Niemann-Pick disease type C

Marie T Vanier, Marie T Vanier

Abstract

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

Figures

Figure 1
Figure 1
Age of onset of neurological disease vs lifespan. Study on 97 cases for whom appropriate clinical information was available from the cohort of 181 patients originating from French hospitals. Each horizontal bar depicts one patient. The green color indicates the period during which the patient did not present neurological symptoms, irrespective of the presence or absence of preexisting systemic disease. Patients who died in their first days or months of life from systemic disease (n = 19) are not shown on this graph.
Figure 2
Figure 2
Niemann-Pick disease type C as a neurovisceral disease. Schematic representation of the main forms of the disease, with particular emphasis on type and age of onset of first neurological symptoms
Figure 3
Figure 3
Laboratory diagnosis algorithm. Footnote: This algorithm is as proposed in Wraith et al. Mol Genet Metab 2009, 98:152-165 [27] *Sphingomyelinase deficiency (including late-onset type A) may give a dubious filipin pattern, with normal kinetics of LDL-induced cholesteryl ester formation ** False positive: I-cell disease (but very different clinical features) ***Heterozygotes may show a pattern (filipin staining and kinetics of LDL-induced cholesteryl ester formation) similar to that in "variant" patients ****In many countries, NPC1 p.P1007A or different missense mutations on codon 992 constitute the most frequent "variant" mutations Genetic studies can also be undertaken if clinical symptoms are very suggestive of a diagnosis of NP-C, even with negative results from filipin testing.
Figure 4
Figure 4
Age at diagnosis vs life span. Study in a cohort of 141 patients originating from French hospitals. Each horizontal bar depicts one patient. The change of color shows at which age the diagnosis was established. Median: 3.1 years; 0-9 months: 30%; < 2 years: 36%; < 5 years: 60%; > 16 years: 12%

References

    1. Crocker AC, Farber S. Niemann-Pick disease: a review of eighteen patients. Medicine (Baltimore) 1958;37:1–95. doi: 10.1097/00005792-195802000-00001.
    1. Crocker AC. The cerebral defect in Tay-Sachs disease and Niemann-Pick disease. J Neurochem. 1961;7:69–80. doi: 10.1111/j.1471-4159.1961.tb13499.x.
    1. Brady RO, Kanfer JN, Mock MB, Fredrickson DS. The metabolism of sphingomyelin. II. Evidence of an enzymatic deficiency in Niemann-Pick diseae. Proc Natl Acad Sci USA. 1966;55:366–369. doi: 10.1073/pnas.55.2.366.
    1. Pentchev PG, Boothe AD, Kruth HS, Weintroub H, Stivers J, Brady RO. A genetic storage disorder in BALB/C mice with a metabolic block in esterification of exogenous cholesterol. J Biol Chem. 1984;259:5784–5791.
    1. Pentchev PG, Brady RO, Blanchette-Mackie EJ, Vanier MT, Carstea ED, Parker CC, Goldin E, Roff CF. The Niemann-Pick C lesion and its relationship to the intracellular distribution and utilization of LDL cholesterol. Biochim Biophys Acta. 1994;1225:235–243.
    1. Pentchev PG, Comly ME, Kruth HS, Vanier MT, Wenger DA, Patel S, Brady RO. A defect in cholesterol esterification in Niemann-Pick disease (type C) patients. Proc Natl Acad Sci USA. 1985;82:8247–8251. doi: 10.1073/pnas.82.23.8247.
    1. Pentchev PG, Comly ME, Kruth HS, Tokoro T, Butler J, Sokol J, Filling-Katz M, Quirk JM, Marshall DC, Patel S, Vanier MT, Brady RO. Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J. 1987;1:40–45.
    1. Sokol J, Blanchette-Mackie J, Kruth HS, Dwyer NK, Amende LM, Butler JD, Robinson E, Patel S, Brady RO, Comly ME, Vanier MT, Pentchev PG. Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol. J Biol Chem. 1988;263:3411–3417.
    1. Liscum L, Ruggiero RM, Faust JR. The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J Cell Biol. 1989;108:1625–1636. doi: 10.1083/jcb.108.5.1625.
    1. Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, Blanchette-Mackie JE, Pentchev P. In: The Metabolic and Molecular Bases of Inherited Disease. 8. Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B, editor. New York: Mc Graw Hill; 2001. Niemann-Pick disease type C: a lipid trafficking disorder; pp. 3611–3634.
    1. Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003;64:269–281. doi: 10.1034/j.1399-0004.2003.00147.x.
    1. Ioannou YA. Guilty until proven innocent: the case of NPC1 and cholesterol. Trends Biochem Sci. 2005;30:498–505. doi: 10.1016/j.tibs.2005.07.007.
    1. Steinberg SJ, Ward CP, Fensom AH. Complementation studies in Niemann-Pick disease type C indicate the existence of a second group. J Med Genet. 1994;31:317–320. doi: 10.1136/jmg.31.4.317.
    1. Vanier MT, Duthel S, Rodriguez-Lafrasse C, Pentchev P, Carstea ED. Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet. 1996;58:118–125.
    1. Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF III, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O'Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997;277:228–231. doi: 10.1126/science.277.5323.228.
    1. Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000;290:2298–2301. doi: 10.1126/science.290.5500.2298.
    1. Greer WL, Riddell DC, Gillan TL, Girouard GS, Sparrow SM, Byers DM, Dobson MJ, Neumann PE. The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097→T transversion in NPC1. Am J Hum Genet. 1998;63:52–54. doi: 10.1086/301931.
    1. Sleat DE, Wiseman JA, El Banna M, Price SM, Verot L, Shen MM, Tint GS, Vanier MT, Walkley SU, Lobel P. Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci USA. 2004;101:5886–5891. doi: 10.1073/pnas.0308456101.
    1. Kwon HJ, Abi-Mosleh L, Wang ML, Deisenhofer J, Goldstein JL, Brown MS, Infante RE. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell. 2009;137:1213–1224. doi: 10.1016/j.cell.2009.03.049.
    1. Pentchev PG, Vanier MT, Suzuki K, Patterson M. In: The Metabolic and Molecular Bases of Inherited Disease. 7. Scriver CR, Beaudet AL, Sly WS, Valle D, editor. New York: McGraw Hill; 1995. Niemann-Pick disease type C: a cellular cholesterol lipidosis; pp. 2625–2639.
    1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–254. doi: 10.1001/jama.281.3.249.
    1. Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP. The frequency of lysosomal storage diseases in The Netherlands. Hum Genet. 1999;105:151–156.
    1. Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, Pinto E, Silva E, Rocha S, Marcao A, Ribeiro I, Lacerda L, Ribeiro G, Amaral O, Sa Miranda MC. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004;12:87–92. doi: 10.1038/sj.ejhg.5201044.
    1. Winsor EJ, Welch JP. Genetic and demographic aspects of Nova Scotia Niemann-Pick disease (type D) Am J Hum Genet. pp. 530–538.
    1. Wenger DA, Barth G, Githens JH. Nine cases of sphingomyelin lipidosis, a new variant in Spanish-American Children. Juvenile variant of Niemann-Pick Disease with foamy and sea-blue histiocytes. Am J Dis Child. 1977;131:955–961.
    1. Millat G, Marcais C, Rafi MA, Yamamoto T, Morris JA, Pentchev PG, Ohno K, Wenger DA, Vanier MT. Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet. 1999;65:1321–1329. doi: 10.1086/302626.
    1. Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E, Pineda M, Sedel F, Topcu M, Vanier MT, Widner H, Wijburg FA, Patterson MC. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009;98:152–165. doi: 10.1016/j.ymgme.2009.06.008.
    1. Spiegel R, Raas-Rothschild A, Reish O, Regev M, Meiner V, Bargal R, Sury V, Meir K, Nadjari M, Hermann G, Iancu TC, Shalev SA, Zeigler M. The clinical spectrum of fetal Niemann-Pick type C. Am J Med Genet A. 2009;149A:446–450. doi: 10.1002/ajmg.a.32642.
    1. Vanier MT, Wenger DA, Comly ME, Rousson R, Brady RO, Pentchev PG. Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients. Clin Genet. 1988;33:331–348.
    1. Trendelenburg G, Vanier MT, Maza S, Millat G, Bohner G, Munz DL, Zschenderlein R. Niemann-Pick type C disease in a 68-year-old patient. J Neurol Neurosurg Psychiatry. 2006;77:997–998. doi: 10.1136/jnnp.2005.086785.
    1. Schiffmann R. Niemann-Pick disease type C. From bench to bedside. JAMA. 1996;276:561–564. doi: 10.1001/jama.276.7.561.
    1. Iturriaga C, Pineda M, Fernandez-Valero EM, Vanier MT, Coll MJ. Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci. 2006;249:1–6. doi: 10.1016/j.jns.2006.05.054.
    1. Imrie J, Dasgupta S, Besley GT, Harris C, Heptinstall L, Knight S, Vanier MT, Fensom AH, Ward C, Jacklin E, Whitehouse C, Wraith JE. The natural history of Niemann-Pick disease type C in the UK. J Inherit Metab Dis. 2007;30:51–59. doi: 10.1007/s10545-006-0384-7.
    1. Garver WS, Francis GA, Jelinek D, Shepherd G, Flynn J, Castro G, Walsh VC, Coppock DL, Pettit KM, Heidenreich RA, Meaney FJ. The National Niemann-Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A. 2007;143A:1204–1211. doi: 10.1002/ajmg.a.31735.
    1. Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F. The adult form of Niemann-Pick disease type C. Brain. 2007;130:120–133. doi: 10.1093/brain/awl260.
    1. Solomon D, Winkelman AC, Zee DS, Gray L, Buttner-Ennever J. Niemann-Pick type C disease in two affected sisters: ocular motor recordings and brain-stem neuropathology. Ann N Y Acad Sci. 2005;1039:436–445. doi: 10.1196/annals.1325.041.
    1. Kandt RS, Emerson RG, Singer HS, Valle DL, Moser HW. Cataplexy in variant forms of Niemann-Pick disease. Ann Neurol. 1982;12:284–288. doi: 10.1002/ana.410120313.
    1. Oyama K, Takahashi T, Shoji Y, Oyamada M, Noguchi A, Tamura H, Takada G, Kanbayashi T. Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid. Tohoku J Exp Med. 2006;209:263–267. doi: 10.1620/tjem.209.263.
    1. Imrie J, Wraith JE. Isolated splenomegaly as the presenting feature of Niemann-Pick disease type C. Arch Dis Child. 2001;84:427–429. doi: 10.1136/adc.84.5.427.
    1. Vanier MT, Suzuki K. In: Neurodystrophies and Neurolipidoses. Moser HW, editor. Amsterdam: Elsevier Science; 1996. Niemann-Pick diseases; pp. 133–162. Handbook of Clinical Neurology. Vol. 66/Revised Series Vol. 22.
    1. Kelly DA, Portmann B, Mowat AP, Sherlock S, Lake BD. Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease. J Pediatr. 1993;123:242–247. doi: 10.1016/S0022-3476(05)81695-6.
    1. Yerushalmi B, Sokol RJ, Narkewicz MR, Smith D, Ashmead JW, Wenger DA. Niemann-Pick disease type C in neonatal cholestasis at a North American Center. J Pediatr Gastroenterol Nutr. 2002;35:44–50. doi: 10.1097/00005176-200207000-00011.
    1. Bjurulf B, Spetalen S, Erichsen A, Vanier MT, Strom EH, Stromme P. Niemann-Pick disease type C2 presenting as fatal pulmonary alveolar lipoproteinosis: morphological findings in lung and nervous tissue. Med Sci Monit. 2008;14:CS71–CS75.44.
    1. Griese M, Brasch F, Aldana VR, Cabrera MM, Goelnitz U, Ikonen E, Karam BJ, Liebisch G, Linder MD, Lohse P, Meyer W, Schmitz G, Pamir A, Ripper J, Rolfs A, Schams A, Lezana FJ. Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis. Clin Genet. 2010;77:119–130. doi: 10.1111/j.1399-0004.2009.01325.x.
    1. Fensom AH, Grant AR, Steinberg SJ, Ward CP, Lake BD, Logan EC, Hulman G. An adult with a non-neuronopathic form of Niemann-Pick C disease. J Inherit Metab Dis. 1999;22:84–86. doi: 10.1023/A:1005463718823.
    1. Fröhlich E, Harzer K, Heller T, Ruhl U. Sonographisch echodichte Milztumoren: Knotige Manifestation eines Morbus Niemann-Pick Typ C [Ultrasound echogenic splenic tumors: nodular manifestation of type C Niemann-Pick disease] Ultraschall Med. 1990;11:119–122. doi: 10.1055/s-2007-1011543.
    1. Millat G, Marcais C, Tomasetto C, Chikh K, Fensom AH, Harzer K, Wenger DA, Ohno K, Vanier MT. Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. Am J Hum Genet. 2001;68:1373–1385. doi: 10.1086/320606.
    1. Dvorakova L, Sikora J, Hrebicek M, Hulkova H, Bouckova M, Stolnaja L, Elleder M. Subclinical course of adult visceral Niemann-Pick type C1 disease. A rare or underdiagnosed disorder? J Inherit Metab Dis. 2006;29:591. doi: 10.1007/s10545-006-0330-z.
    1. Shulman LM, David NJ, Weiner WJ. Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C. Neurology. 1995;45:1739–1743.
    1. Imrie J, Vijayaraghaven S, Whitehouse C, Harris S, Heptinstall L, Church H, Cooper A, Besley GT, Wraith JE. Niemann-Pick disease type C in adults. J Inherit Metab Dis. 2002;25:491–500. doi: 10.1023/A:1021259403196.
    1. Klünemann HH, Elleder M, Kaminski WE, Snow K, Peyser JM, O'Brien JF, Munoz D, Schmitz G, Klein HE, Pendlebury WW. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol. 2002;52:743–749. doi: 10.1002/ana.10366.
    1. Walterfang M, Fietz M, Fahey M, Sullivan D, Leane P, Lubman DI, Velakoulis D. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Neuropsychiatry Clin Neurosci. 2006;18:158–170.
    1. Klarner B, Klünemann HH, Lurding R, Aslanidis C, Rupprecht R. Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations. J Inherit Metab Dis. 2007;30:60–67. doi: 10.1007/s10545-006-0417-6.
    1. Higgins ME, Davies JP, Chen FW, Ioannou YA. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab. 1999;68:1–13. doi: 10.1006/mgme.1999.2882.
    1. Vanier MT, Millat G. Structure and function of the NPC2 protein. Biochim Biophys Acta. 2004;1685:14–21.
    1. Storch J, Xu Z. Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochim Biophys Acta. 2009;1791:671–678.
    1. Vincent I, Bu B, Erickson RP. Understanding Niemann-Pick type C disease: a fat problem. Curr Opin Neurol. 2003;16:155–161. doi: 10.1097/00019052-200304000-00006.
    1. Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta. 2004;1685:48–62.
    1. Vanier MT. Biochemical studies in Niemann-Pick disease. I. Major sphingolipids of liver and spleen. Biochim Biophys Acta. 1983;750:178–184.
    1. Vanier MT. Lipid changes in Niemann-Pick disease type C brain: personal experience and review of the literature. Neurochem Res. 1999;24:481–489. doi: 10.1023/A:1022575511354.
    1. Goldin E, Roff CF, Miller SP, Rodriguez-Lafrasse C, Vanier MT, Brady RO, Pentchev PG. Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver. Biochim Biophys Acta. 1992;1127:303–311.
    1. Rodriguez-Lafrasse C, Rousson R, Pentchev PG, Louisot P, Vanier MT. Free sphingoid bases in tissues from patients with type C Niemann-Pick disease and other lysosomal storage disorders. Biochim Biophys Acta. 1994;1226:138–144.
    1. Walkley SU, Vanier MT. Secondary lipid accumulation in lysosomal disease. Biochim Biophys Acta. 2009;1793:726–736. doi: 10.1016/j.bbamcr.2008.11.014.
    1. Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One. 2009;4:e6951. doi: 10.1371/journal.pone.0006951.
    1. Abi-Mosleh L, Infante RE, Radhakrishnan A, Goldstein JL, Brown MS. Cyclodextrin overcomes deficient lysosome-to-endoplasmic reticulum transport of cholesterol in Niemann-Pick type C cells. Proc Natl Acad Sci USA. 2009;106:19316–19321. doi: 10.1073/pnas.0910916106.
    1. Rosenbaum AI, Zhang G, Warren JD, Maxfield FR. Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells. Proc Natl Acad Sci USA. 2010;107:5477–5482. doi: 10.1073/pnas.0914309107.
    1. Vanier MT, Rodriguez-Lafrasse C, Rousson R, Gazzah N, Juge MC, Pentchev PG, Revol A, Louisot P. Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta. 1991;1096:328–337.
    1. Argoff CE, Comly ME, Blanchette-Mackie J, Kruth HS, Pye HT, Goldin E, Kaneski C, Vanier MT, Brady RO, Pentchev PG. Type C Niemann-Pick disease: cellular uncoupling of cholesterol homeostasis is linked to the severity of disruption in the intracellular transport of exogenously derived cholesterol. Biochim Biophys Acta. 1991;1096:319–327.
    1. Vanier MT. Phenotypic and genetic heterogeneity in Niemann-Pick disease type C: current knowledge and practical implications. Wien Klin Wochenschr. 1997;109:68–73.
    1. Vanier MT, Suzuki K. Recent advances in elucidating Niemann-Pick C disease. Brain Pathol. 1998;8:163–174.
    1. Salvioli R, Scarpa S, Ciaffoni F, Tatti M, Ramoni C, Vanier MT, Vaccaro AM. Glucosylceramidase mass and subcellular localization are modulated by cholesterol in Niemann-Pick disease type C. J Biol Chem. 2004;279:17674–17680. doi: 10.1074/jbc.M313517200.
    1. Ganley IG, Pfeffer SR. Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells. J Biol Chem. 2006;281:17890–17899. doi: 10.1074/jbc.M601679200.
    1. Vance JE, Hayashi H, Karten B. Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol. 2005;16:193–212. doi: 10.1016/j.semcdb.2005.01.005.
    1. Reid PC, Sakashita N, Sugii S, Ohno-Iwashita Y, Shimada Y, Hickey WF, Chang TY. A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res. 2004;45:582–591. doi: 10.1194/jlr.D300032-JLR200.
    1. Liu Y, Wu YP, Wada R, Neufeld EB, Mullin KA, Howard AC, Pentchev PG, Vanier MT, Suzuki K, Proia RL. Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse. Hum Mol Genet. 2000;9:1087–1092. doi: 10.1093/hmg/9.7.1087.
    1. Karten B, Vance DE, Campenot RB, Vance JE. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J Neurochem. 2002;83:1154–1163. doi: 10.1046/j.1471-4159.2002.01220.x.
    1. Karten B, Peake KB, Vance JE. Mechanisms and consequences of impaired lipid trafficking in Niemann-Pick type C1-deficient mammalian cells. Biochim Biophys Acta. 2009;1791:659–670.
    1. Reid PC, Sugii S, Chang TY. Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice. J Lipid Res. 2003;44:1010–9. doi: 10.1194/jlr.M300009-JLR200.
    1. Martin JJ, Lowenthal A, Ceuterick C, Vanier MT. Juvenile dystonic lipidosis (variant of Niemann-Pick disease type C) J Neurol Sci. 1984;66:33–45. doi: 10.1016/0022-510X(84)90139-4.
    1. Neufeld EB, Wastney M, Patel S, Suresh S, Cooney AM, Dwyer NK, Roff CF, Ohno K, Morris JA, Carstea ED, Incardona JP, Strauss JF III, Vanier MT, Patterson MC, Brady RO, Pentchev PG, Blanchette-Mackie EJ. The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem. 1999;274:9627–9635. doi: 10.1074/jbc.274.14.9627.
    1. Davies JP, Ioannou YA. Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J Biol Chem. 2000;275:24367–24374. doi: 10.1074/jbc.M002184200.
    1. Verot L, Chikh K, Freydiere E, Honore R, Vanier MT, Millat G. Niemann-Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clin Genet. 2007;71:320–330. doi: 10.1111/j.1399-0004.2007.00782.x.
    1. Infante RE, Wang ML, Radhakrishnan A, Kwon HJ, Brown MS, Goldstein JL. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc Natl Acad Sci USA. 2008;105:15287–15292. doi: 10.1073/pnas.0807328105.
    1. Cruz JC, Chang TY. Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells. J Biol Chem. 2000;275:41309–41316. doi: 10.1074/jbc.M008272200.
    1. Lloyd-Evans E, Morgan AJ, He X, Smith DA, Elliot-Smith E, Sillence DJ, Churchill GC, Schuchman EH, Galione A, Platt FM. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008;14:1247–1255. doi: 10.1038/nm.1876.
    1. Lloyd-Evans E, Platt FM. Lipids on Trial: The Search for the Offending Metabolite in Niemann-Pick type C Disease. Traffic. 2010;11:419–428. doi: 10.1111/j.1600-0854.2010.01032.x.
    1. Runz H, Dolle D, Schlitter AM, Zschocke J. NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat. 2008;29:345–350. doi: 10.1002/humu.20636.
    1. Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, Akaboshi S, Watanabe Y, Takeshima T, Inui K, Okada S, Tanaka A, Sakuragawa N, Millat G, Vanier MT, Morris JA, Pentchev PG, Ohno K. NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C. Hum Genet. 1999;105:1016. doi: 10.1007/s004390051057.
    1. Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE. Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. Am J Hum Genet. 1999;65:1252–1260. doi: 10.1086/302620.
    1. Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet. 2001;68:1361–1372. doi: 10.1086/320599.
    1. Ribeiro I, Marcao A, Amaral O, Sa Miranda MC, Vanier MT, Millat G. Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Hum Genet. 2001;109:24–32. doi: 10.1007/s004390100531.
    1. Millat G, Chikh K, Naureckiene S, Sleat DE, Fensom AH, Higaki K, Elleder M, Lobel P, Vanier MT. Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet. 2001;69:1013–1021. doi: 10.1086/324068.
    1. Park WD, O'Brien JF, Lundquist PA, Kraft DL, Vockley CW, Karnes PS, Patterson MC, Snow K. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat. 2003;22:313–325. doi: 10.1002/humu.10255.
    1. Fernandez-Valero EM, Ballart A, Iturriaga C, Lluch M, Macias J, Vanier MT, Pineda M, Coll MJ. Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet. 2005;68:245–254. doi: 10.1111/j.1399-0004.2005.00490.x.
    1. Millat G, Bailo N, Molinero S, Rodriguez C, Chikh K, Vanier MT. Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab. 2005;86:220–232. doi: 10.1016/j.ymgme.2005.07.007.
    1. Fancello T, Dardis A, Rosano C, Tarugi P, Tappino B, Zampieri S, Pinotti E, Corsolini F, Fecarotta S, D'Amico A, Di Rocco M, Uziel G, Calandra S, Bembi B, Filocamo M. Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations. Neurogenetics. 2009;10:229–239. doi: 10.1007/s10048-009-0175-3.
    1. Garver WS, Jelinek D, Meaney FJ, Flynn J, Pettit KM, Shepard G, Heidenreich RA, Walsh Vockley CM, Castro G, Francis GA. The National Niemann-Pick Type C1 disease database: Correlation of lipid profiles, mutations, and biochemical phenotypes. J Lipid Res. 2009.
    1. Gelsthorpe ME, Baumann N, Millard E, Gale SE, Langmade SJ, Schaffer JE, Ory DS. Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. J Biol Chem. 2008;283:8229–8236. doi: 10.1074/jbc.M708735200.
    1. Blom TS, Linder MD, Snow K, Pihko H, Hess MW, Jokitalo E, Veckman V, Syvanen AC, Ikonen E. Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Hum Mol Genet. 2003;12:257–272. doi: 10.1093/hmg/ddg025.
    1. Macias-Vidal J, Gort L, Lluch M, Pineda M, Coll MJ. Nonsense-mediated mRNA decay process in nine alleles of Niemann-Pick type C patients from Spain. Mol Genet Metab. 2009;97:60–64. doi: 10.1016/j.ymgme.2009.01.007.
    1. Chikh K, Rodriguez C, Vey S, Vanier MT, Millat G. Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. Hum Mutat. 2005;26:20–28. doi: 10.1002/humu.20173.
    1. Rottach KG, von Maydell RD, Das VE, Zivotofsky AZ, Discenna AO, Gordon JL, Landis DM, Leigh RJ. Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease. Vision Res. 1997;37:3627–3638. doi: 10.1016/S0042-6989(96)00066-1.
    1. Abel LA, Walterfang M, Fietz M, Bowman EA, Velakoulis D. Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits. Neurology. 2009;72:1083–1086. doi: 10.1212/01.wnl.0000345040.01917.9d.
    1. Boustany RN, Kaye E, Alroy J. Ultrastructural findings in skin from patients with Niemann-Pick disease, type C. Pediatr Neurol. 1990;6:177–183. doi: 10.1016/0887-8994(90)90059-A.
    1. Ries M, Schaefer E, Luhrs T, Mani L, Kuhn J, Vanier MT, Krummenauer F, Gal A, Beck M, Mengel E. Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease. J Inherit Metab Dis. 2006;29:647–652. doi: 10.1007/s10545-006-0363-3.
    1. Rodriguez-Pascau L, Coll MJ, Vilageliu L, Grinberg D. Antisense oligonucleotide treatment for a pseudoexon-generating mutation in the NPC1 gene causing Niemann-Pick type C diseaseb. Hum Mutat. 2009;30:1117–1122. doi: 10.1002/humu.21018.
    1. Vanier MT, Rodriguez-Lafrasse C, Rousson R, Mandon G, Boue J, Choiset A, Peyrat MF, Dumontel C, Juge MC, Pentchev PG, Revol A, Louisot P. Prenatal diagnosis of Niemann-Pick type C disease: current strategy from an experience of 37 pregnancies at risk. Am J Hum Genet. 1992;51:111–122.
    1. Vanier MT. Prenatal diagnosis of Niemann-Pick diseases types A, B and C. Prenat Diagn. 2002;22:630–632. doi: 10.1002/pd.368.
    1. Imrie J, Galani C, Gairy K, Lock K, Hunsche E. Cost of illness associated with Niemann-Pick disease type C in the UK. J Med Econ. 2009;12:219–229. doi: 10.3111/13696990903245863.
    1. Hsu YS, Hwu WL, Huang SF, Lu MY, Chen RL, Lin DT, Peng SS, Lin KH. Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant. 1999;24:103–107. doi: 10.1038/sj.bmt.1701826.
    1. Gartner JC Jr, Bergman I, Malatack JJ, Zitelli BJ, Jaffe R, Watkins JB, Shaw BW, Iwatsuki S, Starzl TE. Progression of neurovisceral storage disease with supranuclear ophthalmoplegia following orthotopic liver transplantation. Pediatrics. 1986;77:104–106.
    1. Bonney DK, O'Meara A, Shabani A, Imrie J, Bigger BW, Jones S, Wraith JE, Wynn RF. Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe "graft versus substrate" effect. J Inherit Metab Dis. 2010. in press .
    1. Zervas M, Somers KL, Thrall MA, Walkley SU. Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol. 2001;11:1283–1287. doi: 10.1016/S0960-9822(01)00396-7.
    1. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 2007;6:765–772. doi: 10.1016/S1474-4422(07)70194-1.
    1. Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, Wraith JE. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300–305. doi: 10.1177/0883073809344222.
    1. Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, Giorgino R, Patterson MC. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010;99:351–357. doi: 10.1016/j.ymgme.2009.12.006.
    1. Chien YH, Lee NC, Tsai LK, Huang AC, Peng SF, Chen SJ, Hwu WL. Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year. J Inherit Metab Dis. 2007;30:826. doi: 10.1007/s10545-007-0630-y.
    1. Santos ML, Raskin S, Telles DS, Lohr JA, Liberalesso PB, Vieira SC, Cordeiro ML. Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: A case report in Brazil. J Inherit Metab Dis. 2008. short report online #123.
    1. Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M, Bembi B, Walterfang M, Korenke GC, Marquardt T, Luzy C, Giorgino R, Patterson MC. Miglustat in patients with Niemann-Pick disease Type C (NP-C): A multicenter observational retrospective cohort study. Mol Genet Metab. 2009;98:243–249. doi: 10.1016/j.ymgme.2009.07.003.
    1. Pineda M, Perez-Poyato MS, O'Callaghan M, Vilaseca MA, Pocovi M, Domingo R, Portal LR, Perez AV, Temudo T, Gaspar A, Penas JJ, Roldan S, Fumero LM, de la Barca OB, Silva MT, Macias-Vidal J, Coll MJ. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab. 2010;99:358–366. doi: 10.1016/j.ymgme.2009.11.007.
    1. Jacklin E, Imrie J, Jones S, Wraith E. Review of 11 patients with NPC1 treated with miglustat. Mol Genet Metab. 2010;99:S22. doi: 10.1016/j.ymgme.2009.10.087.
    1. Wraith JE, Imrie J. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat. Ther Clin Risk Manag. 2009;5:877–887.
    1. Yanjanin NM, Velez JI, Gropman A, King K, Bianconi SE, Conley SK, Brewer CC, Solomon B, Pavan WJ, Arcos-Burgos M, Patterson MC, Porter FD. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet. 2009;153B:132–140.
    1. Wraith JE, Guffon N, Rohrbach M, Hwu WL, Korenke GC, Bembi B, Luzy C, Giorgino R, Sedel F. Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study. Mol Genet Metab. 2009;98:250–254. doi: 10.1016/j.ymgme.2009.06.009.
    1. Floyd AG, Yu QP, Piboolnurak P, Wraith E, Patterson MC, Pullman SL. Kinematic analysis of motor dysfunction in Niemann-Pick type C. Clin Neurophysiol. 2007;118:1010–1018. doi: 10.1016/j.clinph.2007.01.011.
    1. Hsu AW, Piboolnurak PA, Floyd AG, Yu QP, Wraith JE, Patterson MC, Pullman SL. Spiral analysis in Niemann-Pick disease type C. Mov Disord. 2009;24:1984–1990. doi: 10.1002/mds.22744.
    1. Klarner B, Klünemann HH, Lurding R, Aslanidis C, Rupprecht R. Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations. J Inherit Metab Dis. 2007;30:60–67. doi: 10.1007/s10545-006-0417-6.
    1. Tedeschi G, Bonavita S, Barton NW, Betolino A, Frank JA, Patronas NJ, Alger JR, Schiffmann R. Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry. 1998;65:72–79. doi: 10.1136/jnnp.65.1.72.
    1. Galanaud D, Tourbah A, Lehericy S, Leveque N, Heron B, Billette d. V. Guffon N, Feillet F, Baumann N, Vanier MT, Sedel F. 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol Genet Metab. 2009;96:55–58. doi: 10.1016/j.ymgme.2008.10.002.
    1. Scheel M, Abegg M, Lanyon LJ, Mattman A, Barton JJ. Eye movement and diffusion tensor imaging analysis of treatment effects in a Niemann-Pick Type C patient. Mol Genet Metab. 2010;99:291–295. doi: 10.1016/j.ymgme.2009.10.180.
    1. Choudhury A, Dominguez M, Puri V, Sharma DK, Narita K, Wheatley CL, Marks DL, Pagano RE. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest. 2002;109:1541–1550.
    1. Walter M, Davies JP, Ioannou YA. Telomerase immortalization upregulates Rab9 expression and restores LDL cholesterol egress from Niemann-Pick C1 late endosomes. J Lipid Res. 2003;44:243–253. doi: 10.1194/jlr.M200230-JLR200.
    1. Kaptzan T, West SA, Holicky EL, Wheatley CL, Marks DL, Wang T, Peake KB, Vance J, Walkley SU, Pagano RE. Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of Niemann-Pick type C disease. Am J Pathol. 2009;174:14–20. doi: 10.2353/ajpath.2009.080660.
    1. Zhang M, Strnatka D, Donohue C, Hallows JL, Vincent I, Erickson RP. Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1-/- mice. J Neurosci Res. 2008;86:2848–2856. doi: 10.1002/jnr.21730.
    1. Pentchev PG, Gal AE, Booth AD, Omodeo-Sale F, Fouks J, Neumeyer BA, Quirk JM, Dawson G, Brady RO. A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase. Biochim Biophys Acta. 1980;619:669–679.
    1. Somers KL, Royals MA, Carstea ED, Rafi MA, Wenger DA, Thrall MA. Mutation analysis of feline Niemann-Pick C1 disease. Mol Genet Metab. 2003;79:99–103. doi: 10.1016/S1096-7192(03)00074-X.
    1. Alvarez AR, Klein A, Castro J, Cancino GI, Amigo J, Mosqueira M, Vargas LM, Yevenes LF, Bronfman FC, Zanlungo S. Imatinib therapy blocks cerebellar apoptosis and improves neurological symptoms in a mouse model of Niemann-Pick type C disease. FASEB J. 2008;22:3617–3627. doi: 10.1096/fj.07-102715.
    1. Smith D, Wallom KL, Williams IM, Jeyakumar M, Platt FM. Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiol Dis. 2009;36:242–251. doi: 10.1016/j.nbd.2009.07.010.
    1. Mellon SH, Gong W, Schonemann MD. Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease. Brain Res Rev. 2008;57:410–420. doi: 10.1016/j.brainresrev.2007.05.012.
    1. Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM. Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1-/- mouse. Proc Natl Acad Sci USA. 2009;106:2377–2382. doi: 10.1073/pnas.0810895106.
    1. Ward S, O'donnell P, Fernandez S, Vite CH. 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res. 2010. in press .
    1. Peake KB, Vance JE. Defective cholesterol trafficking in Niemann-Pick C-deficient cells. FEBS Lett. 2010.
    1. Ory D, Porter F, Scherrer D, Lanier M, Langmade S, Molugu V, Gale S, Olzeski D, Sidhu R, Wassif C, Yanjanin N, Schaffer J. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Mol Genet Metab. 2010;99:S28. doi: 10.1016/j.ymgme.2009.10.116.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する