Type_C/canonical_npc1_npc2_cholesterol_lysosomal_trafficking_model;
    openscientist timed out at 3600s) finds SUPPORTED. The
    canonical NPC1 (lysosomal membrane) / NPC2 (lysosomal lumen)
    chain → blocked LDL-derived cholesterol egress → lysosomal
    cholesterol/sphingolipid storage → multisystem dysfunction
    is strongly validated. Recent extensions: (1) NPC1 directly
    interacts with and mediates SPHINGOSINE export in addition to
    cholesterol, indicating multi-lipid export biology; (2) more
    explicit downstream causal links to neurodegeneration via
    organelle contact-site dysfunction, Ca²⁺ dysregulation, and
    cell-type-specific neuron/microglia vulnerabilities. Three
    caveats: (1) some downstream steps (autophagy impairment,
    Ca²⁺ defects, neuroinflammation) remain incompletely ordered
    causally in humans; (2) therapy-linked biomarker changes
    (cholesterol mobilization with 2-hydroxypropyl-β-cyclodextrin,
    miglustat) show target engagement but inconsistent linkage
    to neuronal-injury markers across small cohorts;
    (3) tissue specificity is substantial — e.g., lung-restricted
    cholesterol accumulation from TMEM241 perturbation —
    indicating modifiers/upstream dependencies beyond NPC1/NPC2
    genotype alone. Acetyl-DL-leucine (Aqneursa, FDA 2024) and
    arimoclomol further validate the lipid-trafficking axis.
  evidence:
  - reference: PMID:22572546
    reference_title: "Niemann-Pick disease type C."
    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 accum"
    explanation: >
      Existing canonical mechanism citation in the dismech
      knowledge base, used as the seed for the hypothesis-search
      deep-research run.
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:14537
      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
      reference_title: Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.
      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
      reference_title: Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.
      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
      reference_title: '[Research advances in diagnosis and therapy of Niemann-Pick disease type C].'
      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.
  - target: Sphingosine Storage as Initiating Factor
    description: NPC1/NPC2 trafficking failure is modeled upstream of early lysosomal sphingosine storage.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33445799
    reference_title: Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1.
    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
    reference_title: 'Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.'
    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
    reference_title: 'Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.'
    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.
  downstream:
  - target: Unesterified Cholesterol Accumulation
    causal_link_type: DIRECT
  - target: Low Cholesterol Esterification Rate
    causal_link_type: DIRECT
    description: Cholesterol trapped in lysosomes is unavailable for normal esterification in NPC fibroblasts.
  - target: Plasma 24(S)-Hydroxycholesterol
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Disturbed neuronal cholesterol handling is reflected by oxysterol biomarker changes.
  - target: Hepatosplenomegaly
    causal_link_type: DIRECT
    description: Visceral cholesterol and lipid storage contribute to liver and spleen enlargement.
  - target: Hepatomegaly
    causal_link_type: DIRECT
  - target: Splenomegaly
    causal_link_type: DIRECT
  - target: Neonatal Cholestasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Infantile hepatic storage disease produces cholestatic liver involvement.
  - target: Jaundice
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Neonatal cholestasis manifests clinically as prolonged jaundice.
  - target: Bone-Marrow Foam Cells
    causal_link_type: DIRECT
    description: Stored lipids in tissue macrophages produce foam cells and sea-blue histiocytes.
- 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
    reference_title: Niemann-Pick disease type C.
    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
    reference_title: Accumulation of glycosphingolipids in Niemann-Pick C disease disrupts endosomal transport.
    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.
  downstream:
  - target: Cerebellar Purkinje Cell Degeneration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Ganglioside and glycosphingolipid storage contributes to selective neuronal vulnerability in the cerebellum.
  - target: Progressive Neurological Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Brain lipid storage drives the progressive neurologic syndrome in NPC.
- 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
    reference_title: 'Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.'
    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.
  downstream:
  - target: Cerebellar Ataxia
    causal_link_type: DIRECT
  - target: Gait Disturbance
    causal_link_type: DIRECT
    description: Purkinje cell loss produces cerebellar gait and coordination impairment.
- 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
      reference_title: Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.
      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.
  - target: Sphingosine Accumulation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:18953351
    reference_title: Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.
    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
    reference_title: Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.
    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.
  downstream:
  - target: Lysosomal Unesterified Cholesterol Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Altered lysosomal calcium homeostasis contributes to secondary cholesterol storage.
  - target: Glycosphingolipid and Ganglioside Accumulation in Brain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Altered lysosomal calcium homeostasis contributes to secondary sphingolipid and ganglioside 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
    reference_title: '[Research advances in diagnosis and therapy of Niemann-Pick disease type C].'
    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.
  downstream:
  - target: Progressive Neurological Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Defective lysosomal autophagy contributes to neuronal dysfunction and disease progression.
- 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
      reference_title: Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T.
      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
      reference_title: Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T.
      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 Mental Deterioration
    description: Ongoing neurological dysfunction contributes to progressive dementia and mental deterioration in NPC.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33924575
      reference_title: Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T.
      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.
  - target: Vertical Supranuclear Gaze Palsy
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Gelastic Cataplexy
    causal_link_type: DIRECT
  - target: Psychiatric Manifestations
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Adult-onset NPC can present with psychiatric manifestations before or alongside neurologic decline.
  - target: Hearing Impairment
    causal_link_type: UNKNOWN
    description: Hearing impairment is a recurrent neurologic/sensory manifestation, but the proximal path in this graph is not separated.
  - target: Progressive Neurologic Deterioration
    causal_link_type: DIRECT
  - target: Cognitive Impairment
    causal_link_type: DIRECT
  - target: Dysphonia
    causal_link_type: DIRECT
    description: Bulbar neurologic dysfunction contributes to voice impairment.
  - target: Feeding Difficulties
    causal_link_type: DIRECT
    description: Bulbar dysfunction and dysphagia contribute to feeding problems.
  evidence:
  - reference: PMID:33924575
    reference_title: Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T.
    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
  description: >-
    NPC neurons develop hyperphosphorylated tau protein, paralleling
    Alzheimer-like tau pathology. Plasma phosphorylated-tau217 is elevated in
    NPC and inversely correlates with age at disease onset, indicating active
    tau phosphorylation as a disease process.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: Protein Phosphorylation
    modifier: INCREASED
    term:
      id: GO:0006468
      label: protein phosphorylation
  evidence:
  - reference: PMID:39502943
    reference_title: Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.
    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 hyperphosphorylation paralleling Alzheimer-like neurodegeneration.
  downstream:
  - target: Neurofibrillary Tangle Formation
    causal_link_type: DIRECT
    description: Hyperphosphorylated tau aggregates into insoluble neurofibrillary tangles.
  - target: Plasma Phosphorylated-Tau217
    causal_link_type: UNKNOWN
    description: Plasma p-tau217 is modeled as a blood biomarker reflecting tau pathology, not as a causal downstream disease mechanism.
- name: Neurofibrillary Tangle Formation
  description: >-
    Hyperphosphorylated tau aggregates into insoluble intraneuronal
    neurofibrillary tangles, a neuropathological lesion that NPC shares with
    Alzheimer disease.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neurofibrillary tangle assembly
    modifier: INCREASED
    term:
      id: GO:1902988
      label: neurofibrillary tangle assembly
  evidence:
  - reference: PMID:39502943
    reference_title: Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.
    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.
  downstream:
  - target: Neurofibrillary Tangles
    causal_link_type: DIRECT
  - target: Progressive Mental Deterioration
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Tau pathology is modeled as one contributor to cognitive decline in NPC.
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
    reference_title: Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000511 | Vertical supranuclear gaze palsy | Very frequent (99-80%)"
    explanation: Orphanet confirms VSGP as very frequent (99-80%) in NPC.
- name: Cerebellar Ataxia
  category: Neurological
  frequency: 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
    reference_title: Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001251 | Ataxia | Frequent (79-30%)"
    explanation: Orphanet reports ataxia as frequent (79-30%) in NPC.
- name: Dysarthria
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20525256
    reference_title: Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001260 | Dysarthria | Frequent (79-30%)"
    explanation: Orphanet reports dysarthria as frequent (79-30%) in 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
    reference_title: Niemann-Pick disease type C.
    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
    reference_title: Niemann-Pick Disease Type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002015 | Dysphagia | Very frequent (99-80%)"
    explanation: Orphanet reports dysphagia as very frequent (99-80%) in NPC.
- name: Progressive Mental Deterioration
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Progressive cognitive decline is a hallmark of NPC
  phenotype_term:
    preferred_term: Mental deterioration
    term:
      id: HP:0001268
      label: Mental deterioration
  evidence:
  - reference: PMID:20525256
    reference_title: Niemann-Pick disease type C.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia."
    explanation: Progressive cognitive decline is a core neurological feature of NPC.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001268 | Mental deterioration | Very frequent (99-80%)"
    explanation: Orphanet reports mental deterioration as very frequent (99-80%) in NPC.
- name: Dystonia
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:20525256
    reference_title: Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001332 | Dystonia | Frequent (79-30%)"
    explanation: Orphanet reports dystonia as frequent (79-30%) in 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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001250 | Seizure | Frequent (79-30%)"
    explanation: Orphanet reports seizures as frequent (79-30%) in NPC.
- name: Gelastic Cataplexy
  category: Neurological
  frequency: OCCASIONAL
  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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002524 | Cataplexy | Occasional (29-5%)"
    explanation: Orphanet reports cataplexy as occasional (29-5%) in NPC.
- name: Hepatosplenomegaly
  category: Gastrointestinal
  frequency: OCCASIONAL
  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
    reference_title: Niemann-Pick Disease Type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001433 | Hepatosplenomegaly | Occasional (29-5%)"
    explanation: Orphanet reports hepatosplenomegaly as occasional (29-5%) in NPC; hepatomegaly alone (HP:0002240) is rated very frequent.
- 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
    reference_title: Niemann-Pick Disease Type C.
    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: OCCASIONAL
  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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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
    reference_title: Niemann-Pick disease type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000709 | Psychosis | Occasional (29-5%)"
    explanation: Orphanet reports psychosis as occasional (29-5%) in 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
    reference_title: Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.
    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.
- name: Hearing Impairment
  category: Neurological
  frequency: FREQUENT
  notes: Sensorineural hearing loss reported in NPC patients
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000365 | Hearing impairment | Frequent (79-30%)"
    explanation: Orphanet reports hearing impairment as frequent (79-30%) in NPC.
- name: Hepatomegaly
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  notes: Isolated hepatomegaly more common than combined hepatosplenomegaly across all age groups
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002240 | Hepatomegaly | Very frequent (99-80%)"
    explanation: Orphanet reports hepatomegaly as very frequent (99-80%) in NPC.
- name: Splenomegaly
  category: Gastrointestinal
  frequency: FREQUENT
  notes: Isolated splenomegaly may be presenting sign; Orphanet definition notes isolated unexplained splenomegaly
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
    explanation: Orphanet reports splenomegaly as frequent (79-30%) in NPC.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "isolated unexplained splenomegaly"
    explanation: Orphanet definition notes isolated unexplained splenomegaly as a characteristic clinical sign.
- name: Gait Disturbance
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Progressive gait abnormality related to cerebellar and extrapyramidal dysfunction
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001288 | Gait disturbance | Very frequent (99-80%)"
    explanation: Orphanet reports gait disturbance as very frequent (99-80%) in NPC.
- name: Jaundice
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  notes: Neonatal jaundice frequently presenting sign; overlaps with neonatal cholestasis
  phenotype_term:
    preferred_term: Jaundice
    term:
      id: HP:0000952
      label: Jaundice
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0000952 | Jaundice | Very frequent (99-80%)"
    explanation: Orphanet reports jaundice as very frequent (99-80%) in NPC.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prolonged unexplained neonatal jaundice or cholestasis"
    explanation: Orphanet definition highlights prolonged neonatal jaundice as a characteristic sign.
- name: Progressive Neurologic Deterioration
  category: Neurological
  frequency: VERY_FREQUENT
  notes: Hallmark of NPC; rate depends on age of onset
  phenotype_term:
    preferred_term: Progressive neurologic deterioration
    term:
      id: HP:0002344
      label: Progressive neurologic deterioration
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0002344 | Progressive neurologic deterioration | Very frequent (99-80%)"
    explanation: Orphanet reports progressive neurologic deterioration as very frequent (99-80%) in NPC.
- name: Bone-Marrow Foam Cells
  category: Hematologic
  frequency: FREQUENT
  notes: Sea-blue histiocytes / foam cells in bone marrow; diagnostically suggestive
  phenotype_term:
    preferred_term: Bone-marrow foam cells
    term:
      id: HP:0004333
      label: Bone-marrow foam cells
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0004333 | Bone-marrow foam cells | Frequent (79-30%)"
    explanation: Orphanet reports bone-marrow foam cells as frequent (79-30%) in NPC.
- name: Cognitive Impairment
  category: Neurological
  frequency: FREQUENT
  notes: Ranges from learning difficulties to frank dementia depending on age of onset
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0100543 | Cognitive impairment | Frequent (79-30%)"
    explanation: Orphanet reports cognitive impairment as frequent (79-30%) in NPC.
- name: Dysphonia
  category: Neurological
  frequency: FREQUENT
  notes: Voice abnormality from bulbar dysfunction
  phenotype_term:
    preferred_term: Dysphonia
    term:
      id: HP:0001618
      label: Dysphonia
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0001618 | Dysphonia | Frequent (79-30%)"
    explanation: Orphanet reports dysphonia as frequent (79-30%) in NPC.
- name: Feeding Difficulties
  category: Gastrointestinal
  frequency: FREQUENT
  notes: Includes poor feeding in infancy and progressive swallowing difficulty
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0011968 | Feeding difficulties | Frequent (79-30%)"
    explanation: Orphanet reports feeding difficulties as frequent (79-30%) in NPC.
biochemical:
- name: Unesterified Cholesterol Accumulation
  biomarker_term:
    preferred_term: Unesterified cholesterol
    term:
      id: CHEBI:16113
      label: cholesterol
  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
    reference_title: Niemann-Pick disease type C.
    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
  biomarker_term:
    preferred_term: Plasma 24(S)-hydroxycholesterol
    term:
      id: CHEBI:34310
      label: (24S)-24-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
    reference_title: 'Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.'
    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
  biomarker_term:
    preferred_term: Sphingosine
    term:
      id: CHEBI:16393
      label: sphingosine
  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
    reference_title: Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium.
    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: Low Cholesterol Esterification Rate
  presence: Abnormal
  context: >
    Impaired esterification of LDL-derived cholesterol is a hallmark biochemical
    abnormality in NPC fibroblasts, reflecting the underlying cholesterol trafficking
    defect. Used as a diagnostic marker.
  evidence:
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HP:0003349 | Low cholesterol esterification rate | Very frequent (99-80%)"
    explanation: Orphanet reports low cholesterol esterification rate as very frequent (99-80%) in NPC.
- name: Plasma Phosphorylated-Tau217
  biomarker_term:
    preferred_term: Plasma phosphorylated-tau217
    term:
      id: NCIT:C202389
      label: Phosphorylated Tau Protein 217 Measurement
  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
    reference_title: Plasma phosphorylated-tau217 is increased in Niemann-Pick disease type C.
    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
    reference_title: 'Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.'
    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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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:14537
      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
    reference_title: 'Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update.'
    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
    reference_title: Niemann-Pick Disease Type C.
    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.
  - reference: ORPHA:646
    reference_title: Niemann-Pick disease type C
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive"
    explanation: Orphanet confirms autosomal recessive inheritance for NPC.
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: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: miglustat
      term:
        id: CHEBI:50381
        label: miglustat
  target_mechanisms:
  - target: Glycosphingolipid and Ganglioside Accumulation in Brain
    treatment_effect: INHIBITS
    description: Miglustat inhibits glucosylceramide synthase to reduce glycosphingolipid substrate accumulation.
  evidence:
  - reference: PMID:20525256
    reference_title: Niemann-Pick disease type C.
    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: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Lysosomal Unesterified Cholesterol Accumulation
    treatment_effect: MODULATES
    description: Intrathecal HPbCD mobilizes cholesterol from lysosomes and modifies the core storage abnormality.
  - target: Progressive Neurological Dysfunction
    treatment_effect: MODULATES
    description: Clinical trial evidence supports slowed neurologic disease progression.
  evidence:
  - reference: PMID:28803710
    reference_title: 'Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial.'
    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: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levacetylleucine
      term:
        id: CHEBI:17786
        label: N-acetyl-L-leucine
  target_mechanisms:
  - target: Progressive Neurological Dysfunction
    treatment_effect: MODULATES
    description: Levacetylleucine is modeled as symptomatic neurologic therapy rather than correction of lysosomal lipid trafficking.
  evidence:
  - reference: PMID:20301473
    reference_title: Niemann-Pick Disease Type C.
    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: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: arimoclomol
      term:
        id: CHEBI:747211
        label: arimoclomol
  target_mechanisms:
  - target: Progressive Neurological Dysfunction
    treatment_effect: MODULATES
    description: Arimoclomol is approved for neurologic manifestations in combination with miglustat.
  evidence:
  - reference: PMID:20301473
    reference_title: Niemann-Pick Disease Type C.
    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
    reference_title: Niemann-Pick Disease Type C.
    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
    reference_title: Niemann-Pick Disease Type C.
    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: []
references:
- reference: PMID:20301473
  title: "Niemann-Pick Disease Type C."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:20301473

Niemann-Pick Disease Type C.

No top-level findings curated for this source.

Deep Research

1

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Niemann-Pick Disease Type C. Core disease mechanisms, molecular and cellul...

Asta Scientific Corpus Retrieval 20 citations 2026-03-30T17:39:00.120087

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Niemann-Pick Disease Type C. Core disease mechanisms, molecular and cellul...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

Authors: Masahiro Watanabe, Masamitsu Maekawa, Keitaro Miyoshi, Toshihiro Sato, Yu Sato et al.
Year: 2024
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/27c7aa8f74e2997a59b92b38aec1fb9ff9cbb608
DOI: 10.3390/metabo14100515
PMID: 39452896
PMCID: 11509386
Citations: 2
Summary: Several metabolite characteristics of Niemann-Pick disease type C that may fluctuate in a cellular model of the disease are identified using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry.
Evidence snippets:
Snippet 1 (score: 0.585) > Background: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by a functional deficiency of cholesterol transport proteins. However, the molecular mechanisms and pathophysiology of the disease remain unknown. Methods: In this study, we identified several metabolite characteristics of NPC that may fluctuate in a cellular model of the disease, using both global and targeted metabolomic analyses by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Three cell lines, HepG2 cells (wild-type[WT]) and two NPC model HepG2 cell lines in which NPC1 was genetically ablated (knockout [KO]1 and KO2), were used for metabolomic analysis. Data were subjected to enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Results: The enrichment analysis of global metabolomics revealed that 8 pathways in KO1 and 16 pathways in KO2 cells were notably altered. In targeted metabolomics for 15 metabolites, 4 metabolites in KO1 and 10 metabolites in KO2 exhibited statistically significant quantitative changes in KO1 or KO2 relative to WT. Most of the altered metabolites were related to creatinine synthesis and cysteine metabolism pathways. Conclusions: In the future, our objective will be to elucidate the relationship between these metabolic alterations and pathophysiology.

[2] Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T

Authors: Maik Liedtke, Christin Völkner, Alexandra V. Jürs, Franziska Peter, M. Rabenstein et al.
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/dece27ded976e5c321087cfd5cfa52c3675a3fee
DOI: 10.3390/ijms22084009
PMID: 33924575
PMCID: 8069078
Citations: 4
Summary: A profile of pathophysiological in vitro features, shared byNP-C1 and NP-C2, of neural differentiated cells obtained from the patient specific iPSCs is presented, suggesting that they do not suffer from oxidative stress and express catalase at a high level.
Evidence snippets:
Snippet 1 (score: 0.558) > Niemann-Pick type C (NP-C) disease is a hereditary disease caused by mutations in the NPC1 or NPC2 gene. The proteins NPC1 and NPC2 accomplish the exclusion of cholesterol from late endosomes and lysosomes and are essential for maintaining cellular cholesterol homeostasis [1]. Consequently, mutations in NPC1 or NPC2 result in pathophysiological accumulation of cholesterol and sphingolipids in lysosomes and late endosomes. Comparison of clinical and biochemical phenotypes in human patients disclosed no qualitative difference, proving that NPC1 and NPC2 proteins are essential for the transport of cholesterol in lysosomal compartments in a cooperative manner [2]. Clinical manifestation of Niemann-Pick type C1 (NP-C1) disease and Niemann-Pick type C2 (NP-C2) disease share several commonalities; however, about 95% of NP-C patients show mutations of the NPC1 gene and only 5% harbor mutations of the NPC2 gene [3]. Naturally, the knowledge of the clinical presentation of NP-C1 is much more advances than the knowledge of NP-C2. Progression and severity of NP-C1 pathophysiology depends on the onset of the disease, wherein an early onset (early infantile form) is commonly linked to a severe phenotype with systemic involvement and an early demise of patients. An onset of NP-C1 in childhood (late infantile/juvenile form) or adulthood (adolescence/adult form) is frequently related to a neurological phenotype, although this cannot be considered as a generalized rule as the clinical presentation is heterogeneous and a clear genotype; phenotype correlation for NP-C1 is not given [3]. Regarding NP-C2, clinical case reports cite an early death of patients accompanied frequently with severe lung deficiencies [4]. 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 [3].

[3] Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?

Authors: E. Piscianz, L. Vecchi Brumatti, A. Tommasini, A. Marcuzzi
Year: 2019
Venue: Neural Regeneration Research
URL: https://www.semanticscholar.org/paper/60ed5edaa8b3b324f6d871c79d22e936ee02d6e4
DOI: 10.4103/1673-5374.247441
PMID: 30632494
PMCID: 6352582
Citations: 5
Influential citations: 1
Summary: Manipulating the process of autophagy can offer possible strategies for improving neuronal cell viability and function in these genetic disorders.
Evidence snippets:
Snippet 1 (score: 0.546) > Niemann-Pick disease is a very severe rare genetic disorder, which belongs to the family of lysosomal storage diseases, a condition that affects many body systems. Patients with Niemann-Pick disease cannot metabolize cholesterol and other lipids properly, leading to abnormal accumulation of these substances in liver, spleen and other organs (Guo et al., 2016). > Niemann-Pick disease presents a broad clinical spectrum, depending on the degree of defect in lipid trafficking. The onset can be at birth with a fatal disorder, or in children or even adults, with milder phenotypes characterized by progressive psychomotor impairment, in addition to liver and spleen enlargement. The defect of cholesterol trafficking to mitochondria is associated to mitochondrial dysfunction and impairment in antioxidant defense strategies. Moreover, besides the neurodegenerative aspect of the disease, Niemann-Pick disease phenotype implies systemic features since non-esterified cholesterol accumulate also in liver and spleen (Vanier, 1999(Vanier, , 2010;;Patterson et al., 2012). Different genetic forms of Niemann-Pick disease are known and, in particular, Niemann-Pick disease type C (NPC) is caused by mutations in NPC1 (OMIM #257220, 95% of cases) (Carstea et al., 1993(Carstea et al., , 1997) ) and NPC2 genes (OMIM #607625, 5% of cases) (Naureckiene et al., 2000) resulting in functional defects of proteins with lysosomal localization (Torres et al., 2017;Liu and Lieberman, 2018) that trigger an accumulation of non-degraded substrates that interferes with different cellular functions (Sarkar et al., 2013). These molecular mechanisms are not fully elucidated yet, and a deepen knowledge of these processes is of crucial importance because each step of the pathogenetic cascade in Niemann-Pick disease may be a potential target of therapy (Schultz et al., 2018;Wang et al., 2018).

[4] Metabolic Alteration Analysis of Steroid Hormones in Niemann–Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry

Authors: Ai Abe, Masamitsu Maekawa, Toshihiro Sato, Yu Sato, Masaki Kumondai et al.
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/a31ba1a3e494b6af87a03ac9ea184c94a82802b9
DOI: 10.3390/ijms23084459
PMID: 35457276
PMCID: 9025463
Citations: 11
Summary: A comprehensive steroid hormone analysis method using liquid chromatography/tandem mass spectrometry (LC–MS/MS) and applied to analyze changes in steroid hormone concentrations in NPC model cells indicates that some steroid hormones change during NPC pathophysiology and this change is accompanied by mitochondrial abnormalities.
Evidence snippets:
Snippet 1 (score: 0.488) > Niemann-Pick disease type C (NPC) is an autosomal recessive disorder characterized by functional deficiencies affecting lysosomal cholesterol transport [1]. These deficits originate from a mutation in the NPC1 [2,3] or NPC2 genes [4,5], resulting in lipid accumulation [3,6] and the manifestation of various symptoms [1,[7][8][9]. The main symptoms associated with the systemic and central nervous system include hepatosplenomegaly, cholestasis, lung lesions, epilepsy, cognitive dysfunction, and ataxia [10]. Neuropathologically, it is characterized by progressive degeneration of nerve cells, particularly cerebellar Purkinje cells, and foam macrophage infiltration [11]. NPC therapeutic agents, such as miglustat and 2-hydroxypropyl-β-cyclodextrin, have been developed, and although the use of miglustat has been approved in some countries [12], 2-hydroxypropyl-β-cyclodextrin is still undergoing clinical trials [13]. Thus, despite various drug discovery approaches [14][15][16][17], clinical drug development has not yet been achieved. To date, the NPC pathology remains ambiguous, highlighting the necessity to explicate the associated underlying molecular mechanisms in an effort to overcome this disease. > Numerous studies have recently explored mitochondrial abnormalities in NPC. Briefly, these findings indicated that NPC-related lipid accumulation resulted in impaired autophagy, eventuating in abnormal mitochondrial activity [18][19][20][21]. Additionally, increased mitochondrial oxidative stress [22], downregulated ATP production [23], and reduced mitochondrial membrane potential have also been reported [24]. > Steroid hormones are vital bioactive metabolites derived from cholesterol, and are synthesized in the endoplasmic reticulum and mitochondria [25][26][27].

[5] Practical recommendations for diagnosis, management, and follow-up of Niemann-Pick type-C disease patients: a Brazilian perspective

Authors: D. Horovitz, A. Pessoa, Marcondes Cavalcanti França Júnior, Roberto Giugliani, C. F. Souza et al.
Year: 2024
Venue: Arquivos de Neuro-Psiquiatria
URL: https://www.semanticscholar.org/paper/f04b5f111939b479cc92ac171b23af0365ee772e
DOI: 10.1055/s-0045-1807714
PMID: 40345672
PMCID: 12064313
Citations: 2
Influential citations: 1
Summary: Recommendations include patient characteristics on clinical presentation, as systemic and neurological manifestations according to the age group and atypical manifestations; a flowchart for diagnostic confirmation, considering the Brazilian scenario; and treatment, encompassing disease-modifying therapy, supportive care, and patients' follow-up.
Evidence snippets:
Snippet 1 (score: 0.486) > Niemann-Pick type-C (NPC) disease is a rare genetic condition, caused by biallelic pathogenic variants in homozygosity or compound heterozygosity in any of two genes (NPC1 and NPC2) that encode proteins involved in the intralysosomal cholesterol trafficking. The clinical spectrum ranges from a fatal prenatal disorder to an adult-onset, chronic, neurodegenerative disease. The rare prevalence of the disease and the lack of specialized care lead to misdiagnosis or late diagnosis, in addition to barriers to proper care. Such aspects contribute to physical, psychological, and intellectual impairments, resulting in major disability. 1 Niemann-Pick type-C disease is a rare condition with an estimated incidence of 1 case per 100,000 live births. The disease is pan-ethnic, and pathogenic variants in the NPC1 gene cause at least 95% of all cases. 2 Burton et al. ( 2021) conducted a study to determine the disease prevalence in the United States and estimated 2.9 cases per million inhabitants. 3 The minimal incidence for Brazil was calculated as 0.304/100,000. 4 iemann-Pick type-C disease has a complex physiopathology, starting from a simple failure of cholesterol export, progressing via multiple pathways to affect numerous cellular functions and results leading to early cellular death. This multi-faceted pathology poses a difficult challenge to develop therapies for this disorder. 5 To date, as it happens with other rare disorders, no specific curative therapy is available, and NPC disease usually progresses to premature death. Miglustat, a substrate-reducing therapy, is the only disease-modifying drug approved in Brazil for treating neurological manifestations, attenuating, or even stopping disease progression. 7][8][9] The most recently published document proposes the use of supportive therapies in addition to miglustat for all patients with a confirmed diagnosis, except for those presymptomatic or presenting only an enlarged spleen or liver. In addition, diagnostic guidelines have been proposed. 8 ven the scarcity of information regarding NPC in Brazil, a group of experts was invited to discuss some disease-related aspects at the national level.

[6] δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

Authors: Miao Xu, Ke Liu, M. Swaroop, F. Porter, Rohini Sidhu et al.
Year: 2012
Venue: The Journal of Biological Chemistry
URL: https://www.semanticscholar.org/paper/5cc1f90c4676e68745524d4add44afc26b907f68
DOI: 10.1074/jbc.M112.357707
PMID: 23035117
Citations: 126
Influential citations: 6
Summary: The data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.
Evidence snippets:
Snippet 1 (score: 0.479) > Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that ␦-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a ␦-tocopherol-induced intracellular Ca 2؉ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that ␦-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases. > Niemann-Pick disease type C (NPC) 3 is caused by mutations in either the NPC1 or NPC2 gene, encoding two distinct lysosomal cholesterol-binding proteins (1,2). The NPC cellular phenotype is characterized by lysosomal accumulation of unesterified cholesterol and other lipids, resulting from impaired cholesterol export from the late endosomal and lysosomal compartments (2,3). Wolman disease is caused by mutations in the gene encoding lysosomal acid lipase (LAL). Deficiency of LAL function results in two distinct disease phenotypes that accumulate

[7] Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

Authors: S. Torres, Elisa Balboa, S. Zanlungo, C. Enrich, C. Garcia-Ruiz et al.
Year: 2017
Venue: Frontiers in Physiology
URL: https://www.semanticscholar.org/paper/fee7f30e342ac595aa3e669ce33743baa695f1f3
DOI: 10.3389/fphys.2017.00982
PMID: 29249985
PMCID: 5714892
Citations: 73
Influential citations: 2
Summary: A better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.
Evidence snippets:
Snippet 1 (score: 0.469) > Niemann-Pick (NP) diseases encompass a group of autosomal recessive lysosomal storage disorders (LSD), characterized by the accumulation of diverse lipid species in lysosomes. While these diseases were initially considered a single entity with overlapping biochemical, pathological and clinical features, developing evidence demonstrated differential etiological causes (Patterson and Walkley, 2017;Schuchman and Desnick, 2017). Niemann-Pick type A and B (NPA and NPB) diseases are caused by deficits in the activity of acid sphingomyelinase (ASMase), an enzyme that regulates lysosomal sphingomyelin (SM) homeostasis, while Niemann-Pick type C (NPC) disease is caused by mutations in NPC1 and NPC2 genes, resulting in functional defects in the lysosomal proteins NPC1 and NPC2, involved in cholesterol efflux from lysosomes. > Although the primary consequence of ASMase inactivation results in the accumulation of lysosomal SM, cholesterol and other lipids types, such as bis(monoacylglycero)phosphate, glucocerebroside, GM2 and GM3 gangliosides and sphingosine also accumulate in lysosomes (Rodriguez-Lafrasse et al., 1994;Vanier, 2013;Schuchman and Desnick, 2014). Similarly, although in NPC disease cholesterol accumulation is the direct consequence of NPC1/NPC2 loss of function, SM and other sphingolipids, such as lactosylceramide, glucosylceramide, GM2 and GM3 gangliosides and sphingosine, accumulate as well (Pentchev et al., 1984;Lloyd-Evans et al., 2008;Patterson et al., 2012). Hence, these findings imply that the trafficking and metabolism of different lipid species through the endocytic pathway are severily affected in these lysosomal diseases, likely contributing to their pathogenesis. However, the molecular mechanisms and signaling pathways responsable for cell death and tissue damage in these diseases are not entirely clear.

[8] Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1

Authors: Christin Völkner, Maik Liedtke, A. Hermann, M. Frech
Year: 2021
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/34258d343bc77def5ce926bad7f201ab6597cf02
DOI: 10.3390/ijms22020710
PMID: 33445799
PMCID: 7828283
Citations: 9
Summary: The lysosomal storage disorders Niemann-Pick disease Type C1 (NPC1) and Type C2 (NPC2) are rare diseases caused by mutations in the NPC1 or NPC2 gene. 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. A total of 95% of cases are due to a deficiency of NPC1 and onl...
Evidence snippets:
Snippet 1 (score: 0.466) > Niemann-Pick disease type C is a rare monogenic neurovisceral lysosomal storage disorder, inherited in an autosomal recessive manner, with an estimated incidence of 1/120,000 [1]. Homozygous or compound heterozygous mutations in the NPC1 (95%; OMIM # 257220) or NPC2 (5%, OMIM # 607625) gene lead to impaired intracellular transport of cholesterol and glycosphingolipids, resulting in the accumulation of these lipids in late endosomes/lysosomes (LE/LY). Currently, 549 mutations in NPC1 and 29 mutations in NPC2 have been described [2]. The location of observed mutations is not limited to the cholesterol binding site; rather, they can be found throughout the whole sequence and can lead to misfolded protein, resulting in proteasomal degradation and hampered trafficking to the lysosome and therefore reduced lipid turnover. Clinical manifestations of patients do not show a strong genotype-phenotype correlation, but rather Niemann-Pick disease type C is characterized by heterogeneous phenotypic expression. Therefore, it is hardly possible to predict the clinical outcome caused by a specific mutation, suggesting that several factors may be involved in the pathogenesis of the disease. > The clinical spectrum of NPC1 includes visceral manifestations, such as hepatosplenomegaly, and neurological symptoms, such as hypotonia, loss of motor skills, ataxia, seizures, dysphagia, dysarthria, supranuclear gaze palsy (VSGP), and dementia, as well as psychiatric symptoms. Systemic and neurological symptoms occur at different times, with systemic symptoms, which may be absent in 10-15% of cases, preceding neurological symptoms. The age of onset of symptoms defines the classification into perinatal, infantile (early and late), juvenile, and adolescent/adult forms of NPC1.

[9] Biomarkers in Lysosomal Storage Diseases

Authors: Joaquín Bobillo Lobato, Maria Jiménez Hidalgo, L. M. Jiménez Jiménez
Year: 2016
Venue: Diseases
URL: https://www.semanticscholar.org/paper/6a8bdc58db4d91dd2efe5adec28c651c2a2a41aa
DOI: 10.3390/diseases4040040
PMID: 28933418
PMCID: 5456325
Citations: 34
Influential citations: 1
Summary: The most promising biomarkers in major LSDs are summarized and discussed and why these are the most promising candidates for screening systems are discussed.
Evidence snippets:
Snippet 1 (score: 0.465) > The term "Niemann-Pick disease" (NP) includes a heterogeneous group of lysosomal lipid accumulation diseases with clinical, biochemical, and molecular features. > In 1961, Crocker classified them into four subgroups (types A-D) [49]. In types A and B (OMIM 257200, 607616; prevalence of 0.25 and 0.4/100,000 [12] respectively), the accumulation of sphingomyelin in different organs and tissues is due to a deficit of acid sphingomyelinase enzyme (ASM; EC 3.1.4.12) caused by mutations in the sphingomyelin phosphodiesterase-1 gene. In types C and D (OMIM 257220, 1/100,000 prevalence) [12] however, a defect in cellular lipid transport can result in several pathological forms of the disorder [50]. > We now know that NP-C disease is clinically, biochemically, and genetically distinct from types A and B. The NP-D disease is an allelic variant of type C found only in patients in Nova Scotia (Canada). > As in most lysosomal storage disorders, the clinical spectrum of Niemann-Pick disease A/B is increasingly regarded as a continuum from the most severe to relatively mild presentation [51]. > Acid sphingomyelinase plays a major role in sphingolipid metabolism, because it catalyzes the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Ceramide and related products (such as sphingosine-1-phosphate) are involved in a variety of molecular and cellular processes, and play a central role in a growing number of human diseases [52]. The ASM deficiency in Niemann-Pick disease types A and B causes the accumulation of sphingomyelin and other lipids in various tissues, mainly in the monocyte-macrophage system. > Until recently, sphingomyelin was the only biomarker available for the disease. Although its levels have been shown to be elevated more than 10-fold in the livers and spleens of NP-B patients, levels in plasma have been found to overlap those of normal controls [53].

[10] Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

Authors: E. Uribe-Carretero, Verónica Rey, J. M. Fuentes, Isaac Tamargo-Gómez
Year: 2024
Venue: Biology
URL: https://www.semanticscholar.org/paper/170a8e8c7d82acd3f25b107a238b3ae439337661
DOI: 10.3390/biology13010034
PMID: 38248465
PMCID: 10813815
Citations: 8
Summary: Insight into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, is provided, and recent advancements and breakthroughs in this field are highlighted.
Evidence snippets:
Snippet 1 (score: 0.463) > Niemann-Pick type C (NPC) disease is a genetic autosomal recessive lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2 (5% of cases). These genes encode proteins involved in the intracellular trafficking of lipids and cholesterol [225]. Mutations in these genes result in the accumulation of unesterified cholesterol in the liver, spleen, and brain, which, in turn, disrupts lipid transport. In fact, these alterations cause a disruption that leads to the loss of Purkinje cells in the cerebellum and degeneration of other components of the central nervous system [226]. > From a clinical perspective, NPC is typically a disease with juvenile or later onset, and the rate of progression inversely correlates with the age of onset. Common symptoms of NPC include ataxia, splenomegaly, hepatomegaly, hypotonia, severe liver disease, respiratory infections, and abnormal eye movements [227]. > In this context, there is an alteration of the autophagic mechanism in NPC, as an accumulation of autophagosomes in skin fibroblasts from NPC patients is described. In the molecular landscape of this disease, this accumulation is partially due to the function of BECN1 and LC3B. In wild-type fibroblasts, their levels increase when exposed to U18666A, a small molecule used to induce NPC-like lipid trafficking defects. Moreover, NPC exhibits a blocked autophagic flux due to impaired autophagosome maturation [228] and specific defects in mitophagy [229]. > Therefore, autophagy is significantly disrupted in NPC. This disruption interferes in the maintenance of cellular and tissue homeostasis, contributing to the pathological changes observed in NPC patients. The accumulation of autophagosomes, their impaired maturation, and the defective mitochondrial function all contribute to the disease's progression, affecting cellular and tissue health.

[11] Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

Authors: M. E. López, M. Scott
Year: 2013
Venue: Disease Models & Mechanisms
URL: https://www.semanticscholar.org/paper/88ebd1599676b2ea0ad531fbaca09899ec5b970b
DOI: 10.1242/dmm.012385
PMID: 23907005
PMCID: 3759329
Citations: 24
Summary: Progress in mouse-model-based studies of NPC disease is reviewed, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking.
Evidence snippets:
Snippet 1 (score: 0.452) > Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC) is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

[12] Case Report: Be Aware of “New” Features of Niemann–Pick Disease: Insights From Two Pediatric Cases

Authors: Fan Chen, Shan Guo, Xuesong Li, Shengxuan Liu, L. Wang et al.
Year: 2022
Venue: Frontiers in Genetics
URL: https://www.semanticscholar.org/paper/0e90092e587e5a751cb719feea6600be63ee7e7d
DOI: 10.3389/fgene.2022.845246
PMID: 35360843
PMCID: 8961870
Citations: 2
Summary: The findings suggest that immune activation should be considered as a “new” clinical phenotype of lysosomal storage diseases.
Evidence snippets:
Snippet 1 (score: 0.444) > Lysosomal storage diseases (LSDs) comprise a group of more than 70 distinct genetic diseases. LSDs are characterized by the accumulation of undigested macromolecules in lysosomes of various body cells. Although these disorders are rare, they affect 1 in 5,000 live births, accounting for 14% of all inherited metabolic diseases. LSDs have similar clinical features despite different pathogenetic mechanisms (Rigante et al., 2017;Platt et al., 2018). Niemann-Pick disease is a relatively common autosomal recessive LSD. Clinical manifestations and pathogenic genes are mainly classified into types A, B, and C (Vanier, 2013). Niemann-Pick disease type C (NPC) is a progressive and fatal disorder caused by mutations in the NPC1 (OMIM 257220) or NPC2 (OMIM 607625) gene, which results in the intracellular accumulation of unesterified cholesterol. As cholesterol accumulates in cells, it affects the brain, liver, spleen, and lungs, leading to premature death. The estimated incidence of NPC is 1:100,000, with variable age of onset and clinical features (Vanier, 2010;Patterson et al., 2012;Geberhiwot et al., 2018). Perinatal manifestations of NPC often include splenomegaly, hepatomegaly, fetal ascites, or nonimmune fetal hydrops (Spiegel et al., 2009;Surmeli-Onay et al., 2013). Severe hepatic diseases, associated or not with pulmonary disease, are neonatal manifestations of NPC (Bjurulf et al., 2008;Griese et al., 2010). In comparison with the adult period, cholestatic liver disease is a typical clinical phenotype in infants. However, some affected infants may also present hypotonia and developmental delay with little hepatic and pulmonary involvement (Vanier et al., 1988).

[13] Complex N-Linked Glycosylation: A Potential Modifier of Niemann–Pick Disease, Type C1 Pathology

Authors: N. Cawley, Anna T. Lyons, D. Abebe, Rachel Luke, Julia Yerger et al.
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/1aef8b0292ef503509b14727e6f7384549321396
DOI: 10.3390/ijms23095082
PMID: 35563467
PMCID: 9103943
Citations: 6
Summary: The results suggest that reduced asparagine-linked glycosylation increases NPC1 disease severity in mice, and leads to the hypothesis that mutations in genes involved in asparagin- linked glycosolation may contribute to disease severity progression in individuals with NPC1.
Evidence snippets:
Snippet 1 (score: 0.437) > Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative lysosomal disorder. It is inherited in an autosomal recessive manner and occurs with an estimated incidence of 1:100,000 to 1:150,000 births [1,2]. Patients have pathological variants in either NPC1 (95% of cases) or NPC2, which code for proteins involved in the binding and efflux of unesterified cholesterol out of the late endosome/lysosome compartments [3,4]. Pathological variants in either gene results in the accumulation of unesterified cholesterol and glycosphingolipids within the late endosomal/lysosomal system [5,6]. This eventually leads to cellular dysfunction, and in the case of the cerebellum, to the degeneration of Purkinje neurons [7]. The clinical phenotype of this disease is marked by hepatosplenomegaly, cerebellar ataxia, and progressive cognitive decline [1]. Early death of the patient ultimately occurs [8]. > As a key organelle in the progression of NPC, the integrity and function of the lysosome, and its limiting membrane, is critical. The lysosomal membrane is of particular interest, where the complexity and integrity of the ~8 nm glycocalyx [9] is important since increased lysosomal membrane permeability has been shown to occur in microglia, resulting in the leakage of hydrolytic enzymes, such as cathepsin B, and cell death [10]. Heat shock protein 70 (HSP70) has been shown to stabilize lysosomal membrane permeability as part of its pro-survival mechanism [11,12]. Thus, Arimoclomol TM , a drug currently undergoing clinical trials for treatment of NPC1, which induces HSP70, is proposed to stabilize the lysosomal membrane in NPC1 as part of its mechanism of action.

[14] A human neuronal model of Niemann Pick C disease developed from stem cells isolated from patient’s skin

Authors: N. Bergamin, A. Dardis, A. Beltrami, D. Cesselli, S. Rigo et al.
Year: 2013
Venue: Orphanet Journal of Rare Diseases
URL: https://www.semanticscholar.org/paper/aa4c61fb8788db926e8f667a45cb81e436149315
DOI: 10.1186/1750-1172-8-34
PMID: 23433359
PMCID: 3648447
Citations: 36
Influential citations: 2
Summary: A human neuronal model of NPC disease is generated through the induction of differentiation of stem cells obtained from patient’s easily accessible sources and may be applied to easily generate human neuronal models of other neurodegenerative diseases.
Evidence snippets:
Snippet 1 (score: 0.435) > Niemann Pick C [NPC-MIM 257220; MIM607625] disease is a neurodegenerative lysosomal storage disorder due to mutations in NPC1 or NPC2 genes, characterized by the accumulation of endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosomes/late endosomes. Both proteins are involved in the intracellular trafficking of cholesterol and other lipids. Thus, the deficiency of either of them leads to the accumulation of the endocytosed unesterified cholesterol, gangliosides and other lipids within the lysosome/late endosome compartment [1]. > Clinically, NPC disease presents a highly variable phenotype ranging from fetal to adult age. Even though initial manifestations are typically systemic, including liver and spleen enlargement, the disease has been classified according to the age at onset of neurological symptoms in: severe infantile form (onset before 2 y of age), late infantile form (onset between 3-5 y of age), juvenile form (onset between 5 and 16 y) and adult form (onset at age>16 y) [1,2]. > Approximately 95% of NPC patients present mutations in NPC1 gene (MIM 607623; chr 18q11-q12) [3,4], which encodes a membrane glycoprotein of 1,278 amino acids containing 13 transmembrane domains and localized in late endosomes [5]. The other 5% of patients present mutations in NPC2 gene (MIM 601015; chr 14q24.3) [6] encoding a soluble 151 amino acid protein that is present in the lumen of lysosomes. > Despite the progress in characterizing the biochemical and genetic defects in NPC disease, the mechanisms underlying the pathophysiology of this disorder are not clear and the currently available therapeutic interventions are limited. In particular, the analysis of the molecular pathways linking the lipid accumulation and cellular damage in the brain has been challenging due to the limited availability of neuronal models. > Two mouse models of NPC disease have been described and used to study NPC pathogenesis, the BALB

[15] Necroptosis in neurodegenerative diseases: a potential therapeutic target

Authors: Shuo Zhang, Mi-bo Tang, Hai-yang Luo, Changhe Shi, Yu-ming Xu
Year: 2017
Venue: Cell Death & Disease
URL: https://www.semanticscholar.org/paper/ef425bdd135e925a09d44e21fac8ffab70314905
DOI: 10.1038/cddis.2017.286
PMID: 28661482
PMCID: 5520937
Citations: 166
Influential citations: 6
Summary: The present review is aimed at summarizing the molecular mechanisms of necroPTosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases.
Evidence snippets:
Snippet 1 (score: 0.431) > Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal lipid storage disorder with progressive neurodegeneration. 79 NPC is classified as type C1 (NPC1) or type C2 (NPC2), which are caused by mutations in the NPC1 or NPC2 genes, respectively. Mutations in the NPC1 gene account for 95% of NPC patients. 80 Degeneration of cerebellar Purkinje neurons is a prominent early feature in the disease progression, which leads to clinical symptoms of motor impairments. 81 Very little is known about the cellular death mechanisms leading to neuronal loss in NPC1, and thus the potential efficacy of cell death inhibitors remains unexplored. A recent study reported that activation of the necroptotic pathway contributes to neuronal death in NPC1 82 The expression level of RIP1 and RIP3 are raised with the formation of the necrosome in NPC1 fibroblasts. 82 Consist with the results in NPC1-mutant mice and human patients brain tissue, thus strongly suggesting that necroptosis has a pathological role in NPC1. 82 Of note, the formation of the necrosomal complex appeared to be more prominent in fibroblast lines from subjects with age adjusted neurological severity scores 83 less than or equal to 1.5. 82 Indicates that activation of the necroptotic pathway may be correlate with disease severity. > The mechanism by mutant NPC1 influences the disease are not fully understood. It is clear that necroptosis activation occurs during NPC1 progression, with an abundance of RIP1 and RIP3 found in NPC1 fibroblasts and post-mortem brain tissue of NPC patients compared to controls. 82 Treatment of NPC1 fibroblasts from NPC1 patient with Nec-1 or suppression of either RIP1 or RIP3 expression can significant suppress cell death. 82 Treatment of Npc1 − / − mice with Nec-1 resulted in delayed cerebellar Purkinje cell loss, delayed progression of neurological manifestations and significantly prolonged lifespan. 82 These results provide a strong link between necroptosis with the molecular mechanism that contributes to neuronal loss in NPC1.

[16] Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature

Authors: J. Sheth, Jijo John Joseph, K. Shah, M. Muranjan, M. Mistri et al.
Year: 2017
Venue: BMC Medical Genetics
URL: https://www.semanticscholar.org/paper/c16e1b25dd6dfaceb68774d5ee7fd79da15df977
DOI: 10.1186/s12881-017-0367-x
PMID: 28095804
PMCID: 5240394
Citations: 25
Influential citations: 1
Summary: This study demonstrates that NPC2 can present in early years of life with pulmonary complications like alveolar proteinosis and hepatosplenomegaly or hepatomeGaly due to mutation in NPC2 gene.
Evidence snippets:
Snippet 1 (score: 0.430) > Niemann-Pick disease type C (NPC) is a fatal autosomal recessive neurovisceral disorder due to mutation in NPC1 and NPC2 genes leading to alterations in trafficking of endocytosed cholesterol [1]. Due to heterogeneous clinical phenotype, NPC is underdiagnosed and often missed altogether. In NPC, the protein product of the NPC1 gene functions as a transporter of cholesterol and glycolipids in the endosomal-lysosomal system whereas the smaller protein product of NPC2 cooperates with the NPC1 protein [2,3]. NPC2 plays a vital role in endosomal/ lysosomal cholesterol trafficking by markedly accelerating the rates of transport from and between membranes [4]. The mechanism of NPC2 action involves direct interaction of the protein with membranes. The defects in NPC1 and NPC2 proteins, leads to sequestration of cholesterol derived products in the cell leading to hepatosplenomegaly, pulmonary and neurological manifestations [3]. NPC1 gene is responsible for 95% of manifestations with main phenotype being hepatosplenomegaly and nervous system. The other ~5% of the NPC is caused by NPC2 gene where pulmonary manifestations with respiratory failure have been documented [5]. Till date nearly twenty cases have been reported of NPC2 with twelve homoallelic mutations and none from India. Present study is the first report of NPC2 from India with primary pulmonary manifestations and hepatosplenomegaly highlighting phenotype-genotype correlation.

[17] Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals

Authors: R. Mashima, Masamitsu Maekawa, A. Narita, T. Okuyama, N. Mano
Year: 2018
Venue: Molecular Genetics and Metabolism Reports
URL: https://www.semanticscholar.org/paper/bd3ee59c4f6a9a7c023644d5336f745cbf938514
DOI: 10.1016/j.ymgmr.2018.03.005
PMID: 30023294
PMCID: 6047109
Citations: 14
Influential citations: 1
Summary: The efficacy of plasma SPC and lysosphingomyelin-509 as promising biomarkers for this disorder was supported by the finding that the urinary concentration of 3β-sulfooxy-7β-N-acetylglucosaminyl-5-cholen-24-oic acid, an established biomarker for NPC, was also elevated in the NPC-affected individuals.
Evidence snippets:
Snippet 1 (score: 0.429) > Niemann-Pick disease type C (NPC) is a neurovisceral disorder caused by a defective mutation in either the NPC1 (OMIM 607623) or the NPC2 (OMIM 601015) gene [1,2]. The impaired egress of cholesterol from the late endosome/lysosomal compartment has been suggested to be a relevant mechanism for the pathogenesis of NPC. Early evidence showed consistently that NPC was associated with the accumulation of various lipids, including cholesterol in humans [3]. These lipids include a variety of cholesterol metabolites such as oxysterol, including cholestane-3β,5α,6β-triol and 7-ketocholesterol [4][5][6][7][8][9], bile acids [10][11][12][13][14], and glucosylated cholesterol [15], respectively. The NPC1 protein is a membraneous protein in the lysosome, which facilitates the transportation of cholesterol from the lysosome to plasma membrane, whereas NPC2 is a soluble protein in the lysosome, which binds stoichiometrically to cholesterol. Based on these biochemical properties of NPC1 and NPC2, the mechanism(s) of NPC might be, at least partly, attributed to the failure of proper lipid trafficking in the cells [2]. This possibility was evidenced in several murine NPC models that showed positive therapeutic outcomes on the established NPC manifestations by treatment with cyclodextrin, a circular oligosaccharide that facilitates cholesterol transportation across the plasma membrane [16][17][18]. A recent study revealed the prevalence of classical NPC is 1/89,229, while the incidence of late-onset NPC incompletely predicted [19]. > Both clinical and experimental evidence have indicated that the level of sphingomyelin is increased in NPC in the liver and spleen [2,3]. In mammals, the biosynthesis of sphingomyelin is initiated by serine https [20]. Sphingomyelin is

[18] The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase

Authors: C. Fog, P. Zago, E. Malini, Lukasz M. Solanko, P. Peruzzo et al.
Year: 2018
Venue: EBioMedicine
URL: https://www.semanticscholar.org/paper/38f5b73dd632f30a0cfff54f8068f4a69253fd8e
DOI: 10.1016/j.ebiom.2018.11.037
PMID: 30497978
PMCID: 6306395
Citations: 42
Summary: Data demonstrate the potential of HSP-targeting therapies in GCase-deficiencies and strongly support the clinical development of arimoclomol as a potential therapeutic option for the neuronopathic forms of GD.
Evidence snippets:
Snippet 1 (score: 0.429) > Our results demonstrate that arimoclomol is a heat shock protein amplifying small molecule that may be useful for the treatment of Gaucher disease including its neuronopathic forms which have no approved treatments available. > In these studies we have focused on ex vivo systems in order to address the fundamental concept of HSP-mediated refolding across the major genotypes of Gaucher disease and investigating the biological rationale for clinical development of arimoclomol for neuronopathic Gaucher disease. > We demonstrate that arimoclomol amplifies the production of disease mechanism-relevant molecular chaperones of the HSP70 family and improves mutant GCase maturation and function across major neuronopathic and non-neuronopathic genotypes in both human primary GD fibroblasts as well as in a neuronal cellular model of the disease. > As arimoclomol is a clinically enabled compound already in phase II/ III clinical trials for Niemann-Pick disease type C, sporadic Inclusion Body Myositis and Amyotrophic Lateral Sclerosis (Clinicaltrials.gov identifiers NCT02612129, NCT02753530, and NCT03491462 respectively), the data reported herein provide preclinical proof-of-concept for the investigation of arimoclomol's therapeutic value in Gaucher disease. > While it is a known challenge to translate doses from in vitro studies to a human clinical setting, let alone across diseases, the arimoclomol doses used herein are congruent with the doses used for the preclinical studies in the sphingolipid storage disease Niemann-Pick type C (Kirkegaard et al., Science Transl. Med. 2016 and manuscript in prep.) which recently reported encouraging top-line results from a phase III clinical trial. Furthermore, the same type of in vitro studies has formed basis for the development of the recently approved drug migalastat, a small chemical chaperone developed for misfolded versions of the enzyme alpha-galactosidase A, in the sphingolipid storage disease Fabry disease (https://www.fda.gov/newsevents/newsroom/ pressannouncements/uc

[19] Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

Authors: Elisa Balboa, T. Marín, J. E. Oyarzún, Pablo S Contreras, R. Hardt et al.
Year: 2021
Venue: Cells
URL: https://www.semanticscholar.org/paper/208ed0f3ffeefd13edf13d4abe6cb9f9aa435123
DOI: 10.3390/cells10082159
PMID: 34440927
PMCID: 8392304
Citations: 11
Influential citations: 1
Summary: This study found potential therapeutic targets for the treatment of liver damage in NPCD by analyzing hepatocytes derived from wild type and Npc1−/− mice by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis.
Evidence snippets:
Snippet 1 (score: 0.427) > Niemann Pick type C disease (NPCD) is a neurovisceral lysosomal storage disorder (LSD) with an estimated incidence of 1/90,000 live births [1]. It is caused by mutations in the NPC1 or NPC2 genes, which encode lysosomal cholesterol transport proteins that mediate free cholesterol efflux from this compartment. Therefore, NPC1 or NPC2 deficient cells accumulate cholesterol in lysosomes. The most affected tissues are the central nervous system (CNS) and the liver [2]. The symptoms and clinical presentation are extremely heterogeneous, with age of onset ranging from the perinatal period to adulthood. Visceral involvement includes the liver, spleen, and sometimes the lungs, while possible neurological disorders consist mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. The onset of systemic symptoms frequently precedes the start of neurological symptoms [3]. Although most patients with NPCD die from complications of the neurological disorder [3], some also develop fatal liver disease [4]. Aside from liver failure [5,6], NPC patients frequently present with neonatal jaundice (52%), enlargement of the spleen (36%), liver (31%), and ascites (19%) [7]. At the organ and tissue levels, mice lacking the NPC1 protein (NPC mice) develop liver disease with hepatomegaly, cell death, infiltration of foamy macrophages, inflammation, proliferation of hepatic stellate cells, and fibrosis [8][9][10]. > Usually, the systemic disease is not very severe, except for the perinatal period in which a small subset of patients die in the first six months of life [3]. Given the hepatic manifestations in the development of NPCD and to design treatments for liver symptoms that will provide a better quality of life for patients, it is necessary to understand the molecular pathways that are affected in NPC liver cells. > Proteomics technology is a tool that allows full-scale analysis of all proteins involved in a pathological process.

[20] Retinal axonal degeneration in Niemann–Pick type C disease

Authors: J. Havla, M. Moser, C. Sztatecsny, Amelie S Lotz-Havla, E. Maier et al.
Year: 2020
Venue: Journal of Neurology
URL: https://www.semanticscholar.org/paper/f4fe3e3da2fd6b506a1f05e1779558a264469c45
DOI: 10.1007/s00415-020-09796-2
PMID: 32222928
PMCID: 7320959
Citations: 23
Summary: Using OCT, retinal degeneration in NPC1-P and significant correlation between retinal neuroaxonal degeneration with clinical measurements was shown and OCT may be an important marker of neurodegeneration in NPCs1-disease after onset of clinical symptoms.
Evidence snippets:
Snippet 1 (score: 0.425) > Niemann-Pick disease type C (NPC) is an autosomal recessively inherited neurovisceral lysosomal disorder caused by mutations in the NPC1 or NPC2 gene [1,2]. The clinical phenotype ranges from an infancy-onset progressive, fatal disorder to an adult-onset, chronic neurodegenerative disease with heterogeneous clinical symptoms such as cognitive impairment, cerebellar symptoms, dystonia, vertical supranuclear saccade and gaze palsy, psychiatric disorders, and, less frequently, epilepsy [3]. Optic nerve pallor and perimacular gray discoloration are observed ophthalmologically, as well as histologically [4]. However, markers reflecting disease progression in NPC are not well established. Pathophysiologically, NPC is characterized by abnormalities of intracellular transport of endocytosed cholesterol and further lipids with their sequestration in lysosomes and late endosomes [5,6]. Notably, dysregulation of brain cholesterol homeostasis is also present in some of the common neurodegenerative central nerve system (CNS) disorders Tatiana Bremova-Ertl and Susanne A. Schneider have contributed equally to this work. such as Alzheimer`s disease (AD) and Parkinson's disease (PD) [7][8][9]. In addition, NPC and AD share common pathophysiological mechanisms such as neurofibrillary tangle formation, increased amyloidogenic amyloid precursor protein (APP), early development of endosome abnormalities, and neuronal death [10][11][12][13]. Optical coherence tomography (OCT) is a non-invasive, cost-effective, and widely used imaging technique of the retinal layers introduced in the last few years as a potential marker of neurodegeneration in various neuroinflammatory and neurodegenerative disorders [14,15].

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Niemann-Pick Disease Type C. Core disease mechanisms, molecular and cellul...

Relevant Papers

[1] Global and Targeted Metabolomics for Revealing Metabolomic Alteration in Niemann-Pick Disease Type C Model Cells

[2] Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T

[3] Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism?

[4] Metabolic Alteration Analysis of Steroid Hormones in Niemann–Pick Disease Type C Model Cell Using Liquid Chromatography/Tandem Mass Spectrometry

[5] Practical recommendations for diagnosis, management, and follow-up of Niemann-Pick type-C disease patients: a Brazilian perspective

[6] δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

[7] Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

[8] Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Niemann-Pick Type C1

[9] Biomarkers in Lysosomal Storage Diseases

[10] Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases

[11] Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

[12] Case Report: Be Aware of “New” Features of Niemann–Pick Disease: Insights From Two Pediatric Cases

[13] Complex N-Linked Glycosylation: A Potential Modifier of Niemann–Pick Disease, Type C1 Pathology

[14] A human neuronal model of Niemann Pick C disease developed from stem cells isolated from patient’s skin

[15] Necroptosis in neurodegenerative diseases: a potential therapeutic target

[16] Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature

[17] Elevation of plasma lysosphingomyelin-509 and urinary bile acid metabolite in Niemann-Pick disease type C-affected individuals

[18] The heat shock protein amplifier arimoclomol improves refolding, maturation and lysosomal activity of glucocerebrosidase

[19] Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

[20] Retinal axonal degeneration in Niemann–Pick type C disease

Notes