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Niemann-Pick disease, type C(NPC)

MedGen UID:
67399
Concept ID:
C0220756
Disease or Syndrome
Synonym: NPC
SNOMED CT: Niemann-Pick disease, type C (66751000); Supraoptic vertical ophthalmoplegia (66751000); Niemann-Pick disease type C (66751000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Related genes: NPC2, NPC1
 
Monarch Initiative: MONDO:0018982
OMIM®: 257220
Orphanet: ORPHA646

Disease characteristics

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

Additional descriptions

From OMIM
Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2 (607625). The clinical manifestations of types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by Vance, 2006). Historically, Crocker (1961) delineated 4 types of Niemann-Pick disease: the classic infantile form (type A; 257200), the visceral form (type B; 607616), the subacute or juvenile form (type C), and the Nova Scotian variant (type D). Types C1 and D are indistinguishable except for the occurrence of type D in patients of Nova Scotian Acadian ancestry. Since then, types E and F have also been described (see 607616), and phenotypic variation within each group has also been described.  http://www.omim.org/entry/257220
From MedlinePlus Genetics
The signs and symptoms of Niemann-Pick disease types C1 and C2 are very similar; these types differ only in their genetic cause. Niemann-Pick disease types C1 and C2 usually become apparent in childhood, although signs and symptoms can develop at any time. People with these types usually develop difficulty coordinating movements (ataxia), an inability to move the eyes vertically (vertical supranuclear gaze palsy), poor muscle tone (dystonia), severe liver disease, and interstitial lung disease. Individuals with Niemann-Pick disease types C1 and C2 have problems with speech and swallowing that worsen over time, eventually interfering with feeding. Affected individuals often experience progressive decline in intellectual function and about one-third have seizures. People with these types may survive into adulthood.

Niemann-Pick disease type B usually presents in mid-childhood. The signs and symptoms of this type are similar to type A, but not as severe. People with Niemann-Pick disease type B often have hepatosplenomegaly, recurrent lung infections, and a low number of platelets in the blood (thrombocytopenia). They also have short stature and slowed mineralization of bone (delayed bone age). About one-third of affected individuals have the cherry-red spot eye abnormality or neurological impairment. People with Niemann-Pick disease type B usually survive into adulthood.

Infants with Niemann-Pick disease type A usually develop an enlarged liver and spleen (hepatosplenomegaly) by age 3 months and fail to gain weight and grow at the expected rate (failure to thrive). The affected children develop normally until around age 1 year when they experience a progressive loss of mental abilities and movement (psychomotor regression). Children with Niemann-Pick disease type A also develop widespread lung damage (interstitial lung disease) that can cause recurrent lung infections and eventually lead to respiratory failure. All affected children have an eye abnormality called a cherry-red spot, which can be identified with an eye examination. Children with Niemann-Pick disease type A generally do not survive past early childhood.

Niemann-Pick disease is a condition that affects many body systems. It has a wide range of symptoms that vary in severity. Niemann-Pick disease is divided into four main types: type A, type B, type C1, and type C2. These types are classified on the basis of genetic cause and the signs and symptoms of the condition.  https://medlineplus.gov/genetics/condition/niemann-pick-disease

Professional guidelines

PubMed

Ishitsuka Y, Irie T, Matsuo M
Adv Drug Deliv Rev 2022 Dec;191:114617. Epub 2022 Nov 8 doi: 10.1016/j.addr.2022.114617. PMID: 36356931
Sitarska D, Tylki-Szymańska A, Ługowska A
Metab Brain Dis 2021 Dec;36(8):2215-2221. Epub 2021 Oct 1 doi: 10.1007/s11011-021-00842-0. PMID: 34596813Free PMC Article
Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, Vanier MT, Walterfang M, Bolton S, Dawson C, Héron B, Stampfer M, Imrie J, Hendriksz C, Gissen P, Crushell E, Coll MJ, Nadjar Y, Klünemann H, Mengel E, Hrebicek M, Jones SA, Ory D, Bembi B, Patterson M; International Niemann-Pick Disease Registry (INPDR)
Orphanet J Rare Dis 2018 Apr 6;13(1):50. doi: 10.1186/s13023-018-0785-7. PMID: 29625568Free PMC Article

Recent clinical studies

Etiology

Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M
Trials 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494Free PMC Article
Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C
J Inherit Metab Dis 2021 Nov;44(6):1463-1480. Epub 2021 Sep 7 doi: 10.1002/jimd.12428. PMID: 34418116Free PMC Article
Pineda M, Walterfang M, Patterson MC
Orphanet J Rare Dis 2018 Aug 15;13(1):140. doi: 10.1186/s13023-018-0844-0. PMID: 30111334Free PMC Article
Patterson MC, Walkley SU
Mol Genet Metab 2017 Jan-Feb;120(1-2):34-37. Epub 2016 Nov 29 doi: 10.1016/j.ymgme.2016.11.008. PMID: 27923544
Vanier MT
Handb Clin Neurol 2013;113:1717-21. doi: 10.1016/B978-0-444-59565-2.00041-1. PMID: 23622394

Diagnosis

Pfrieger FW
Prog Lipid Res 2023 Apr;90:101225. Epub 2023 Mar 31 doi: 10.1016/j.plipres.2023.101225. PMID: 37003582
Erwood S, Bily TMI, Lequyer J, Yan J, Gulati N, Brewer RA, Zhou L, Pelletier L, Ivakine EA, Cohn RD
Nat Biotechnol 2022 Jun;40(6):885-895. Epub 2022 Feb 21 doi: 10.1038/s41587-021-01201-1. PMID: 35190686
Berry-Kravis E
Semin Pediatr Neurol 2021 Apr;37:100879. Epub 2021 Feb 12 doi: 10.1016/j.spen.2021.100879. PMID: 33892845
Vanier MT
Handb Clin Neurol 2013;113:1717-21. doi: 10.1016/B978-0-444-59565-2.00041-1. PMID: 23622394
Vanier MT
Orphanet J Rare Dis 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16. PMID: 20525256Free PMC Article

Therapy

Fields T, M Bremova T, Billington I, Churchill GC, Evans W, Fields C, Galione A, Kay R, Mathieson T, Martakis K, Patterson M, Platt F, Factor M, Strupp M
Trials 2023 May 29;24(1):361. doi: 10.1186/s13063-023-07399-6. PMID: 37248494Free PMC Article
Bremova-Ertl T, Schneider S
Expert Opin Pharmacother 2023 May-Aug;24(11):1229-1247. Epub 2023 May 21 doi: 10.1080/14656566.2023.2215386. PMID: 37211769
Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C
J Inherit Metab Dis 2021 Nov;44(6):1463-1480. Epub 2021 Sep 7 doi: 10.1002/jimd.12428. PMID: 34418116Free PMC Article
Wheeler S, Sillence DJ
J Neurochem 2020 Jun;153(6):674-692. Epub 2019 Nov 15 doi: 10.1111/jnc.14895. PMID: 31608980
Vanier MT
Orphanet J Rare Dis 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16. PMID: 20525256Free PMC Article

Prognosis

Bremova-Ertl T, Schneider S
Expert Opin Pharmacother 2023 May-Aug;24(11):1229-1247. Epub 2023 May 21 doi: 10.1080/14656566.2023.2215386. PMID: 37211769
Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, Vanier MT, Walterfang M, Bolton S, Dawson C, Héron B, Stampfer M, Imrie J, Hendriksz C, Gissen P, Crushell E, Coll MJ, Nadjar Y, Klünemann H, Mengel E, Hrebicek M, Jones SA, Ory D, Bembi B, Patterson M; International Niemann-Pick Disease Registry (INPDR)
Orphanet J Rare Dis 2018 Apr 6;13(1):50. doi: 10.1186/s13023-018-0785-7. PMID: 29625568Free PMC Article
Di Lazzaro V, Marano M, Florio L, De Santis S
Int J Neurosci 2016 Nov;126(11):963-71. Epub 2016 Mar 29 doi: 10.3109/00207454.2016.1161623. PMID: 26998855
Mengel E, Klünemann HH, Lourenço CM, Hendriksz CJ, Sedel F, Walterfang M, Kolb SA
Orphanet J Rare Dis 2013 Oct 17;8:166. doi: 10.1186/1750-1172-8-166. PMID: 24135395Free PMC Article
Vanier MT
Orphanet J Rare Dis 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16. PMID: 20525256Free PMC Article

Clinical prediction guides

Pfrieger FW
Prog Lipid Res 2023 Apr;90:101225. Epub 2023 Mar 31 doi: 10.1016/j.plipres.2023.101225. PMID: 37003582
Erwood S, Bily TMI, Lequyer J, Yan J, Gulati N, Brewer RA, Zhou L, Pelletier L, Ivakine EA, Cohn RD
Nat Biotechnol 2022 Jun;40(6):885-895. Epub 2022 Feb 21 doi: 10.1038/s41587-021-01201-1. PMID: 35190686
Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Grønborg S, Harmatz P, Héron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsøe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, Í Dali C
J Inherit Metab Dis 2021 Nov;44(6):1463-1480. Epub 2021 Sep 7 doi: 10.1002/jimd.12428. PMID: 34418116Free PMC Article
Newton J, Milstien S, Spiegel S
Adv Biol Regul 2018 Dec;70:82-88. Epub 2018 Aug 28 doi: 10.1016/j.jbior.2018.08.001. PMID: 30205942Free PMC Article
Vanier MT
Orphanet J Rare Dis 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16. PMID: 20525256Free PMC Article

Recent systematic reviews

Maresca G, Formica C, Nocito V, Latella D, Leonardi S, De Cola MC, Triglia G, Bramanti P, Corallo F
Neurol Sci 2021 Aug;42(8):3167-3175. Epub 2021 May 22 doi: 10.1007/s10072-021-05337-5. PMID: 34021815
Bonnot O, Klünemann HH, Velten C, Torres Martin JV, Walterfang M
World J Biol Psychiatry 2019 Apr;20(4):320-332. Epub 2018 Mar 12 doi: 10.1080/15622975.2018.1441548. PMID: 29457916
Hendriksz CJ, Anheim M, Bauer P, Bonnot O, Chakrapani A, Corvol JC, de Koning TJ, Degtyareva A, Dionisi-Vici C, Doss S, Duning T, Giunti P, Iodice R, Johnston T, Kelly D, Klünemann HH, Lorenzl S, Padovani A, Pocovi M, Synofzik M, Terblanche A, Then Bergh F, Topçu M, Tranchant C, Walterfang M, Velten C, Kolb SA
Curr Med Res Opin 2017 May;33(5):877-890. Epub 2017 Mar 2 doi: 10.1080/03007995.2017.1294054. PMID: 28276873
Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M
Orphanet J Rare Dis 2014 Apr 28;9:65. doi: 10.1186/1750-1172-9-65. PMID: 24775716Free PMC Article
Walterfang M, Chien YH, Imrie J, Rushton D, Schubiger D, Patterson MC
Orphanet J Rare Dis 2012 Oct 6;7:76. doi: 10.1186/1750-1172-7-76. PMID: 23039766Free PMC Article

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