Niemann–Pick disease#Classification

{{Infobox medical condition (new)

| name = Niemann–Pick disease

| synonyms =

| image = Niemann-Pick Disease 2.jpg

| caption = Child with Niemann–Pick disease

| pronounce = {{IPAc-en|n|iː|m|ən|ˈ|p|ɪ|k}} {{respell|nee-mən|PIK|'}}){{OED|Niemann–Pick}}

| field = Medical genetics

| symptoms =

| complications =

| onset =

| duration =

| types =

| causes =

| risks =

| diagnosis =

| differential =

| prevention =

| treatment =

| medication =

| prognosis =

| frequency =

| deaths =

| alt =

}}

Niemann–Pick disease (NP), also known as acid sphingomyelinase deficiency, is a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A/B, and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM). NP type C is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM.

These disorders involve the dysfunctional metabolism of sphingolipids, which are fats found in cell membranes. They can be considered as a kind of sphingolipidosis, which is included in the larger family of lysosomal storage diseases.{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |year=2006 |isbn=978-0-7216-2921-6 |page=536|display-authors=etal}}

Signs and symptoms

Symptoms are related to the organs in which sphingomyelin accumulates. Enlargement of the liver and spleen (hepatosplenomegaly) may cause reduced appetite, abdominal distension, and pain. Enlargement of the spleen (splenomegaly) may also cause low levels of platelets in the blood (thrombocytopenia).{{citation needed|date=June 2020}}

Accumulation of sphingomyelin in the central nervous system (including the cerebellum) results in unsteady gait (ataxia), slurring of speech (dysarthria), and difficulty swallowing (dysphagia). Basal ganglia dysfunction causes abnormal posturing of the limbs, trunk, and face (dystonia). Upper brainstem disease results in impaired voluntary rapid eye movements (supranuclear gaze palsy). More widespread disease involving the cerebral cortex and subcortical structures causes gradual loss of intellectual abilities, causing dementia and seizures.{{citation needed|date=June 2020}}

Bones also may be affected, with the disease-causing enlarged bone marrow cavities, thinned cortical bone, or a distortion of the hip bone called coxa vara. Sleep-related disorders also occur with the condition, such as sleep inversion, sleepiness during the day and wakefulness at night. Gelastic cataplexy, the sudden loss of muscle tone when the affected patient laughs, is also seen.{{cn|date=October 2021}}

Causes

Image:Autosomal recessive - en.svg

Mutations in the SMPD1 gene cause Niemann–Pick disease types A and B. They produce a deficiency in the activity of the lysosomal enzyme acid sphingomyelinase, that breaks down the lipid sphingomyelin.

Mutations in NPC1 or NPC2 cause Niemann–Pick disease, type C (NPC), which affects a protein used to transport lipids.

Type D originally was separated from type C to delineate a group of patients with otherwise identical disorders who shared a common Nova Scotian ancestry. Patients in this group are known to share a specific mutation in the NPC1 gene, so NPC is used for both groups. Before the molecular defects were described, the terms "Niemann–Pick type I" and "Niemann–Pick type II" were proposed to separate the high- and low-sphingomyelin forms of the disease in the early 1980s.{{fact|date=February 2019}}

Niemann–Pick disease is inherited in an autosomal recessive pattern,{{Cite web|url=https://ghr.nlm.nih.gov/condition/niemann-pick-disease#inheritance|title=Niemann-Pick disease|website=Genetics Home Reference}}{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/niemann-pick/symptoms-causes/syc-20355887|title = Niemann-Pick - Symptoms and causes|website = Mayo Clinic}} which means both copies or both alleles of the gene, must be defective to cause the disease. "Defective" means they are altered in a way that impairs their function. Most often, the parents of a child with an autosomal recessive disorder are carriers: they have one copy of the altered gene but are not affected because the other copy produces the enzyme. If both parents are carriers, each pregnancy has a 25% chance of producing an affected child. Genetic counseling and genetic testing are recommended for families who may be carriers of the disease.{{cn|date=June 2022}}

Pathophysiology

File:Niemann-Pick Disease 1.jpg

Niemann–Pick diseases are a subgroup of lipid storage disorders called sphingolipidoses in which harmful quantities of fatty substances, or lipids, accumulate in the spleen, liver, lungs, bone marrow, and brain.{{cn|date=October 2021}}

In the classic infantile type-A variant, a missense mutation causes complete deficiency of sphingomyelinase. Sphingomyelin is a component of the cell membrane including the organellar membrane, so the enzyme deficiency blocks the degradation of lipids, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 μm in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Histology shows lipid-laden macrophages in the marrow and "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, giving the cytoplasm a foamy appearance.{{fact|date=February 2019}}

Diagnosis

For types A and B, levels of sphingomyelinase can be measured from a blood sample. To diagnose type C, a skin sample can help determine whether the transporter is affected via the Filipin test which detects build-up of unesterified cholesterol via fluorescent staining.{{Cite web|url=https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890|title = Niemann-Pick - Diagnosis and treatment - Mayo Clinic|website = Mayo Clinic}}{{Cite book|url=https://pubmed.ncbi.nlm.nih.gov/25665455/|pmid = 25665455|year = 2015|last1 = Vanier|first1 = M. T.|last2 = Latour|first2 = P.| chapter=Laboratory diagnosis of Niemann–Pick disease type C: The filipin staining test |title = Lysosomes and Lysosomal Diseases|series = Methods in Cell Biology|volume = 126|pages = 357–75|doi = 10.1016/bs.mcb.2014.10.028|isbn = 9780128000793}}

=Classification=

The four types of Niemann–Pick disease are divided into categories. People with ASM deficiency are classified into types A and B. Type A patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement and are unable to survive beyond two years of age. Type B patients also show hepatosplenomegaly and pathologic alterations of their lungs, but usually without the involvement of their central nervous system. Some can develop significant life-threatening complications, including liver failure, hemorrhage, oxygen dependency, pulmonary infections, and splenic rupture. Some develop coronary arterial or valvular heart disease. In a longitudinal natural history study, nearly 20% of the patients died. For those classified into type C, they may have mild hepatosplenomegaly, but their central nervous system is profoundly affected.

Niemann–Pick disease, SMPD1-associated, which includes types A and B

:* Niemann–Pick disease type A: classic infantile

:* Niemann–Pick disease type B: visceral

Niemann–Pick disease, type C: subacute/juvenile, includes types C1 (95% of type C) and C2. Type C is the most common form of the disease{{cite web |title=Neimann-Pick Disease |url=http://ghr.nlm.nih.gov/condition/niemann-pick-disease |work=Genetics Home Reference |publisher=NIH |date=January 2008 |access-date=2 October 2012}} Type C2 is a rare form of the disease.{{EMedicine|article|951564|Sphingomyelinase Deficiency}}

Niemann–Pick disease type D (or Nova Scotia form) is now believed to be the same condition as Niemann–Pick disease type C.{{Cite web | url=https://rarediseases.org/rare-diseases/niemann-pick-disease-type-c/ | title=Niemann Pick Disease Type C|website = National Organization for Rare Disorders}} Two poorly characterized forms of Niemann–Pick disease have also been described as types E and F.{{cite web|url = http://omim.org/entry/607616 |website =OMIM|id= 607616| title = NIEMANN-PICK DISEASE, TYPE B |date = 9 April 2019}}

Treatment

In adults with type B, physicians try to keep cholesterol levels down to normal levels. If the spleen is enlarged and platelet levels low, acute episodes of bleeding may require transfusions of blood products. If they have symptoms of interstitial lung disease, they may need oxygen.{{EMedicine|article|951564|Sphingomyelinase Deficiency|treatment}}

Possible treatments include enzyme replacement therapy and gene therapy. Bone marrow transplant has been tried for type B.{{cite journal |doi=10.1016/j.beem.2014.10.002 |pmid=25987176 |title=Types a and B Niemann-Pick disease |journal=Best Practice & Research Clinical Endocrinology & Metabolism |volume=29 |issue=2 |pages=237–247 |year=2015 |last1=Schuchman |first1=Edward H. |last2=Wasserstein |first2=Melissa P. |pmc=5347465 }}

In January 2009, miglustat (Zavesca) was authorized in the European Union for the treatment of progressive neurological manifestations in people with Niemann-Pick type C disease.{{cite web | title=Zavesca EPAR | website=European Medicines Agency (EMA) | date=18 October 2000 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zavesca | access-date=25 September 2024}}{{cite web | title=Miglustat Product information | website=Union Register of medicinal products | date=21 November 2002 | url=https://ec.europa.eu/health/documents/community-register/html/h238.htm | access-date=25 September 2024}} The medication is available to people in the United States on an experimental basis. In March 2010, the US Food and Drug Administration (FDA) requested additional pre-clinical and clinical information regarding miglustat from Actelion before making a final decision on approving it in the United States for Niemann-Pick type C disease.{{cite press release |url = https://www.drugs.com/nda/actelion-pharmaceuticals-ltd-ch-actelion-receives-fda-complete-response-letter-zavesca-miglustat-2828.html |title = Actelion receives FDA complete response letter for Zavesca (miglustat) for the treatment of Niemann-Pick type C disease|website = Drugs.com|date = 9 March 2010}}

Olipudase alfa (Xenpozyme) was approved for medical use in Japan in March 2022.{{cite press release | title=Xenpozyme (olipudase alfa) approved in Japan, first and only approved therapy indicated to treat acid sphingomyelinase deficiency | url=https://www.sanofi.com/media-room/press-releases/2022/2022-03-28%2009-00-00%202410648 | publisher=Sanofi | access-date=20 May 2022 | date=28 March 2022 | archive-date=21 May 2022 | archive-url=https://web.archive.org/web/20220521063633/https://www.sanofi.com/media-room/press-releases/2022/2022-03-28%2009-00-00%202410648 | url-status=dead }}

Arimoclomol (Miplyffa) was approved for medical use in the United States in September 2024.{{cite press release |date=20 September 2024 |title=FDA Approves First Treatment for Niemann-Pick Disease, Type C |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-niemann-pick-disease-type-c |access-date=20 September 2024 |website=U.S. Food and Drug Administration (FDA)}} It is the first medication approved by the FDA to treat Niemann-Pick Disease, Type C.

Levacetylleucine (Aqneursa) was approved for medical use in the United States in September 2024.{{cite press release | title=FDA Approves New Drug to Treat Niemann-Pick Disease, Type C | website=U.S. Food and Drug Administration | date=24 September 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-niemann-pick-disease-type-c | access-date=25 September 2024}} {{PD-notice}} Levacetylleucine is the second medication approved by the FDA for the treatment of Niemann-Pick disease type C.

Prognosis

Highly variable, infantile neurovisceral Niemann–Pick disease (type A ASMD) is usually fatal before 3 years of age. In Type B, severity is highly variable, and many patients live well into adulthood and may reach a normal lifespan. Diagnoses have been made in the 7th decade of life. {{cite journal |vauthors=Uz E, Cipil H, Turgut FH, Kaya A, Kargili A, Bavbek N, Ali A, Ali K |title=Niemann-Pick disease type B presenting with hepatosplenomegaly and thrombocytopenia |journal=South Med J |volume=101 |issue=11 |pages=1188 |date=November 2008 |pmid=19088546 |doi=10.1097/SMJ.0b013e3181836b4c }}{{cite journal |vauthors=McGovern MM, Lippa N, Bagiella E, Schuchman EH, Desnick RJ, Wasserstein MP |title=Morbidity and mortality in type B Niemann-Pick disease |journal=Genet Med |volume=15 |issue=8 |pages=618–623 |date=August 2013 |pmid=23412609 |doi=10.1038/gim.2013.4 }}{{cite journal |vauthors=Cassiman D, Packman S, Bembi B, Turkia HB, Al-Sayed M, Schiff M, Imrie J, Mabe P, Takahashi T, Mengel KE, Giugliani R, Cox GF |title=Cause of death in patients with chronic visceral and chronic neurovisceral acid sphingomyelinase deficiency (Niemann-Pick disease type B and B variant): Literature review and report of new cases |journal=Mol Genet Metab |volume=118 |issue=3 |pages=206–213 |date=July 2016 |pmid=27198631 |doi=10.1016/j.ymgme.2016.05.001 |doi-access=free }}

Type C is an entirely different disorder, which also has a highly variable prognosis.{{cn|date=October 2021}}

Incidence

The incidence among Ashkenazi Jews is estimated to be about one in 40,000 for type A of Niemann–Pick disease. The incidence of both Niemann–Pick disease types A and B in all other populations is estimated to be one in 250,000. The incidence of Niemann–Pick disease type C is estimated to be one in 150,000.

History

Albert Niemann published the first description of what now is known as Niemann–Pick disease, type A, in 1914. Ludwig Pick described the pathology of the disease in a series of papers in the 1930s.{{WhoNamedIt|synd|1029}}{{cite journal |first=A. |last=Niemann |title=Ein unbekanntes Krankheitsbild |trans-title=An unknown disease picture |language=de |journal=Jahrbuch für Kinderheilkunde |series=Neue Folge |year=1914 |volume=79 |pages=1–10 }}{{cite journal |first=L. |last=Pick |title=Der Morbus Gaucher und die ihm ähnlichen Krankheiten (die lipoidzellige Splenohepatomegalie Typus Niemann und die diabetische Lipoidzellenhypoplasie der Milz) |trans-title=Gaucher's disease and similar diseases (type Niemann lipoid cell splenohepatomegaly and spleen diabetic lipoid cell hypoplasia) |language=de |journal=Ergebnisse der Inneren Medizin und Kinderheilkunde |year=1926 |volume=29 |pages=519–627 }}

In 1961, the classification of Niemann–Pick disease into types A, B, and C was introduced, and also contained a type D,{{cite journal |doi=10.1111/j.1471-4159.1961.tb13499.x |pmid=13696518 |title=The Cerebral Defect in Tay-Sachs Disease and Niemann-Pick Disease |journal=Journal of Neurochemistry |volume=7 |pages=69–80 |year=1961 |last1=Crocker |first1=Allen C. |s2cid=22103848 }}{{OMIM|257220|Niemann–Pick Disease, Type C1; NPC1}} called the "Nova Scotian type". Genetic studies showed that type D is caused by the same gene as type C1, and the type D designation is no longer used.

Research

Research has been ongoing to better understand the disease and treatments for it, however, at present, there is no cure. {{Citation |last=Patterson |first=Marc |title=Niemann-Pick Disease Type C |date=1993 |url=http://www.ncbi.nlm.nih.gov/books/NBK1296/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |access-date=30 July 2023 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=20301473 |editor2-last=Mirzaa |editor2-first=Ghayda M. |editor3-last=Pagon |editor3-first=Roberta A. |editor4-last=Wallace |editor4-first=Stephanie E.}}

=Pathology=

The loss of myelin in the central nervous system is considered to be a main pathogenic factor. The research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene as seen in Niemann–Pick type C disease. In this model, the expression of myelin gene regulatory factor (MRF) is significantly decreased.{{cite journal |doi=10.1007/s11011-011-9263-9 |pmid=21938520 |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 |year=2011 |last1=Yan |first1=Xin |last2=Lukas |first2=Jan |last3=Witt |first3=Martin |last4=Wree |first4=Andreas |last5=Hübner |first5=Rayk |last6=Frech |first6=Moritz |last7=Köhling |first7=Rüdiger |last8=Rolfs |first8=Arndt |last9=Luo |first9=Jiankai |s2cid=26878522 }} MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths.{{cite journal |doi=10.1523/JNEUROSCI.1069-12.2012 |pmid=22956843 |pmc=3752083 |title=Myelin Gene Regulatory Factor is Required for Maintenance of Myelin and Mature Oligodendrocyte Identity in the Adult CNS |journal=Journal of Neuroscience |volume=32 |issue=36 |pages=12528–12542 |year=2012 |last1=Koenning |first1=M. |last2=Jackson |first2=S. |last3=Hay |first3=C. M. |last4=Faux |first4=C. |last5=Kilpatrick |first5=T. J. |last6=Willingham |first6=M. |last7=Emery |first7=B. }} A perturbation of oligodendrocyte maturation and the myelination process might, therefore, be an underlying mechanism of neurological deficits.

Curiously, in 2011 fibroblast cells derived from patients with Niemann–Pick type C1 disease were shown to be resistant to Ebola virus because of mutations in the NPC1 protein, which is needed for viral escape from the vesicular compartment.{{cite journal |doi=10.1038/nature10348 |pmid=21866103 |pmc=3175325 |title=Ebola virus entry requires the cholesterol transporter Niemann–Pick C1 |journal=Nature |volume=477 |issue=7364 |pages=340–343 |year=2011 |last1=Carette |first1=Jan E. |last2=Raaben |first2=Matthijs |last3=Wong |first3=Anthony C. |last4=Herbert |first4=Andrew S. |last5=Obernosterer |first5=Gregor |last6=Mulherkar |first6=Nirupama |last7=Kuehne |first7=Ana I. |last8=Kranzusch |first8=Philip J. |last9=Griffin |first9=April M. |last10=Ruthel |first10=Gordon |last11=Cin |first11=Paola Dal |last12=Dye |first12=John M. |last13=Whelan |first13=Sean P. |last14=Chandran |first14=Kartik |last15=Brummelkamp |first15=Thijn R. |bibcode=2011Natur.477..340C }}

Other studies have uncovered small molecules that inhibit the receptor and may be a potential therapeutic strategy.{{cite journal |doi=10.1038/nature10380 |pmid=21866101 |pmc=3230319 |title=Small molecule inhibitors reveal Niemann–Pick C1 is essential for Ebola virus infection |journal=Nature |volume=477 |issue=7364 |pages=344–348 |year=2011 |last1=Côté |first1=Marceline |last2=Misasi |first2=John |last3=Ren |first3=Tao |last4=Bruchez |first4=Anna |last5=Lee |first5=Kyungae |last6=Filone |first6=Claire Marie |last7=Hensley |first7=Lisa |last8=Li |first8=Qi |last9=Ory |first9=Daniel |last10=Chandran |first10=Kartik |last11=Cunningham |first11=James |bibcode=2011Natur.477..344C }}

=Treatments under investigation=

==Experimental use of arimoclomol==

In 2014, the European Medicines Agency granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C.{{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=17 September 2018|access-date=21 October 2016|archive-date=28 July 2017|archive-url=https://web.archive.org/web/20170728004205/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fhuman%2Forphans%2F2015%2F01%2Fhuman_orphan_001465.jsp&mid=WC0b01ac058001d12b|url-status=dead}} This was followed in 2015 by the U.S. Food & Drug Administration.{{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}} 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.{{cite journal|title=Arimoclomol Prospective Study in Patients Diagnosed With NiemannPick Disease Type C - Full Text View - ClinicalTrials.gov|url=https://clinicaltrials.gov/ct2/show/NCT02612129|website=clinicaltrials.gov|date=14 April 2021}}

==Experimental use of 2-hydroxypropyl-β-cyclodextrin==

Researchers at the University of Arizona first proposed the use of 2-hydroxypropyl-β-cyclodextrins for the treatment of Niemann–Pick Type C1 in 2001.{{cite journal |doi=10.1016/S0024-3205(01)01384-4 |title=Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease |journal=Life Sciences |volume=70 |issue=2 |pages=131–142 |year=2001 |last1=Camargo |first1=Fernando |last2=Erickson |first2=Robert P. |last3=Garver |first3=William S. |last4=Hossain |first4=G.Showkat |last5=Carbone |first5=Peter N. |last6=Heidenreich |first6=Randall A. |last7=Blanchard |first7=James |pmid=11787939 }} Researchers noted that HPBCDs, with varying levels of 2-hydroxypropyl substitution, had effects in delaying neurological symptoms and in decreasing liver cholesterol storage in a Niemann–Pick mouse model. Later, researchers at the University of Texas Southwestern Medical Center found that when Niemann–Pick type C mice were injected with 2-hydroxypropyl-β-cyclodextrin (HPbCD) when they were seven days old, they showed marked improvement in liver function, much less neurodegeneration, and ultimately, they lived longer lives than the mice that did not receive this treatment. These results suggest HPbCD acutely reverses the storage defect seen in NPC.{{cite journal |doi=10.1073/pnas.0810895106 |pmid=19171898 |pmc=2650164 |title=Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse |journal=Proceedings of the National Academy of Sciences |volume=106 |issue=7 |pages=2377–2382 |year=2009 |last1=Liu |first1=B. |last2=Turley |first2=S. D. |last3=Burns |first3=D. K. |last4=Miller |first4=A. M. |last5=Repa |first5=J. J. |last6=Dietschy |first6=J. M. |doi-access=free }}

In April 2011, the U.S. National Institutes of Health, in collaboration with the Therapeutics for Rare and Neglected Diseases Program,{{cite web |url=http://rarediseases.info.nih.gov/Resources.aspx?PageID=32 |title=Therapeutics for Rare and Neglected Diseases Program |publisher=U.S. National Institutes of Health |date=November 2017 |access-date=20 December 2011 |archive-date=9 April 2013 |archive-url=https://web.archive.org/web/20130409222822/http://www.rarediseases.info.nih.gov/Resources.aspx?PageID=32 |url-status=dead }} announced they were developing a clinical trial using HPbCD for Niemann–Pick type C1 patients. A clinical trial conducted by Vtesse, LLC began in January 2013 and was completed in March 2017.{{cite journal |title=Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease |url=https://clinicaltrials.gov/ct2/show/NCT01747135 |website=ClinicalTrials.gov |date=19 July 2021 |publisher=NIH |access-date=10 January 2022}}

On 26 April 2013, the European Medicines Agency granted International Niemann–Pick Disease Alliance, the United Kingdom, orphan designation for HPbCD for the treatment of Niemann–Pick disease, type C.{{Cite web|title=EU/3/13/1124 {{!}} European Medicines Agency|url=https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3131124|access-date=16 April 2021|website=European Medicines Agency|date=17 September 2018 }}

==Gene therapy==

Gene therapy is being used clinically to treat genetic diseases, including hemophilia and spinal muscular atrophy. It has been used preclinically, in a mouse model of Niemann–Pick type C, using an adeno-associated virus-derived viral vector, and has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain.{{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=1 September 2018|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|pmid=29878115|issn=0964-6906|pmc=6097154}} In a separate proof-of-concept study, a similar vector, but with a modified capsid, was injected intravenously into Niemann–Pick type C mice around four weeks of age; this resulted in extended lifespan and improved weight gain.{{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=1 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|issn=2575-1077|pmid=34407999|pmc=8380657|doi-access=free}} Gene therapy has also been used preclinically in a mouse model of Niemann–Pick type A. Injection into the cisterna magna at seven weeks of age prevented motor and memory impairment and neuronal cell death.{{Cite journal|last1=Samaranch|first1=Lluis|last2=Pérez-Cañamás|first2=Azucena|last3=Soto-Huelin|first3=Beatriz|last4=Sudhakar|first4=Vivek|last5=Jurado-Arjona|first5=Jerónimo|last6=Hadaczek|first6=Piotr|last7=Ávila|first7=Jesús|last8=Bringas|first8=John R.|last9=Casas|first9=Josefina|last10=Chen|first10=Haifeng|last11=He|first11=Xingxuan|date=21 August 2019|title=Adeno-associated viral vector serotype 9–based gene therapy for Niemann-Pick disease type A|journal=Science Translational Medicine|language=en|volume=11|issue=506|pages=eaat3738|doi=10.1126/scitranslmed.aat3738|issn=1946-6234|pmid=31434754|pmc=7285630}}

References

; Attribution

This article incorporates public domain text from [http://ghr.nlm.nih.gov The U.S. National Library of Medicine]

External links

{{NINDS|niemann-pick-disease|Niemann-Pick Disease}}
[https://medlineplus.gov/genetics/condition/niemann-pick-disease/ Genetics Home Reference on Niemann–Pick Disease]

{{Medical resources

| DiseasesDB = 9016

| ICD10 = {{ICD10|E|75|2|e|70}} (ILDS E75.230)

| ICD9 = {{ICD9|272.7}}

| ICDO =

| OMIM = 257200

| OMIM_mult = {{OMIM|257220||none}} {{OMIM|601015||none}} {{OMIM|607608||none}} {{OMIM|607616||none}} {{OMIM|607623||none}} {{OMIM|607625||none}}

| MedlinePlus = 001207

| eMedicineSubj = derm

| eMedicineTopic = 699

| MeshID = D009542

| GeneReviewsNBK = NBK1370