Niemann–Pick disease type C: Difference between revisions

Niemann–Pick disease, type C
Niemann–Pick disease, type C
	Niemann–Pick disease, type C is associated with NPC1 mutations
Specialty	Endocrinology, neurology

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Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimer's"^[1]) is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people.^[2] Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

Signs and symptoms

Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.^{[citation needed]}

Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood.^[3] Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).^{[citation needed]}

Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.^{[citation needed]}

In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia.

Genetics

Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2.^[4] The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.^[5]

The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells.^[6] A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
The NPC2 gene encodes a protein that binds and transports cholesterol.^[7]^[8] It has been shown to closely interact with NPC1.^[9]^[10]

"Type D" variant

Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C.

Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.^[11]

Pathophysiology

Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.^[12]

Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.^{[citation needed]}

Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.

Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network.^[13]
Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form.
Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.^[14]
Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation.^[15]

Diagnosis

Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterification and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab^[16] and the Mayo Clinic.^[17]

Treatment

There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment.^[18] Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube).^[19]

Arimoclomol

In 2014, the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C.^[20] This was followed in 2015 by the U.S. Food and Drug Administration (FDA).^[21] Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.^[22] Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans.^[23]^[24]^[25]^[26]^{[excessive citations]} In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints.^[27] On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor.^[28]

Hydroxypropyl-beta-cyclodextrin (HPbCD)

In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel,^[29] identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice^[30] and feline^[31] models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe hypervitaminosis A.^[32]

On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Children's Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.^{[citation needed]}

On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND with Dr. Diane Williams, through Asante Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both began intrathecal treatments beginning January 2012. In 2014 Peyton had an intrathecal smart port placed by OHSU's neurosurgeon Dr. Lissa Baird, to alleviate sedation during the intrathecal procedures. It was successful and continues to be used for treatment (currently 2023). They continue in 2023 to receive both IV and IT treatments; 8 hour IV from home twice monthly, and IT twice monthly at Asante Rogue Regional Medical Center, rotating with IV and IT every week. These patients have proven safety and benefit shown by NIH Severity Scale Assessments, one slightly less impacted than projected and the other with a profound impact and benefit than projected.^[33]

In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.^{[citation needed]}

On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.^{[citation needed]}

On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012.^[34]

Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy.

On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIH's National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

In January 2021, the Sponsor (Mallinckrodt Pharmaceuticals) concluded that the benefit / risk balance for HPβCD cyclodextrin (adrabetadex) for the treatment of neurologic symptoms of NPC was negative, and that the risks associated with the treatment outweigh the potential benefit. Effective immediately, Mallinckrodt recommended that treatment with adrabetadex be discontinued as soon as possible, with the appropriate physician oversight.^[35]

N-Acetyl-Leucine

N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc.^[36]

N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various genetic diseases, including Niemann-Pick Disease Type C. The US FDA has granted IntraBio a Rare Pediatric Disease Designation for N-Acetyl-Leucine for the treatment of NPC.^[37]

Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.^[38]

In September 2020, IntraBio announced the successful results of a multinational clinical trial with N-acetyl-L-leucine (IB1001) for NPC, which demonstrated IB1001 demonstrated a statistically significant change in both primary and secondary endpoints, and clinically meaningful improvement in symptoms, functioning, and quality of life.^[39]

IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff)^[40] and Ataxia-Telangiectasia.^[41] Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia,^[42] amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine.^[43]

Other treatments under investigation

One drug that has been tried is Miglustat.^[44]^[45] Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.^{[citation needed]}

Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone,^[4]^[46] rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent.^[15] The pregnane X receptor has been identified as a potential target.^[47]

Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.^[48]

Low cholesterol diets are often used,^[49] but there is no evidence of efficacy.^[50]

Gene therapy is being used clinically to treat genetic diseases including haemophilia^[51] and spinal muscular atrophy.^[52] It has been used preclinically, in a mouse model of Niemann-Pick type C, using an adeno-associated virus derived viral vector has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain.^[53] In a separate proof-of-concept study a similar vector, but with a modified capsid capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.^[54]

Prognosis

The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years.^{[citation needed]}

Research directions

Loss of myelin in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene Niemann–Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased.^[55] MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.^[56] A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.^[55]

Recent neuroimaging studies have shown patients with Niemann–Pick, type C to have a corpus callosum with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls.^[57]^[58] Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water.^[58]^[59] These conclusions suggest that the corpus callosum plays an important role in the disease and should be explored for use as a biomarker of disease progression.^{[citation needed]}

Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.^[60]

Findings from Zhang et al.^[61] suggest that NPC is a late endocytic trafficking disease resulted, at least in part, from disruption of communication within late endocytic (LE) compartments and possibly between LE and other subcellular organelles. Crosstalk between the late endocytic compartment and other organelles such as mitochondria, endoplasmic reticulum, plasma membrane, as well as early endocytic compartments has become one of the most interesting frontiers in neurondegenerative disease research including Alzheimer's disease, Parkinson's disease, as well as lysosomal storage disorders.^[62]^[63]

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^ Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. (November 2017). "Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy". The New England Journal of Medicine. 377 (18): 1713–1722. doi:10.1056/NEJMoa1706198. PMID 29091557.
^ Hughes MP, Smith DA, Morris L, Fletcher C, Colaco A, Huebecker M, et al. (September 2018). "AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease". Human Molecular Genetics. 27 (17): 3079–3098. doi:10.1093/hmg/ddy212. PMC 6097154. PMID 29878115.
^ Davidson CD, Gibson AL, Gu T, Baxter LL, Deverman BE, Beadle K, et al. (October 2021). "Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice". Life Science Alliance. 4 (10): e202101040. doi:10.26508/lsa.202101040. PMC 8380657. PMID 34407999.
^ ^a ^b Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, et al. (December 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metabolic Brain Disease. 26 (4): 299–306. doi:10.1007/s11011-011-9263-9. PMID 21938520. S2CID 26878522.
^ Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B (September 2012). "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". The Journal of Neuroscience. 32 (36): 12528–12542. doi:10.1523/JNEUROSCI.1069-12.2012. PMC 3752083. PMID 22956843.
^ Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, et al. (August 2011). "Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables". AJNR. American Journal of Neuroradiology. 32 (7): 1340–1346. doi:10.3174/ajnr.A2490. PMC 7966038. PMID 21596811.
^ ^a ^b Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, et al. (July 2010). "White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study". Neurology. 75 (1): 49–56. doi:10.1212/WNL.0b013e3181e6210e. PMID 20484681. S2CID 9062701.
^ Trouard TP, Heidenreich RA, Seeger JF, Erickson RP (November 2005). "Diffusion tensor imaging in Niemann-Pick Type C disease". Pediatric Neurology. 33 (5): 325–330. doi:10.1016/j.pediatrneurol.2005.05.004. PMID 16243219.
^ Marcus AD (2 November 2014). "Researchers Study Ebola Link to Gene in Rare Disease". Wall Street Journal. Retrieved 12 August 2016.
^ Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease. Proceedings of the National Academy of Sciences. April 2001, 98 (8) 4466-4471; DOI: 10.1073/pnas.081070898
^ Tate BA, Mathews PM (June 2006). "Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment". Science of Aging Knowledge Environment. 2006 (10): re2. doi:10.1126/sageke.2006.10.re2. PMID 16807486.
^ Plotegher N, Duchen MR (2017). "Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease". Frontiers in Cell and Developmental Biology. 5: 110. doi:10.3389/fcell.2017.00110. PMC 5732996. PMID 29312935.{{cite journal}}: CS1 maint: unflagged free DOI (link)

External links

PubMed

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[pmid18815434-3] {{cite journal | vauthors = Rimkunas VM, Graham MJ, Crooke RM, Liscum L | title = TNF-{alpha} plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease | journal = Journal of Lipid Research | volume = 50 | issue = 2 | pages = 327–333 | date = February 2009 | pmid = 18815434 | pmc = 2636917 | doi = 10.1194/jlr.M800415-JLR200 }}

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[51] Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. (November 2014). "Long-term safety and efficacy of factor IX gene therapy in hemophilia B". The New England Journal of Medicine. 371 (21): 1994–2004. doi:10.1056/NEJMoa1407309. PMC 4278802. PMID 25409372.

[52] Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, et al. (November 2017). "Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy". The New England Journal of Medicine. 377 (18): 1713–1722. doi:10.1056/NEJMoa1706198. PMID 29091557.

[53] Hughes MP, Smith DA, Morris L, Fletcher C, Colaco A, Huebecker M, et al. (September 2018). "AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease". Human Molecular Genetics. 27 (17): 3079–3098. doi:10.1093/hmg/ddy212. PMC 6097154. PMID 29878115.

[54] Davidson CD, Gibson AL, Gu T, Baxter LL, Deverman BE, Beadle K, et al. (October 2021). "Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice". Life Science Alliance. 4 (10): e202101040. doi:10.26508/lsa.202101040. PMC 8380657. PMID 34407999.

[yan-55] Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, et al. (December 2011). "Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse". Metabolic Brain Disease. 26 (4): 299–306. doi:10.1007/s11011-011-9263-9. PMID 21938520. S2CID 26878522.

[koenning-56] Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B (September 2012). "Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS". The Journal of Neuroscience. 32 (36): 12528–12542. doi:10.1523/JNEUROSCI.1069-12.2012. PMC 3752083. PMID 22956843.

[pmid21596811-57] Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, et al. (August 2011). "Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables". AJNR. American Journal of Neuroradiology. 32 (7): 1340–1346. doi:10.3174/ajnr.A2490. PMC 7966038. PMID 21596811.

[pmid20484681-58] Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, et al. (July 2010). "White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study". Neurology. 75 (1): 49–56. doi:10.1212/WNL.0b013e3181e6210e. PMID 20484681. S2CID 9062701.

[pmid16243219-59] Trouard TP, Heidenreich RA, Seeger JF, Erickson RP (November 2005). "Diffusion tensor imaging in Niemann-Pick Type C disease". Pediatric Neurology. 33 (5): 325–330. doi:10.1016/j.pediatrneurol.2005.05.004. PMID 16243219.

[60] Marcus AD (2 November 2014). "Researchers Study Ebola Link to Gene in Rare Disease". Wall Street Journal. Retrieved 12 August 2016.

[61] Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA. Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease. Proceedings of the National Academy of Sciences. April 2001, 98 (8) 4466-4471; DOI: 10.1073/pnas.081070898

[62] Tate BA, Mathews PM (June 2006). "Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment". Science of Aging Knowledge Environment. 2006 (10): re2. doi:10.1126/sageke.2006.10.re2. PMID 16807486.

[pmid29312935-63] Plotegher N, Duchen MR (2017). "Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease". Frontiers in Cell and Developmental Biology. 5: 110. doi:10.3389/fcell.2017.00110. PMC 5732996. PMID 29312935.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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 | deaths          =
 }}
-'''Niemann–Pick type C''' ('''NPC''') (colloquially, "Childhood [[Alzheimer's]]"<ref>{{Cite web|title=What Is 'Childhood Alzheimer's'? An Expert Explains|url=https://blogs.webmd.com/webmd-interviews/20170928/what-is-childhood-alzheimers-an-expert-explains|access-date=2021-05-25|website=WebMD|language=en|archive-date=2021-05-25|archive-url=https://web.archive.org/web/20210525044522/https://blogs.webmd.com/webmd-interviews/20170928/what-is-childhood-alzheimers-an-expert-explains|url-status=dead}}</ref>) is a [[lysosomal storage disease]] associated with mutations in ''[[NPC1]]'' and ''[[NPC2]]'' genes. Niemann–Pick type C affects an estimated 1:150,000 people.<ref name="pmid15831488">{{cite journal|vauthors=Chang TY, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CC|title=Niemann–Pick type C disease and intracellular cholesterol trafficking|journal=The Journal of Biological Chemistry|volume=280|issue=22|pages=20917–20|date=June 2005|pmid=15831488|doi=10.1074/jbc.R400040200|doi-access=free}}</ref> Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.
+'''Niemann–Pick type C''' ('''NPC''') (colloquially, "Childhood [[Alzheimer's]]"<ref>{{Cite web|title=What Is 'Childhood Alzheimer's'? An Expert Explains|url=https://blogs.webmd.com/webmd-interviews/20170928/what-is-childhood-alzheimers-an-expert-explains|access-date=2021-05-25|website=WebMD|language=en|archive-date=2021-05-25|archive-url=https://web.archive.org/web/20210525044522/https://blogs.webmd.com/webmd-interviews/20170928/what-is-childhood-alzheimers-an-expert-explains|url-status=dead}}</ref>) is a [[lysosomal storage disease]] associated with mutations in ''[[NPC1]]'' and ''[[NPC2]]'' genes. Niemann–Pick type C affects an estimated 1:150,000 people.<ref name="pmid15831488">{{cite journal | vauthors = Chang TY, Reid PC, Sugii S, Ohgami N, Cruz JC, Chang CC | title = Niemann-Pick type C disease and intracellular cholesterol trafficking | journal = The Journal of Biological Chemistry | volume = 280 | issue = 22 | pages = 20917–20920 | date = June 2005 | pmid = 15831488 | doi = 10.1074/jbc.R400040200 | doi-access = free }}</ref> Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.
 == Signs and symptoms ==
 Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen ([[splenomegaly]]) and liver ([[hepatomegaly]]), or enlarged spleen or liver combined ([[hepatosplenomegaly]]), but this finding may be absent in later onset cases. Prolonged [[jaundice]] or elevated [[bilirubin]] can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or [[Gaucher disease]]. Organ enlargement does not usually cause major complications.{{citation needed|date=September 2020}}
-Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood.<ref name="pmid18815434">{{cite journal |vauthors=Rimkunas VM, Graham MJ, Crooke RM, Liscum L|title=TNF-alpha plays a role in hepatocyte apoptosis in Niemann–Pick type C liver disease|journal=Journal of Lipid Research|volume=50|issue=2|pages=327–33 |date=February 2009|pmid=18815434|pmc=2636917|doi=10.1194/jlr.M800415-JLR200}}</ref> Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline ([[dementia]]).{{citation needed|date=October 2021}}
+Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood.<ref name="pmid18815434">{{cite journal | vauthors = Rimkunas VM, Graham MJ, Crooke RM, Liscum L | title = TNF-{alpha} plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease | journal = Journal of Lipid Research | volume = 50 | issue = 2 | pages = 327–333 | date = February 2009 | pmid = 18815434 | pmc = 2636917 | doi = 10.1194/jlr.M800415-JLR200 }}</ref> Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline ([[dementia]]).{{citation needed|date=October 2021}}
 Neurological signs and symptoms include [[cerebellar ataxia]] (unsteady walking with uncoordinated limb movements), [[dysarthria]] (slurred speech), [[dysphagia]] (difficulty in swallowing), [[tremor]], [[epilepsy]] (both partial and generalized), vertical [[supranuclear palsy]] (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic [[cataplexy]] (sudden loss of muscle tone or drop attacks), [[dystonia]] (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, [[spasticity]] (velocity dependent increase in muscle tone), [[hypotonia]], [[ptosis (eyelid)|ptosis]] (drooping of the upper eyelid), microcephaly (abnormally small head), [[psychosis]], progressive [[dementia]], progressive hearing loss, [[bipolar disorder]], major and psychotic [[Major depressive disorder|depression]] that can include [[hallucinations]], [[delusions]], [[mutism]], or stupor.{{citation needed|date=October 2021}}
@@ Line 36: / Line 36: @@
 == Genetics ==
-Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the ''[[NPC1]]'' gene, referred to as type C1; 5% are caused by mutations in the ''[[NPC2]]'' gene, referred to as type C2.<ref name="pmid17629950">{{cite journal|vauthors=Mellon SH, Gong W, Schonemann MD|title=Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease|journal=Brain Research Reviews|volume=57
+Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the ''[[NPC1]]'' gene, referred to as type C1; 5% are caused by mutations in the ''[[NPC2]]'' gene, referred to as type C2.<ref name="pmid17629950">{{cite journal | vauthors = Mellon SH, Gong W, Schonemann MD | title = Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease | journal = Brain Research Reviews | volume = 57 | issue = 2 | pages = 410–420 | date = March 2008 | pmid = 17629950 | pmc = 2323675 | doi = 10.1016/j.brainresrev.2007.05.012 }}</ref> The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The ''NPC1'' gene is located on [[chromosome 18]] (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.<ref>{{cite web|title=NIH Scientists Identify Gene for Fatal Childhood Disorder, Niemann–Pick Type C|date=July 1997|work=Newsroom|publisher=National Human Genome Research Institute|url=http://www.genome.gov/10000889}}</ref>
+* The ''NPC1'' gene encodes a [[membrane protein|protein]] that is located in membranes inside the cell and is involved in the movement of cholesterol and [[lipids]] within cells.<ref name="pmid18483620">{{cite journal | vauthors = Zhang JR, Coleman T, Langmade SJ, Scherrer DE, Lane L, Lanier MH, Feng C, Sands MS, Schaffer JE, Semenkovich CF, Ory DS | display-authors = 6 | title = Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking | journal = The Journal of Clinical Investigation | volume = 118 | issue = 6 | pages = 2281–2290 | date = June 2008 | pmid = 18483620 | pmc = 2381744 | doi = 10.1172/JCI32561 }}</ref> A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
-|issue=2|pages=410–420|date=March 2008|pmid=17629950|pmc=2323675|doi=10.1016/j.brainresrev.2007.05.012}}</ref> The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The ''NPC1'' gene is located on [[chromosome 18]] (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.<ref>{{cite web|title=NIH Scientists Identify Gene for Fatal Childhood Disorder, Niemann–Pick Type C|date=July 1997|work=Newsroom|publisher=National Human Genome Research Institute|url=http://www.genome.gov/10000889}}</ref>
+* The ''NPC2'' gene encodes a protein that binds and transports cholesterol.<ref name="pmid18668002">{{cite journal | vauthors = Bjurulf B, Spetalen S, Erichsen A, Vanier MT, Strøm EH, Strømme P | title = Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue | journal = Medical Science Monitor | volume = 14 | issue = 8 | pages = CS71-CS75 | date = August 2008 | pmid = 18668002 | url = http://www.medscimonit.com/fulltxt.php?ICID=865795 }}</ref><ref name="pmid17018531">{{cite journal | vauthors = Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P | title = NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols | journal = The Journal of Biological Chemistry | volume = 281 | issue = 48 | pages = 36710–36723 | date = December 2006 | pmid = 17018531 | doi = 10.1074/jbc.M608743200 | doi-access = free }}</ref> It has been shown to closely interact with NPC1.<ref name="pmid18772377">{{cite journal | vauthors = Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL | title = NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 40 | pages = 15287–15292 | date = October 2008 | pmid = 18772377 | pmc = 2563079 | doi = 10.1073/pnas.0807328105 | doi-access = free }}</ref><ref name="pmid18832164">{{cite journal | vauthors = Subramanian K, Balch WE | title = NPC1/NPC2 function as a tag team duo to mobilize cholesterol | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 40 | pages = 15223–15224 | date = October 2008 | pmid = 18832164 | pmc = 2563125 | doi = 10.1073/pnas.0808256105 | doi-access = free | bibcode = 2008PNAS..10515223S }}</ref>
-* The ''NPC1'' gene encodes a [[membrane protein|protein]] that is located in membranes inside the cell and is involved in the movement of cholesterol and [[lipids]] within cells.<ref name="pmid18483620">{{cite journal|vauthors=Zhang JR, Coleman T, Langmade SJ, Scherrer DE, Lane L, Lanier MH, Feng C, Sands MS, Schaffer JE, Semenkovich CF, Ory DS|display-authors=6|title=Niemann–Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking|journal=The Journal of Clinical Investigation|volume=118|issue=6|pages=2281–2290|date=June 2008|pmid=18483620|pmc=2381744 |doi=10.1172/JCI32561}}</ref> A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
-* The ''NPC2'' gene encodes a protein that binds and transports cholesterol.<ref name="pmid18668002">{{cite journal|vauthors=Bjurulf B, Spetalen S, Erichsen A, Vanier MT, Strøm EH, Strømme P|title=Niemann–Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue|journal=Medical Science Monitor|volume=14|issue=8|date=August 2008
-|pages=CS71-5|pmid=18668002|url=http://www.medscimonit.com/fulltxt.php?ICID=865795}}</ref><ref name="pmid17018531">{{cite journal|vauthors=Liou HL, Dixit SS, Xu S, Tint GS, Stock AM, Lobel P|title=NPC2, the protein deficient in Niemann–Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols|journal=The Journal of Biological Chemistry|volume=281|issue=48|pages=36710–36723|date=December 2006
-|pmid=17018531|doi=10.1074/jbc.M608743200|doi-access=free}}</ref> It has been shown to closely interact with NPC1.<ref name="pmid18772377">{{cite journal|vauthors=Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL|title=NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=40|pages=15287–15292|date=October 2008|pmid=18772377|pmc=2563079|doi=10.1073/pnas.0807328105|doi-access=free}}</ref><ref name="pmid18832164">{{cite journal |vauthors=Subramanian K, Balch WE|title=NPC1/NPC2 function as a tag team duo to mobilize cholesterol|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=105|issue=40
-|pages=15223–15224|date=October 2008|pmid=18832164|pmc=2563125|doi=10.1073/pnas.0808256105|bibcode=2008PNAS..10515223S|doi-access=free}}</ref>
 === "Type D" variant ===
@@ Line 49: / Line 45: @@
 Type D Niemann–Pick has only been found in the [[French Canadian]] population of [[Yarmouth County]], [[Nova Scotia]], and is now known to be allelic with Niemann–Pick type C.
-Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.<ref name="pmid736041">{{cite journal|vauthors=Winsor EJ, Welch JP|title=Genetic and demographic aspects of Nova Scotia Niemann–Pick disease (type D)|journal=American Journal of Human Genetics|volume=30|issue=5 |pages=530–538|date=September 1978|pmid=736041|pmc=1685594}}</ref>
+Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.<ref name="pmid736041">{{cite journal | vauthors = Winsor EJ, Welch JP | title = Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D) | journal = American Journal of Human Genetics | volume = 30 | issue = 5 | pages = 530–538 | date = September 1978 | pmid = 736041 | pmc = 1685594 }}</ref>
 == Pathophysiology ==
-Niemann–Pick type C is biochemically, genetically and clinically distinct from [[Niemann–Pick disease, SMPD1-associated|Niemann–Pick Types A or and B]]. In Types A and B, there is complete or partial deficiency of the [[lysosomal]] [[enzyme]] called [[acid sphingomyelinase]]. In Niemann–Pick type C, the [[protein]] product of the major mutated gene ''[[NPC1]]'' is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble [[molecules]] through the [[Cell (biology)|cell]]. The protein coded by the ''[[NPC2]]'' gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of [[cholesterol]] and [[glycolipids]] in [[lysosomes]].<ref>{{cite journal |last1=Tobias |first1=Fernando |last2=Pathmasiri |first2=Koralege C. |last3=Cologna |first3=Stephanie M. |title=Mass spectrometry imaging reveals ganglioside and ceramide localization patterns during cerebellar degeneration in the Npc1−/− mouse model |journal=Analytical and Bioanalytical Chemistry |date=2019 |volume=411 |issue=22 |pages=5659–5668 |doi=10.1007/s00216-019-01989-7 |pmid=31254056 |s2cid=195761181 |url=https://doi.org/10.1007/s00216-019-01989-7}}</ref>
+Niemann–Pick type C is biochemically, genetically and clinically distinct from [[Niemann–Pick disease, SMPD1-associated|Niemann–Pick Types A or and B]]. In Types A and B, there is complete or partial deficiency of the [[lysosomal]] [[enzyme]] called [[acid sphingomyelinase]]. In Niemann–Pick type C, the [[protein]] product of the major mutated gene ''[[NPC1]]'' is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble [[molecules]] through the [[Cell (biology)|cell]]. The protein coded by the ''[[NPC2]]'' gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of [[cholesterol]] and [[glycolipids]] in [[lysosomes]].<ref>{{cite journal | vauthors = Tobias F, Pathmasiri KC, Cologna SM | title = Mass spectrometry imaging reveals ganglioside and ceramide localization patterns during cerebellar degeneration in the Npc1<sup>-/-</sup> mouse model | journal = Analytical and Bioanalytical Chemistry | volume = 411 | issue = 22 | pages = 5659–5668 | date = September 2019 | pmid = 31254056 | doi = 10.1007/s00216-019-01989-7 | s2cid = 195761181 }}</ref>
 Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell [[plasma membrane]]s, which define the cell as a whole and its [[organelles]]. It is also the basic building block of [[steroid]] [[hormones]], including [[neurosteroids]]. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of [[glycosphingolipids]] in the [[nervous system]] has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.{{citation needed|date=October 2021}}
 Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.
-* Neufeld et al. hypothesized that the accumulation of [[mannose 6-phosphate receptor]]s (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans [[Golgi apparatus|Golgi]] network.<ref name="npp">{{cite journal|vauthors=Neufeld EB, Wastney M, Patel S, Suresh S, Cooney AM, Dwyer NK, Roff CF, Ohno K, Morris JA, Carstea ED, Incardona JP, Strauss JF, Vanier MT, Patterson MC, Brady RO, Pentchev PG, Blanchette-Mackie EJ|display-authors=6|title=The Niemann–Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo
+* Neufeld et al. hypothesized that the accumulation of [[mannose 6-phosphate receptor]]s (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans [[Golgi apparatus|Golgi]] network.<ref name="npp">{{cite journal | vauthors = Neufeld EB, Wastney M, Patel S, Suresh S, Cooney AM, Dwyer NK, Roff CF, Ohno K, Morris JA, Carstea ED, Incardona JP, Strauss JF, Vanier MT, Patterson MC, Brady RO, Pentchev PG, Blanchette-Mackie EJ | display-authors = 6 | title = The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo | journal = The Journal of Biological Chemistry | volume = 274 | issue = 14 | pages = 9627–9635 | date = April 1999 | pmid = 10092649 | doi = 10.1074/jbc.274.14.9627 | doi-access = free }}</ref>
-|journal=The Journal of Biological Chemistry|volume=274|issue=14|pages=9627–9635|date=April 1999|pmid=10092649|doi=10.1074/jbc.274.14.9627|doi-access=free}}</ref>
 * Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return [[vesicle (biology)|vesicles]] of cholesterol to the trans Golgi Network cannot bud and form.
-* Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.<ref name="tmp">{{cite journal|vauthors=Davies JP, Chen FW, Ioannou YA|title=Transmembrane molecular pump activity of Niemann–Pick C1 protein|journal=Science|volume=290|issue=5500|pages=2295–2298|date=December 2000 |pmid=11125140|doi=10.1126/science.290.5500.2295|bibcode=2000Sci...290.2295D}}</ref>
+* Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.<ref name="tmp">{{cite journal | vauthors = Davies JP, Chen FW, Ioannou YA | title = Transmembrane molecular pump activity of Niemann-Pick C1 protein | journal = Science | volume = 290 | issue = 5500 | pages = 2295–2298 | date = December 2000 | pmid = 11125140 | doi = 10.1126/science.290.5500.2295 | bibcode = 2000Sci...290.2295D }}</ref>
-* Recent 2008 evidence indicates that NPC-1 may play an important role in [[calcium]] regulation.<ref name="pmid18953351">{{cite journal|vauthors=Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM|display-authors=6|title=Niemann–Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium|journal=Nature Medicine|volume=14|issue=11|pages=1247–1255|date=November 2008|pmid=18953351|doi=10.1038/nm.1876|s2cid=14964042}}</ref>
+* Recent 2008 evidence indicates that NPC-1 may play an important role in [[calcium]] regulation.<ref name="pmid18953351">{{cite journal | vauthors = Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM | display-authors = 6 | title = Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium | journal = Nature Medicine | volume = 14 | issue = 11 | pages = 1247–1255 | date = November 2008 | pmid = 18953351 | doi = 10.1038/nm.1876 | s2cid = 14964042 }}</ref>
 == Diagnosis ==
@@ Line 67: / Line 62: @@
 == Treatment ==
-There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment.<ref name="pmid18782459">{{cite journal|vauthors=Pacheco CD, Lieberman AP|title=The pathogenesis of Niemann–Pick type C disease: a role for autophagy?|journal=Expert Reviews in Molecular Medicine|volume=10|page=e26|date=September 2008|pmid=18782459|pmc=2662713|doi=10.1017/S146239940800080X}}</ref> Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in [[neurology]], [[pulmonology]], [[gastroenterology]], [[psychiatrist]], [[orthopedics]], [[nutrition]], [[physical therapy]] and [[occupational therapy]]. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a [[gastrostomy tube]] (g-tube, feeding tube).<ref>{{Cite book |first=Marc|last=Patterson|date=2013-07-18|title=Niemann–Pick Disease Type C|id=NBK1296|url=https://www.ncbi.nlm.nih.gov/books/NBK1296/|veditors=Pagon RA, Bird TD, Dolan CR, etal|work=GeneReviews™ [Internet]|publisher=University of Washington, Seattle|location=Seattle WA|pmid=20301473 |ref={{harvid|GeneReviews}}}}</ref>
+There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment.<ref name="pmid18782459">{{cite journal | vauthors = Pacheco CD, Lieberman AP | title = The pathogenesis of Niemann-Pick type C disease: a role for autophagy? | journal = Expert Reviews in Molecular Medicine | volume = 10 | pages = e26 | date = September 2008 | pmid = 18782459 | pmc = 2662713 | doi = 10.1017/S146239940800080X }}</ref> Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in [[neurology]], [[pulmonology]], [[gastroenterology]], [[psychiatrist]], [[orthopedics]], [[nutrition]], [[physical therapy]] and [[occupational therapy]]. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a [[gastrostomy tube]] (g-tube, feeding tube).<ref>{{Cite book | vauthors = Patterson M |date=2013-07-18|title=Niemann–Pick Disease Type C|id=NBK1296|url=https://www.ncbi.nlm.nih.gov/books/NBK1296/|veditors=Pagon RA, Bird TD, Dolan CR, etal|work=GeneReviews™ [Internet]|publisher=University of Washington, Seattle|location=Seattle WA|pmid=20301473 |ref={{harvid|GeneReviews}}}}</ref>
 === Arimoclomol ===
-In 2014, the [[European Medicines Agency]] (EMA) granted orphan drug designation to [[arimoclomol]] for the treatment of Niemann–Pick type C.<ref>{{cite web|title=European Medicines Agency - - EU/3/14/1376 |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b|website=www.ema.europa.eu|date=2018-09-17}}</ref> This was followed in 2015 by the [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA).<ref>{{cite web|title=Search Orphan Drug Designations and Approvals|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814|website=www.accessdata.fda.gov}} {{PD-notice}}</ref> Dosing in a [[placebo-controlled]] phase II/III [[clinical trial]] to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.<ref>{{ClinicalTrialsGov|NCT02612129|Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C}}</ref> Arimoclomol, which is orally administered, induces the [[heat shock]] response in cells and is well tolerated in humans.<ref>{{cite journal|vauthors=Kirkegaard T, Gray J, Priestman DA, Wallom KL, Atkins J, Olsen OD, Klein A, Drndarski S, Petersen NH, Ingemann L, Smith DA, Morris L, Bornæs C, Jørgensen SH, Williams I, Hinsby A, Arenz C, Begley D, Jäättelä M, Platt FM|display-authors=6|title=Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses|journal=Science Translational Medicine|volume=8|issue=355|page=355ra118|date=September 2016|pmid=27605553|pmc=6821533|doi=10.1126/scitranslmed.aad9823}}</ref><ref>{{cite journal|vauthors=Ahmed M, Machado PM, Miller A, Spicer C, Herbelin L, He J, Noel J, Wang Y, McVey AL, Pasnoor M, Gallagher P, Statland J, Lu CH, Kalmar B, Brady S, Sethi H, Samandouras G, Parton M, Holton JL, Weston A, Collinson L, Taylor JP, Schiavo G, Hanna MG, Barohn RJ, Dimachkie MM, Greensmith L|display-authors=6|title=Targeting protein homeostasis in sporadic inclusion body myositis|journal=Science Translational Medicine|volume=8|issue=331|page=331ra41|date=March 2016 |pmid=27009270|pmc=5043094|doi=10.1126/scitranslmed.aad4583}}</ref><ref>{{cite journal|vauthors=Rakonczay Z, Iványi B, Varga I, Boros I, Jednákovits A, Németh I, Lonovics J, Takács T|display-authors=6 |title=Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats|journal=Free Radical Biology & Medicine|volume=32|issue=12|pages=1283–1292|date=June 2002|pmid=12057766 |doi=10.1016/s0891-5849(02)00833-x}}</ref><ref>{{cite journal|vauthors=Lanka V, Wieland S, Barber J, Cudkowicz M|title=Arimoclomol: a potential therapy under development for ALS|journal=Expert Opinion on Investigational Drugs|volume=18|issue=12|pages=1907–1918|date=December 2009|pmid=19938902|doi=10.1517/13543780903357486|s2cid=207475296}}</ref>{{citation overkill|date=September 2020}} In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints.<ref>{{cite web|title=ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)|url=https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|website=nnpdf.org/|access-date=2021-08-06|archive-date=2021-08-07|archive-url=https://web.archive.org/web/20210807005438/https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|url-status=dead}}</ref> On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor.<ref>{{cite web|title=ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)|url=https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|website=nnpdf.org/|access-date=2021-08-06|archive-date=2021-08-07|archive-url=https://web.archive.org/web/20210807005438/https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|url-status=dead}}</ref>
+In 2014, the [[European Medicines Agency]] (EMA) granted orphan drug designation to [[arimoclomol]] for the treatment of Niemann–Pick type C.<ref>{{cite web|title=European Medicines Agency - - EU/3/14/1376 |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2015/01/human_orphan_001465.jsp&mid=WC0b01ac058001d12b|website=www.ema.europa.eu|date=2018-09-17}}</ref> This was followed in 2015 by the [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA).<ref>{{cite web|title=Search Orphan Drug Designations and Approvals|url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=458814|website=www.accessdata.fda.gov}} {{PD-notice}}</ref> Dosing in a [[placebo-controlled]] phase II/III [[clinical trial]] to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016.<ref>{{ClinicalTrialsGov|NCT02612129|Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C}}</ref> Arimoclomol, which is orally administered, induces the [[heat shock]] response in cells and is well tolerated in humans.<ref>{{cite journal | vauthors = Kirkegaard T, Gray J, Priestman DA, Wallom KL, Atkins J, Olsen OD, Klein A, Drndarski S, Petersen NH, Ingemann L, Smith DA, Morris L, Bornæs C, Jørgensen SH, Williams I, Hinsby A, Arenz C, Begley D, Jäättelä M, Platt FM | display-authors = 6 | title = Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses | journal = Science Translational Medicine | volume = 8 | issue = 355 | pages = 355ra118 | date = September 2016 | pmid = 27605553 | pmc = 6821533 | doi = 10.1126/scitranslmed.aad9823 }}</ref><ref>{{cite journal | vauthors = Ahmed M, Machado PM, Miller A, Spicer C, Herbelin L, He J, Noel J, Wang Y, McVey AL, Pasnoor M, Gallagher P, Statland J, Lu CH, Kalmar B, Brady S, Sethi H, Samandouras G, Parton M, Holton JL, Weston A, Collinson L, Taylor JP, Schiavo G, Hanna MG, Barohn RJ, Dimachkie MM, Greensmith L | display-authors = 6 | title = Targeting protein homeostasis in sporadic inclusion body myositis | journal = Science Translational Medicine | volume = 8 | issue = 331 | pages = 331ra41 | date = March 2016 | pmid = 27009270 | pmc = 5043094 | doi = 10.1126/scitranslmed.aad4583 }}</ref><ref>{{cite journal | vauthors = Rakonczay Z, Iványi B, Varga I, Boros I, Jednákovits A, Németh I, Lonovics J, Takács T | display-authors = 6 | title = Nontoxic heat shock protein coinducer BRX-220 protects against acute pancreatitis in rats | journal = Free Radical Biology & Medicine | volume = 32 | issue = 12 | pages = 1283–1292 | date = June 2002 | pmid = 12057766 | doi = 10.1016/s0891-5849(02)00833-x }}</ref><ref>{{cite journal | vauthors = Lanka V, Wieland S, Barber J, Cudkowicz M | title = Arimoclomol: a potential therapy under development for ALS | journal = Expert Opinion on Investigational Drugs | volume = 18 | issue = 12 | pages = 1907–1918 | date = December 2009 | pmid = 19938902 | doi = 10.1517/13543780903357486 | s2cid = 207475296 }}</ref>{{citation overkill|date=September 2020}} In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints.<ref>{{cite web|title=ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)|url=https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|website=nnpdf.org/|access-date=2021-08-06|archive-date=2021-08-07|archive-url=https://web.archive.org/web/20210807005438/https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|url-status=dead}}</ref> On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor.<ref>{{cite web|title=ORPHAZYME REPORTS ENCOURAGING ARIMOCLOMOL CLINICAL TRIAL TOP-LINE DATA IN NIEMANN-PICK DISEASE TYPE C (NPC)|url=https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|website=nnpdf.org/|access-date=2021-08-06|archive-date=2021-08-07|archive-url=https://web.archive.org/web/20210807005438/https://nnpdf.org/files/2018/09/ORPHAZYME-Reports-Arimoclomol-Trial-Data-NPC-9.28.2018.pdf|url-status=dead}}</ref>
 === Hydroxypropyl-beta-cyclodextrin (HPbCD) ===
-In April 2009, hydroxypropyl-beta-[[cyclodextrin]] (HPbCD) was approved under [[compassionate use]] by the [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA) to treat Addison and Cassidy Hempel,<ref>{{cite web|url=http://www.addiandcassi.com|title=The Addi and Cassi Fund - Niemann Pick Type-C - Childhood Alzheimer's|access-date=12 August 2016}}</ref> identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice<ref name="pmid19750228">{{cite journal|vauthors=Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU|display-authors=6|title=Chronic cyclodextrin treatment of murine Niemann–Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression|journal=PLOS ONE|volume=4|issue=9|page=e6951|date=September 2009
+In April 2009, hydroxypropyl-beta-[[cyclodextrin]] (HPbCD) was approved under [[compassionate use]] by the [[Food and Drug Administration|U.S. Food and Drug Administration]] (FDA) to treat Addison and Cassidy Hempel,<ref>{{cite web|url=http://www.addiandcassi.com|title=The Addi and Cassi Fund - Niemann Pick Type-C - Childhood Alzheimer's|access-date=12 August 2016}}</ref> identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice<ref name="pmid19750228">{{cite journal | vauthors = Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU | display-authors = 6 | title = Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression | journal = PloS One | volume = 4 | issue = 9 | pages = e6951 | date = September 2009 | pmid = 19750228 | pmc = 2736622 | doi = 10.1371/journal.pone.0006951 | bibcode = 2009PLoSO...4.6951D | doi-access = free }}</ref> and feline<ref name="pmid20357695">{{cite journal | vauthors = Ward S, O'Donnell P, Fernandez S, Vite CH | title = 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease | journal = Pediatric Research | volume = 68 | issue = 1 | pages = 52–56 | date = July 2010 | pmid = 20357695 | pmc = 2913583 | doi = 10.1203/PDR.0b013e3181df4623 }}</ref> models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe [[hypervitaminosis A]].<ref name="pmid3655980">{{cite journal | vauthors = Carpenter TO, Pettifor JM, Russell RM, Pitha J, Mobarhan S, Ossip MS, Wainer S, Anast CS | display-authors = 6 | title = Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake | journal = The Journal of Pediatrics | volume = 111 | issue = 4 | pages = 507–512 | date = October 1987 | pmid = 3655980 | doi = 10.1016/S0022-3476(87)80109-9 }}</ref>
-|pmid=19750228|pmc=2736622|doi=10.1371/journal.pone.0006951|bibcode=2009PLoSO...4.6951D|doi-access=free}}</ref> and feline<ref name="pmid20357695">{{cite journal|vauthors=Ward S, O'Donnell P, Fernandez S, Vite CH|title=2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann–Pick type C disease|journal=Pediatric Research|volume=68|issue=1|pages=52–56|date=July 2010|pmid=20357695 |pmc=2913583|doi=10.1203/PDR.0b013e3181df4623}}</ref> models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe [[hypervitaminosis A]].<ref name="pmid3655980">{{cite journal|vauthors=Carpenter TO, Pettifor JM, Russell RM, Pitha J, Mobarhan S, Ossip MS, Wainer S, Anast CS|display-authors=6|title=Severe hypervitaminosis A in siblings: evidence of variable tolerance to retinol intake|journal=The Journal of Pediatrics|volume=111|issue=4|pages=507–512
-|date=October 1987|pmid=3655980|doi=10.1016/S0022-3476(87)80109-9}}</ref>
 On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Children's Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.{{citation needed|date=September 2020}}
@@ Line 94: / Line 87: @@
 === N-Acetyl-Leucine ===
-[[Acetylleucine|N-Acetyl-Leucine]] is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc.<ref>{{Cite journal |last=Fields |first=T. |last2=Patterson |first2=M. |last3=Bremova-Ertl |first3=T. |last4=Belcher |first4=G. |last5=Billington |first5=I. |last6=Churchill |first6=G. C. |last7=Davis |first7=W. |last8=Evans |first8=W. |last9=Flint |first9=S. |last10=Galione |first10=A. |last11=Granzer |first11=U. |last12=Greenfield |first12=J. |last13=Karl |first13=R. |last14=Kay |first14=R. |last15=Lewi |first15=D. |date=2021 |title=A master protocol to investigate a novel therapy acetyl-l-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia |url=https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-05009-3 |journal=Trials |language=en |volume=22 |issue=1 |doi=10.1186/s13063-020-05009-3 |issn=1745-6215 |pmc=PMC7821839 |pmid=33482890}}</ref>
+[[Acetylleucine|N-Acetyl-Leucine]] is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc.<ref>{{cite journal | vauthors = Fields T, Patterson M, Bremova-Ertl T, Belcher G, Billington I, Churchill GC, Davis W, Evans W, Flint S, Galione A, Granzer U, Greenfield J, Karl R, Kay R, Lewi D, Mathieson T, Meyer T, Pangonis D, Platt FM, Tsang L, Verburg C, Factor M, Strupp M | display-authors = 6 | title = A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia | journal = Trials | volume = 22 | issue = 1 | pages = 84 | date = January 2021 | pmid = 33482890 | pmc = 7821839 | doi = 10.1186/s13063-020-05009-3 }}</ref>
 N-Acetyl-Leucine has been granted multiple orphan drug designations from the [[U.S. Food & Drug Administration]] (FDA) and the [[European Medicines Agency]] (EMA) for the treatment of various genetic diseases, including Niemann-Pick Disease Type C. The US FDA has granted IntraBio a [[Priority review|Rare Pediatric Disease Designation]] for N-Acetyl-Leucine for the treatment of NPC.<ref>{{Cite web |date=2020-03-25 |title=IntraBio Receives FDA Fast Track Designation for Niemann-Pick Disease |url=https://www.npuk.org/intrabio-receives-fda-fast-track-designation-for-niemann-pick-disease/ |access-date=2023-09-19 |website=NPUK |language=en}}</ref>
-Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.<ref>{{cite journal|title=Acetyl-Leucine slows disease progression in lysosomal storage disorders|url=https://www.biorxiv.org/content/10.1101/2020.05.20.105973v1.full|journal=bioRxiv|year=2020|doi=10.1101/2020.05.20.105973|access-date=2021-08-06|last1=Kaya|first1=Ecem|last2=Smith|first2=David A.|last3=Smith|first3=Claire|last4=Morris|first4=Lauren|last5=Bremova-Ertl|first5=Tatiana|last6=Cortina-Borja|first6=Mario|last7=Fineran|first7=Paul|last8=Morten|first8=Karl J.|last9=Poulton|first9=Joanna|last10=Boland|first10=Barry|last11=Spencer|first11=John|last12=Strupp|first12=Michael|last13=Platt|first13=Frances M.|volume=3|issue=1|pages=fcaa148|pmid=33738443|pmc=7954382}}</ref>
+Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.<ref>{{cite journal | vauthors = Kaya E, Smith DA, Smith C, Morris L, Bremova-Ertl T, Cortina-Borja M, Fineran P, Morten KJ, Poulton J, Boland B, Spencer J, Strupp M, Platt FM | display-authors = 6 | title = Acetyl-leucine slows disease progression in lysosomal storage disorders | journal = Brain Communications | volume = 3 | issue = 1 | pages = fcaa148 | year = 2020 | pmid = 33738443 | pmc = 7954382 | doi = 10.1101/2020.05.20.105973 }}</ref>
 In September 2020, IntraBio announced the successful results of a multinational clinical trial with N-acetyl-L-leucine (IB1001) for NPC, which demonstrated IB1001 demonstrated a statistically significant change in both primary and secondary endpoints, and clinically meaningful improvement in symptoms, functioning, and quality of life.<ref>{{cite web|title=IntraBio Reports Further Detail on Positive Data from IB1001 Multinational Clinical Trial for the Treatment of Niemann-Pick disease Type C|url=http://intrabio.com/2020/10/19/intrabio-reports-further-detail-on-positive-data-from-ib1001-multinational-clinical-trial-for-the-treatment-of-niemann-pick-disease-type-c/|website=intrabio.com|date=19 October 2020|access-date=2021-08-06}}</ref>
-IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff)<ref>{{Cite journal|url=https://clinicaltrials.gov/ct2/show/NCT03759665|title=N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)|website=clinicaltrials.gov|date=28 May 2021|language=en|access-date=2021-08-06}}</ref> and [[Ataxia–telangiectasia|Ataxia-Telangiectasia]].<ref>{{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT03759678|title=N-Acetyl-L-Leucine for Ataxia-Telangiectasia|website=clinicaltrials.gov|language=en|access-date=2019-08-01}}</ref> Future opportunities to develop N-Acetyl-Leucine include [[Lewy body dementia]],<ref>{{Cite web|url=http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|title=IntraBio|language=en-GB|access-date=2019-08-01|archive-date=2019-08-01|archive-url=https://web.archive.org/web/20190801041945/http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|url-status=dead}}</ref> [[amyotrophic lateral sclerosis]], [[Restless legs syndrome|restless leg syndrome]], [[multiple sclerosis]], and [[migraine]].<ref>{{Cite journal|last1=Strupp|first1=Michael|last2=Bayer|first2=Otmar|last3=Feil|first3=Katharina|last4=Straube|first4=Andreas|date=2019-02-01|title=Prophylactic treatment of migraine with and without aura with acetyl-dl-leucine: a case series|journal=Journal of Neurology|language=en|volume=266|issue=2|pages=525–529|doi=10.1007/s00415-018-9155-6|pmid=30547273|s2cid=56148131|issn=1432-1459}}</ref>
+IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff)<ref>{{Cite journal|url=https://clinicaltrials.gov/ct2/show/NCT03759665|title=N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)|website=clinicaltrials.gov|date=28 May 2021|language=en|access-date=2021-08-06}}</ref> and [[Ataxia–telangiectasia|Ataxia-Telangiectasia]].<ref>{{Cite web|url=https://clinicaltrials.gov/ct2/show/NCT03759678|title=N-Acetyl-L-Leucine for Ataxia-Telangiectasia|website=clinicaltrials.gov|language=en|access-date=2019-08-01}}</ref> Future opportunities to develop N-Acetyl-Leucine include [[Lewy body dementia]],<ref>{{Cite web|url=http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|title=IntraBio|language=en-GB|access-date=2019-08-01|archive-date=2019-08-01|archive-url=https://web.archive.org/web/20190801041945/http://intrabio.com/2018/12/02/intrabio-announces-clinical-results-for-treatment-of-dementia/|url-status=dead}}</ref> [[amyotrophic lateral sclerosis]], [[Restless legs syndrome|restless leg syndrome]], [[multiple sclerosis]], and [[migraine]].<ref>{{cite journal | vauthors = Strupp M, Bayer O, Feil K, Straube A | title = Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series | journal = Journal of Neurology | volume = 266 | issue = 2 | pages = 525–529 | date = February 2019 | pmid = 30547273 | doi = 10.1007/s00415-018-9155-6 | s2cid = 56148131 }}</ref>
 === Other treatments under investigation ===
-One drug that has been tried is [[Miglustat]].<ref name="pmid17689147">{{cite journal|vauthors=Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE|title=Miglustat for treatment of Niemann–Pick C disease: a randomised controlled study|journal=The Lancet. Neurology|volume=6|issue=9|pages=765–772|date=September 2007|pmid=17689147|doi=10.1016/S1474-4422(07)70194-1|s2cid=9954233}}</ref><ref name="pmid18937049">{{cite journal
+One drug that has been tried is [[Miglustat]].<ref name="pmid17689147">{{cite journal | vauthors = Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE | title = Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study | journal = The Lancet. Neurology | volume = 6 | issue = 9 | pages = 765–772 | date = September 2007 | pmid = 17689147 | doi = 10.1016/S1474-4422(07)70194-1 | s2cid = 9954233 }}</ref><ref name="pmid18937049">{{cite journal | vauthors = Santos ML, Raskin S, Telles DS, Löhr A, Liberalesso PB, Vieira SC, Cordeiro ML | title = Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: a case report in Brazil | journal = Journal of Inherited Metabolic Disease | volume = 31 Suppl 2 | issue = Suppl 2 | pages = S357-S361 | date = December 2008 | pmid = 18937049 | doi = 10.1007/s10545-008-0923-9 | s2cid = 25982189 }}</ref> Miglustat is a [[glucosylceramide]] synthase inhibitor, which inhibits the synthesis of [[glycosphingolipids]] in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the [[United States]] and [[England]] and from case reports suggests that it may ameliorate the course of human NPC.{{citation needed|date=October 2021}}
-|vauthors=Santos ML, Raskin S, Telles DS, Löhr A, Liberalesso PB, Vieira SC, Cordeiro ML|title=Treatment of a child diagnosed with Niemann–Pick disease type C with miglustat: a case report in Brazil
-|journal=Journal of Inherited Metabolic Disease|volume=31|pages=S357-361|date=December 2008|issue=Suppl 2
-|pmid=18937049|doi=10.1007/s10545-008-0923-9|s2cid=25982189
-}}</ref> Miglustat is a [[glucosylceramide]] synthase inhibitor, which inhibits the synthesis of [[glycosphingolipids]] in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the [[United States]] and [[England]] and from case reports suggests that it may ameliorate the course of human NPC.{{citation needed|date=October 2021}}
-Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, [[neurosteroid]] (a special type of hormone that affects brain and other nerve cells) replacement using [[allopregnanolone]],<ref name="pmid17629950"/><ref name="pmid16273542">{{cite journal|vauthors=Ahmad I, Lope-Piedrafita S, Bi X, Hicks C, Yao Y, Yu C, Chaitkin E, Howison CM, Weberg L, Trouard TP, Erickson RP|display-authors=6|title=Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann–Pick C mice |journal=Journal of Neuroscience Research|volume=82|issue=6|pages=811–821|date=December 2005|pmid=16273542|doi=10.1002/jnr.20685|s2cid=37375979}}</ref> rab overexpression to bypass the trafficking block (Pagano lab) and [[Curcumin]] as an [[anti-inflammatory]] and [[calcium]] modulatory agent.<ref name="pmid18953351"/> The [[pregnane X receptor]] has been identified as a potential target.<ref name="pmid16940355">{{cite journal |vauthors=Langmade SJ, Gale SE, Frolov A, Mohri I, Suzuki K, Mellon SH, Walkley SU, Covey DF, Schaffer JE, Ory DS|display-authors=6|title=Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann–Pick C disease|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=103|issue=37|pages=13807–13812|date=September 2006|pmid=16940355
+Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, [[neurosteroid]] (a special type of hormone that affects brain and other nerve cells) replacement using [[allopregnanolone]],<ref name="pmid17629950"/><ref name="pmid16273542">{{cite journal | vauthors = Ahmad I, Lope-Piedrafita S, Bi X, Hicks C, Yao Y, Yu C, Chaitkin E, Howison CM, Weberg L, Trouard TP, Erickson RP | display-authors = 6 | title = Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice | journal = Journal of Neuroscience Research | volume = 82 | issue = 6 | pages = 811–821 | date = December 2005 | pmid = 16273542 | doi = 10.1002/jnr.20685 | s2cid = 37375979 }}</ref> rab overexpression to bypass the trafficking block (Pagano lab) and [[Curcumin]] as an [[anti-inflammatory]] and [[calcium]] modulatory agent.<ref name="pmid18953351"/> The [[pregnane X receptor]] has been identified as a potential target.<ref name="pmid16940355">{{cite journal | vauthors = Langmade SJ, Gale SE, Frolov A, Mohri I, Suzuki K, Mellon SH, Walkley SU, Covey DF, Schaffer JE, Ory DS | display-authors = 6 | title = Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 37 | pages = 13807–13812 | date = September 2006 | pmid = 16940355 | pmc = 1564205 | doi = 10.1073/pnas.0606218103 | doi-access = free | bibcode = 2006PNAS..10313807L }}</ref>
-|pmc=1564205|doi=10.1073/pnas.0606218103|bibcode=2006PNAS..10313807L|doi-access=free}}</ref>
-Neural [[stem cell]]s have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.<ref name="pmid17666780">{{cite journal|vauthors=Ahmad I, Hunter RE, Flax JD, Snyder EY, Erickson RP|title=Neural stem cell implantation extends life in Niemann–Pick C1 mice|journal=Journal of Applied Genetics|volume=48|issue=3|pages=269–272|year=2007|pmid=17666780 |doi=10.1007/BF03195222|s2cid=23689067|url=http://jag.igr.poznan.pl/2007-Volume-48/3/abstracts/403.html}}</ref>
+Neural [[stem cell]]s have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.<ref name="pmid17666780">{{cite journal | vauthors = Ahmad I, Hunter RE, Flax JD, Snyder EY, Erickson RP | title = Neural stem cell implantation extends life in Niemann-Pick C1 mice | journal = Journal of Applied Genetics | volume = 48 | issue = 3 | pages = 269–272 | year = 2007 | pmid = 17666780 | doi = 10.1007/BF03195222 | s2cid = 23689067 }}</ref>
 Low cholesterol diets are often used,<ref name="urleMedicine - Niemann–Pick Disease : Article by Robert A Schwartz">{{cite web|url=http://www.emedicine.com/derm/topic699.htm|title=eMedicine – Niemann–Pick Disease : Article by Robert A Schwartz|access-date=2008-10-27}}</ref> but there is no evidence of efficacy.<ref name="urlNiemann–Pick Disease">{{cite web|url=http://my.clevelandclinic.org/disorders/Niemann–Pick_Disease_NP/hic_Niemann–Pick_Disease.aspx|title=Niemann–Pick Disease|access-date=2008-10-27}}</ref>
-[[Gene therapy]] is being used clinically to treat genetic diseases including [[haemophilia]]<ref>{{Cite journal|last1=Nathwani|first1=Amit C.|last2=Reiss|first2=Ulreke M.|last3=Tuddenham|first3=Edward G.D.|last4=Rosales|first4=Cecilia|last5=Chowdary|first5=Pratima|last6=McIntosh|first6=Jenny|last7=Della Peruta|first7=Marco|last8=Lheriteau|first8=Elsa|last9=Patel|first9=Nishal|last10=Raj|first10=Deepak|last11=Riddell|first11=Anne|date=2014-11-20|title=Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B|journal=New England Journal of Medicine|language=en|volume=371|issue=21|pages=1994–2004|doi=10.1056/NEJMoa1407309|issn=0028-4793|pmc=4278802|pmid=25409372}}</ref> and [[spinal muscular atrophy]].<ref>{{Cite journal|last1=Mendell|first1=Jerry R.|last2=Al-Zaidy|first2=Samiah|last3=Shell|first3=Richard|last4=Arnold|first4=W. Dave|last5=Rodino-Klapac|first5=Louise R.|last6=Prior|first6=Thomas W.|last7=Lowes|first7=Linda|last8=Alfano|first8=Lindsay|last9=Berry|first9=Katherine|last10=Church|first10=Kathleen|last11=Kissel|first11=John T.|date=2017-11-02|title=Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy|journal=New England Journal of Medicine|language=en|volume=377|issue=18|pages=1713–1722|doi=10.1056/NEJMoa1706198|pmid=29091557|issn=0028-4793|doi-access=free}}</ref> It has been used preclinically, in a mouse model of Niemann-Pick type C, using an [[adeno-associated virus]] derived [[viral vector]] has been shown to extend lifespan following injection into the lateral [[Ventricles (brain)|ventricles]] of the neonatal brain.<ref>{{Cite journal|last1=Hughes|first1=Michael P|last2=Smith|first2=Dave A|last3=Morris|first3=Lauren|last4=Fletcher|first4=Claire|last5=Colaco|first5=Alexandria|last6=Huebecker|first6=Mylene|last7=Tordo|first7=Julie|last8=Palomar|first8=Nuria|last9=Massaro|first9=Giulia|last10=Henckaerts|first10=Els|last11=Waddington|first11=Simon N|date=2018-09-01|title=AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann–Pick type C1 disease|url=https://doi.org/10.1093/hmg/ddy212|journal=Human Molecular Genetics|volume=27|issue=17|pages=3079–3098|doi=10.1093/hmg/ddy212|issn=0964-6906|pmc=6097154|pmid=29878115}}</ref> In a separate proof-of-concept study a similar vector, but with a modified [[capsid]] capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.<ref>{{Cite journal|last1=Davidson|first1=Cristin D|last2=Gibson|first2=Alana L|last3=Gu|first3=Tansy|last4=Baxter|first4=Laura L|last5=Deverman|first5=Benjamin E|last6=Beadle|first6=Keith|last7=Incao|first7=Arturo A|last8=Rodriguez-Gil|first8=Jorge L|last9=Fujiwara|first9=Hideji|last10=Jiang|first10=Xuntian|last11=Chandler|first11=Randy J|date=October 2021|title=Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann–Pick disease type C1 mice|journal=Life Science Alliance|language=en|volume=4|issue=10|pages=e202101040|doi=10.26508/lsa.202101040|pmid=34407999|pmc=8380657|issn=2575-1077|doi-access=free}}</ref>
+[[Gene therapy]] is being used clinically to treat genetic diseases including [[haemophilia]]<ref>{{cite journal | vauthors = Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, Della Peruta M, Lheriteau E, Patel N, Raj D, Riddell A, Pie J, Rangarajan S, Bevan D, Recht M, Shen YM, Halka KG, Basner-Tschakarjan E, Mingozzi F, High KA, Allay J, Kay MA, Ng CY, Zhou J, Cancio M, Morton CL, Gray JT, Srivastava D, Nienhuis AW, Davidoff AM | display-authors = 6 | title = Long-term safety and efficacy of factor IX gene therapy in hemophilia B | journal = The New England Journal of Medicine | volume = 371 | issue = 21 | pages = 1994–2004 | date = November 2014 | pmid = 25409372 | pmc = 4278802 | doi = 10.1056/NEJMoa1407309 }}</ref> and [[spinal muscular atrophy]].<ref>{{cite journal | vauthors = Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L'Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AH, Kaspar BK | display-authors = 6 | title = Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy | journal = The New England Journal of Medicine | volume = 377 | issue = 18 | pages = 1713–1722 | date = November 2017 | pmid = 29091557 | doi = 10.1056/NEJMoa1706198 | doi-access = free }}</ref> It has been used preclinically, in a mouse model of Niemann-Pick type C, using an [[adeno-associated virus]] derived [[viral vector]] has been shown to extend lifespan following injection into the lateral [[Ventricles (brain)|ventricles]] of the neonatal brain.<ref>{{cite journal | vauthors = Hughes MP, Smith DA, Morris L, Fletcher C, Colaco A, Huebecker M, Tordo J, Palomar N, Massaro G, Henckaerts E, Waddington SN, Platt FM, Rahim AA | display-authors = 6 | title = AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease | journal = Human Molecular Genetics | volume = 27 | issue = 17 | pages = 3079–3098 | date = September 2018 | pmid = 29878115 | pmc = 6097154 | doi = 10.1093/hmg/ddy212 }}</ref> In a separate proof-of-concept study a similar vector, but with a modified [[capsid]] capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.<ref>{{cite journal | vauthors = Davidson CD, Gibson AL, Gu T, Baxter LL, Deverman BE, Beadle K, Incao AA, Rodriguez-Gil JL, Fujiwara H, Jiang X, Chandler RJ, Ory DS, Gradinaru V, Venditti CP, Pavan WJ | display-authors = 6 | title = Improved systemic AAV gene therapy with a neurotrophic capsid in Niemann-Pick disease type C1 mice | journal = Life Science Alliance | volume = 4 | issue = 10 | pages = e202101040 | date = October 2021 | pmid = 34407999 | pmc = 8380657 | doi = 10.26508/lsa.202101040 | doi-access = free }}</ref>
 == Prognosis ==
@@ Line 124: / Line 112: @@
 == Research directions ==
-Loss of [[myelin]] in the [[central nervous system]] is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the [[NPC1]] gene Niemann–Pick type C disease. In this model the expression of [[Myelin gene Regulatory Factor]] (MRF) has been shown to be significantly decreased.<ref name=yan>{{cite journal|vauthors=Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, Köhling R, Rolfs A, Luo J|display-authors=6|title=Decreased expression of myelin gene regulatory factor in Niemann–Pick type C 1 mouse|journal=Metabolic Brain Disease
+Loss of [[myelin]] in the [[central nervous system]] is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the [[NPC1]] gene Niemann–Pick type C disease. In this model the expression of [[Myelin gene Regulatory Factor]] (MRF) has been shown to be significantly decreased.<ref name=yan>{{cite journal | vauthors = Yan X, Lukas J, Witt M, Wree A, Hübner R, Frech M, Köhling R, Rolfs A, Luo J | display-authors = 6 | title = Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse | journal = Metabolic Brain Disease | volume = 26 | issue = 4 | pages = 299–306 | date = December 2011 | pmid = 21938520 | doi = 10.1007/s11011-011-9263-9 | s2cid = 26878522 }}</ref> [[Myelin gene Regulatory Factor|MRF]] is a [[transcription factor]] of critical importance in the development and maintenance of [[myelin sheath]]s.<ref name=koenning>{{cite journal | vauthors = Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B | title = Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS | journal = The Journal of Neuroscience | volume = 32 | issue = 36 | pages = 12528–12542 | date = September 2012 | pmid = 22956843 | pmc = 3752083 | doi = 10.1523/JNEUROSCI.1069-12.2012 }}</ref> A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.<ref name=yan/>
-|volume=26|issue=4|pages=299–306|date=December 2011|pmid=21938520|doi=10.1007/s11011-011-9263-9|s2cid=26878522}}</ref> [[Myelin gene Regulatory Factor|MRF]] is a [[transcription factor]] of critical importance in the development and maintenance of [[myelin sheath]]s.<ref name=koenning>{{cite journal|vauthors=Koenning M, Jackson S, Hay CM, Faux C, Kilpatrick TJ, Willingham M, Emery B|title=Myelin gene regulatory factor is required for maintenance of myelin and mature oligodendrocyte identity in the adult CNS|journal=The Journal of Neuroscience|volume=32|issue=36|pages=12528–12542|date=September 2012|pmid=22956843|pmc=3752083
-|doi=10.1523/JNEUROSCI.1069-12.2012}}</ref> A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.<ref name=yan/>
-Recent neuroimaging studies have shown patients with Niemann–Pick, type C to have a [[corpus callosum]] with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls.<ref name="pmid21596811">{{cite journal|vauthors=Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, Reutens D, Velakoulis D|display-authors=6
+Recent neuroimaging studies have shown patients with Niemann–Pick, type C to have a [[corpus callosum]] with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls.<ref name="pmid21596811">{{cite journal | vauthors = Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, Reutens D, Velakoulis D | display-authors = 6 | title = Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables | journal = AJNR. American Journal of Neuroradiology | volume = 32 | issue = 7 | pages = 1340–1346 | date = August 2011 | pmid = 21596811 | pmc = 7966038 | doi = 10.3174/ajnr.A2490 | doi-access = free }}</ref><ref name="pmid20484681">{{cite journal | vauthors = Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, Adamson C, Kokkinos C, Fietz M, Velakoulis D | display-authors = 6 | title = White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study | journal = Neurology | volume = 75 | issue = 1 | pages = 49–56 | date = July 2010 | pmid = 20484681 | doi = 10.1212/WNL.0b013e3181e6210e | s2cid = 9062701 }}</ref> Also, studies using [[diffusion tensor imaging]] have shown marked reductions in callosal [[fractional anisotropy]], which suggests architectural abnormalities based on the directional flow of water.<ref name="pmid20484681"/><ref name="pmid16243219">{{cite journal | vauthors = Trouard TP, Heidenreich RA, Seeger JF, Erickson RP | title = Diffusion tensor imaging in Niemann-Pick Type C disease | journal = Pediatric Neurology | volume = 33 | issue = 5 | pages = 325–330 | date = November 2005 | pmid = 16243219 | doi = 10.1016/j.pediatrneurol.2005.05.004 }}</ref> These conclusions suggest that the [[corpus callosum]] plays an important role in the disease and should be explored for use as a [[biomarker]] of disease progression.{{citation needed|date=October 2021}}
-|title=Size and shape of the corpus callosum in adult Niemann–Pick type C reflects state and trait illness variables|journal=AJNR. American Journal of Neuroradiology|volume=32|issue=7|pages=1340–1346
-|date=August 2011|pmid=21596811|doi=10.3174/ajnr.A2490|pmc=7966038
-|doi-access=free}}</ref><ref name="pmid20484681">{{cite journal|vauthors=Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, Adamson C, Kokkinos C, Fietz M, Velakoulis D|display-authors=6|title=White and gray matter alterations in adults with Niemann–Pick disease type C: a cross-sectional study|journal=Neurology|volume=75|issue=1|pages=49–56|date=July 2010|pmid=20484681|doi=10.1212/WNL.0b013e3181e6210e|s2cid=9062701}}</ref> Also, studies using [[diffusion tensor imaging]] have shown marked reductions in callosal [[fractional anisotropy]], which suggests architectural abnormalities based on the directional flow of water.<ref name="pmid20484681"/><ref name="pmid16243219">{{cite journal|vauthors=Trouard TP, Heidenreich RA, Seeger JF, Erickson RP|title=Diffusion tensor imaging in Niemann–Pick Type C disease|journal=Pediatric Neurology|volume=33|issue=5|pages=325–330|date=November 2005|pmid=16243219|doi=10.1016/j.pediatrneurol.2005.05.004}}</ref> These conclusions suggest that the [[corpus callosum]] plays an important role in the disease and should be explored for use as a [[biomarker]] of disease progression.{{citation needed|date=October 2021}}
-Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.<ref>{{cite news|url=https://online.wsj.com/articles/researchers-study-ebola-link-to-gene-in-rare-disease-1414965218 |title=Researchers Study Ebola Link to Gene in Rare Disease|first=Amy Dockser|last=Marcus|date=2 November 2014|access-date=12 August 2016|newspaper=Wall Street Journal}}</ref>
+Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.<ref>{{cite news|url=https://online.wsj.com/articles/researchers-study-ebola-link-to-gene-in-rare-disease-1414965218 |title=Researchers Study Ebola Link to Gene in Rare Disease| vauthors = Marcus AD |date=2 November 2014|access-date=12 August 2016|newspaper=Wall Street Journal}}</ref>
-Findings from Zhang et al.<ref>Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA. [http://www.pnas.org/content/98/8/4466 Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease]. Proceedings of the National Academy of Sciences. April 2001, 98 (8) 4466-4471; DOI: 10.1073/pnas.081070898</ref> suggest that NPC is a late endocytic trafficking disease resulted, at least in part, from disruption of communication within late endocytic (LE) compartments and possibly between LE and other subcellular organelles. Crosstalk between the late endocytic compartment and other organelles such as mitochondria, endoplasmic reticulum, plasma membrane, as well as early endocytic compartments has become one of the most interesting frontiers in neurondegenerative disease research including Alzheimer's disease, Parkinson's disease, as well as lysosomal storage disorders.<ref>{{cite journal | url=https://www.science.org/doi/abs/10.1126/sageke.2006.10.re2 | doi=10.1126/sageke.2006.10.re2 | title=Targeting the Role of the Endosome in the Pathophysiology of Alzheimer's Disease: A Strategy for Treatment | year=2006 | last1=Tate | first1=Barbara A. | last2=Mathews | first2=Paul M. | journal=Science of Aging Knowledge Environment | volume=2006 | issue=10 | pages=re2 | pmid=16807486 }}</ref><ref>Plotegher N, Duchen MR. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732996/ Crosstalk between Lysosomes and Mitochondria in Parkinson’s Disease]. Frontiers in Cell and Developmental Biology. 2017;5:110. doi:10.3389/fcell.2017.00110.</ref>
+Findings from Zhang et al.<ref>Zhang M, Dwyer NK, Love DC, Cooney A, Comly M, Neufeld E, Pentchev PG, Blanchette-Mackie EJ, Hanover JA. [http://www.pnas.org/content/98/8/4466 Cessation of rapid late endosomal tubulovesicular trafficking in Niemann–Pick type C1 disease]. Proceedings of the National Academy of Sciences. April 2001, 98 (8) 4466-4471; DOI: 10.1073/pnas.081070898</ref> suggest that NPC is a late endocytic trafficking disease resulted, at least in part, from disruption of communication within late endocytic (LE) compartments and possibly between LE and other subcellular organelles. Crosstalk between the late endocytic compartment and other organelles such as mitochondria, endoplasmic reticulum, plasma membrane, as well as early endocytic compartments has become one of the most interesting frontiers in neurondegenerative disease research including Alzheimer's disease, Parkinson's disease, as well as lysosomal storage disorders.<ref>{{cite journal | vauthors = Tate BA, Mathews PM | title = Targeting the role of the endosome in the pathophysiology of Alzheimer's disease: a strategy for treatment | journal = Science of Aging Knowledge Environment | volume = 2006 | issue = 10 | pages = re2 | date = June 2006 | pmid = 16807486 | doi = 10.1126/sageke.2006.10.re2 }}</ref><ref name="pmid29312935">{{cite journal | vauthors = Plotegher N, Duchen MR | title = Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease | journal = Frontiers in Cell and Developmental Biology | volume = 5 | issue = | pages = 110 | date = 2017 | pmid = 29312935 | pmc = 5732996 | doi = 10.3389/fcell.2017.00110 }}</ref>
 == References ==

Classification	D ICD-10: E75.2 (ILDS E75.230) ICD-9-CM: 272.7 OMIM: 257220 601015 607623 607625 MeSH: D052556 DiseasesDB: 33390
External resources	eMedicine: derm/699 GeneReviews: Niemann–Pick Disease Type C