Beyond the Typical Syndrome: Understanding Non-motor Features in Niemann-Pick Type C Disease


Niemann-Pick type C (NPC) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome. NPC’s clinical presentation is highly heterogeneous, depending on the time of onset. It encompasses visceral, neurological, and/or psychiatric manifestations. As the motor findings are so important and devastating in this disease, there is a lack of description about non-motor symptoms, even though they play important role in quality of life of NPC patients. We described the most common non-motor findings in NPC like cognitive dysfunction, neuroimaging, psychiatric symptoms, sleep disorders, seizures, hearing problems, respiratory and other systemic features, bladder and fecal dysfunction, hypersalivation, and malnutrition. In this review, we highlighted the importance of these undervalued symptoms and their management. Specific measures of all aforementioned clinical features may work as relevant biomarkers in order to evaluate successful therapies in future clinical trials.

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  1. 1.

    Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Vanier MT. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis. 2015;38(1):187–99.

    CAS  PubMed  Google Scholar 

  3. 3.

    Patterson MC, Mengel E, Wijburg FA, Muller A, Schwierin B, Drevon H, et al. Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis. 2013;8(12):1750–172.

    Google Scholar 

  4. 4.

    Garver WS, Francis GA, Jelinek D, Shepherd G, Flynn J, Castro G, et al. The National Niemann–Pick C1 disease database: report of clinical features and health problems. Am J Med Genet A. 2007;143A(11):1204–11.

    PubMed  Google Scholar 

  5. 5.

    Geberhiwot, et al. Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis. 2018;13:50.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Crocker AC. The cerebral defect in Tay-Sachs disease and Niemann-Pick disease. J Neurochem. 1961;7:69–80.

    CAS  PubMed  Google Scholar 

  7. 7.

    Rangel DM, Sobreira-Neto MA, Nepomuceno CR, Marques ER, Braga-Neto P. Sleep disorders in Niemann-Pick disease type C, beyond cataplexy. Sleep Med. 2019;57:122–7.

    PubMed  Google Scholar 

  8. 8.

    Hinton V, Vecchio D, Prady H, Wraith E, Patterson M. The cognitive phenotype of type C disease: neuropsychological characteristics of patients at baseline in a clinical trial with oral miglustat. Poster presented at the American Society of Human Genetics conference, Salt Lake City, 2005.

  9. 9.

    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;30:60–7.

    CAS  PubMed  Google Scholar 

  10. 10.

    Heitz C, Epelbaum S, Nadjar Y. Cognitive impairment profile in adult patients with Niemann pick type C disease. Orphanet J Rare Dis. 2017;12(1):166.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Johnen A, Pawlowski M, Duning T. Distinguishing neurocognitive deficits in adult patients with NP-C from early onset Alzheimer's dementia. Orphanet J Rare Dis. 2018;13(1):91.

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bergeron D, Poulin S, Laforce R Jr. Cognition and anatomy of adult Niemann-Pick disease type C: insights for the Alzheimer field. Cogn Neuropsychol. 2017;35:1–14.

    Google Scholar 

  13. 13.

    Balázs N, Milanovich D, Hornyák C, Bereczki D, Kovács T. Late-onset Niemann-Pick disease type C overlapping with frontotemporal dementia syndromes: a case report. J Neural Transm (Vienna). 2019;126(11):1501–4.

    Google Scholar 

  14. 14.

    Hendriksz CJ, Anheim M, Bauer P, Bonnot O, Chakrapani A, Corvol JC, et al. The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease. Curr Med Res Opin. 2017;33(5):877–90.

    PubMed  Google Scholar 

  15. 15.

    Micheli F, Perandones C, Giugni J, et al. Is progressive supranuclear palsy part of the phenotypic spectrum of Niemann-Pick disease type C? Neurology. 2013;80:P04.158.

    Google Scholar 

  16. 16.

    Zech M, Nübling G, Castrop F, Jochim A, Schulte EC et al. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders. PLoS ONE 2013;8(12): e82879.

  17. 17.

    Boenzi S, Dardis A, Russo P, Bellofatto M, Imbriglio T, Fico T, et al. Screening for Niemann-Pick type C disease in neurodegenerative diseases. J Clin Neurosci. 2019;68:266–7.

    PubMed  Google Scholar 

  18. 18.

    Kluenemann HH, Nutt JG, Davis MY, Bird TD. Parkinsonism syndrome in heterozygotes for Niemann-Pick C1. J Neurol Sci. 2013;335(1–2):219–20.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Schneider SA, Tahirovic S, Hardy J, Strupp M, & Bremova-Ertl T. Do heterozygous mutations of Niemann–Pick type C predispose to late-onset neurodegeneration: a review of the literature. J Neurol 2019.

  20. 20.

    Evans WRH, Hendriksz CJ. Niemann–Pick type C disease – the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment. BJPsych Bull. 2017;41(2):109–14.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Mengel E, et al. Differences in Niemann-Pick disease type C symptomatology observed in patients of different ages. Genét Mol Metab. 2017;120:80–189.

    Google Scholar 

  22. 22.

    Walterfang M, Macfarlane MD, Looi JC, et al. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol. 2012;19(3):462–7.

    CAS  PubMed  Google Scholar 

  23. 23.

    Walterfang M, Fahey M, Abel L, Fietz M, Wood A, Bowman E, et al. Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables. AJNR Am J Neuroradiol. 2011;32(7):1340–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Gburek-Augustat J, Groeschel S, Kern J, Beck-Woedl S, Just J, Harzer K, et al. Comparative analysis of cerebral magnetic resonance imaging changes in nontreated infantile, juvenile and adult patients with Niemann-Pick disease type C. Neuropediatrics. 2019.

  25. 25.

    Masingue M, Adanyeguh I, Nadjar Y, Sedel F, Galanaud D, Mochel F. Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-Pick type C under treatment. Orphanet J Rare Dis. 2017;12(1):22.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    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(3):291–5.

    CAS  PubMed  Google Scholar 

  27. 27.

    Walterfang M, Fahey M, Desmond P, Wood A, Seal ML, Steward C, et al. White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology. 2010;75(1):49–56.

    CAS  PubMed  Google Scholar 

  28. 28.

    Kumar A, Chugani HT. Niemann-Pick disease type C: unique 2-deoxy-2[18F] fluoro-D-glucose PET abnormality. Pediatr Neurol. 2011;44(1):57–60.

    PubMed  Google Scholar 

  29. 29.

    Tedeschi G, Bonavita S, Barton NW, Bertolino A, Frank JA, Patronas NJ, et al. Proton magnetic resonance spectroscopic imaging in the clinical evaluation of patients with Niemann-Pick type C disease. J Neurol Neurosurg Psychiatry. 1998;65(1):72–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Galanaud D, Tourbah A, Lehéricy S, Leveque N, Heron B, Billette de Villemeur T, et al. 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy. Mol Genet Metab. 2009;96(2):55–8.

    CAS  PubMed  Google Scholar 

  31. 31.

    Benussi A, Cotelli MS, Padovani A, Borroni B. Recent neuroimaging, neurophysiological, and neuropathological advances for the understanding of NPC. F1000Res. 2018;7:194.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Esposito M, Dubbioso R, Tozza S, Iodice R, Aiello M, Nicolai E, et al. Evidência in vivo de deposição de amilóide cortical na forma adulta de Niemann Pick tipo C. Heliyon. 2019;5(11):e02776.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Saito Y, Suzuki K, Nanba E, Yamamoto T, Ohno K, Murayama S. NiemannPick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity. Ann Neurol. 2002;52:351–5.

    CAS  PubMed  Google Scholar 

  34. 34.

    Bonnot O, Klünemann HH, Velten C, Torres Martin JV, Walterfang M. Systematic review of psychiatric signs in Niemann-Pick disease type C. World J Biol Psychiatry. 2019;20(4):320–32.

    PubMed  Google Scholar 

  35. 35.

    Bonnot O, Klunemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis. 2014;9:65.

    PubMed  PubMed Central  Google Scholar 

  36. 37.

    Walterfang M, et al. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Neuropsychiatry Clin Neurosci. 2007;218:2.

    Google Scholar 

  37. 38.

    Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, et al. The adult form of Niemann-Pick disease type C. Brain. 2007;130:120–33.

    PubMed  Google Scholar 

  38. 39.

    Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012;106(3):330–44.

    CAS  PubMed  Google Scholar 

  39. 40.

    Bauer P, Balding DJ, Klünemann HH, Linden DE, Ory DS, Pineda M, et al. Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study. Hum Mol Genet. 2013;22:4349–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 36.

    Maubert A, Hanon C, Sedel F. Psychiatric disorders in adult form of NiemannPick disease type C. Encephale. 2016;42:208–13.

    CAS  PubMed  Google Scholar 

  41. 41.

    Imrie J, Vijayaraghaven S, Whitehouse C, Harris S, Heptinstall L, Church H, et al. Niemann-Pick disease type C in adults. J Inherit Metab Dis. 2002;25(6):491–500.

    CAS  PubMed  Google Scholar 

  42. 42.

    Klünemann HH, Santosh PJ, Sedel F. Treatable metabolic psychoses that go undetected: what Niemann-Pick type C can teach us. Int J Psychiatry Clin Pract. 2012;16:162–9.

    PubMed  Google Scholar 

  43. 43.

    Friston K, Frith C. Schizophrenia: a disconnection syndrome? Clin Neurosci. 1995;3:89–97.

    CAS  PubMed  Google Scholar 

  44. 44.

    Rego T, Farrand S, Goh AMY, Eratne D, Kelso W, Mangelsdorf S, et al. Psychiatric and cognitive symptoms associated with Niemann-Pick type C disease: neurobiology and management. CNS Drugs. 2019;33(2):125–42.

    PubMed  Google Scholar 

  45. 45.

    Davidson CD, Walkley SU. Niemann-Pick type C disease – pathophysiology and future perspectives for treatment. US Neurol Touch Brief. 2010;6:88–94.

    Google Scholar 

  46. 46.

    Eratne D, Loi SM, Li QX, Varghese S, McGlade A, Collins S, et al. Cerebrospinal fluid neurofilament light chain is elevated in Niemann-Pick type C compared to psychiatric disorders and healthy controls and may be a marker of treatment response. Aust N Z J Psychiatry. 2019;4867419893431.

  47. 47.

    Vankova J, Stepanova I, Jech R, Elleder M, Ling L, Mignot E, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep. 2003;26(4):427–30.

    PubMed  Google Scholar 

  48. 48.

    Nevsimalova S, Malinova V. Cataplexy and sleep disorders in Niemann-Pick type C disease. Curr Neurol Neurosci Rep. 2015;15(1):522.

    PubMed  Google Scholar 

  49. 49.

    Kawazoe T, Yamamoto T, Narita A, Ohno K, Adachi K, Nanba E, et al. Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report. BMC Neurol. 2018;18:117.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Harzer K, Beck-Wödl S, Bauer P. Niemann-pick disease type C: new aspects in a long published family - partial manifestations in heterozygotes. JIMD Rep. 2014;12:25–9.

    PubMed  Google Scholar 

  51. 51.

    Reading P. Cataplexy. Pract Neurol. 2019 Feb;19(1):21–7.

    PubMed  Google Scholar 

  52. 52.

    Patterson M. Niemann-pick disease type C. 2000 Jan 26 [Updated 2019 Aug 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

  53. 53.

    Pedroso JL, Fusão EF, Ladeia-Frota C, Arita JH, Barsottini OG, Masruha MR, et al. Teaching video neuroimages: gelastic cataplexy as the first neurologic manifestation of Niemann-Pick disease type C. Neurology. 2012 Nov 27;79(22):e189.

    PubMed  Google Scholar 

  54. 54.

    Canto CB, Onuki Y, Bruinsma B, van der Werf YD, De Zeeuw CI. The sleeping cerebellum. Trends Neurosci. 2017;40(5):309–23.

    CAS  PubMed  Google Scholar 

  55. 55.

    Xu S, Zhou S, Xia D, Xia J, Chen G, Duan S, et al. Defects of synaptic vesicle turnover at excitatory and inhibitory synapses in Niemann-Pick C1-deficient neurons. Neuroscience. 2010;167(3):608–20.

    CAS  PubMed  Google Scholar 

  56. 56.

    Sáez PJ, Orellana JA, Vega-Riveros N, Figueroa VA, Hernández DE, Castro JF, et al. Disruption in connexin-based communication is associated with intracellular Ca2+ signal alterations in astrocytes from Niemann-pick type C mice. PLoS One. 2013;8(8):e71361.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, et al. Niemann-Pick disease Type C clinical database: cognitive and coordination deficits are early disease indicators. Orphanet J Rare Dis. 2013;8(1):35.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Munoz T, Raiman J. Epilepsy and Niemann Pick C disease. J Pediatric Epilepsy. 2015;03(04):229–34.

    Google Scholar 

  59. 59.

    Skorpen J, Helland IB, Tennøe B. Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report. J Med Case Rep. 2012;6:383.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Higgins JJ, Patterson MC, Dambrosia JM, Pikus AT, Pentchev PG, Sato S, et al. A clinical staging classification for type C Niemann-Pick disease. Neurology. 1992;42(12):2286–90.

    CAS  PubMed  Google Scholar 

  61. 61.

    Santos ML, Raskin S, Telles DS, Lohr A Jr, Liberalesso PB, Vieira SC, et al. Treatment of a child diagnosed with NiemannPick disease type C with miglustat: a case report in Brazil. J Inherit Metab Dis. 2008;31(Suppl 2):S357–61.

    PubMed  Google Scholar 

  62. 62.

    Karimzadeh P, Tonekaboni SH, Ashrafi MR, Shafeghati Y, Rezayi A, Salehpour S, et al. Effects of miglustat on stabilization of neurological disorder in niemann-pick disease type C: Irania. J Child Neurol. 2013;28(12):1599–606.

    PubMed  Google Scholar 

  63. 63.

    Heron B, Valayannopoulos V, Baruteau J, Chabrol B, Ogier H, Latour P, et al. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C. Orphanet J Rare Dis. 2012;7:36.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Wijburg FA, Sedel F, Pineda M, Hendriksz CJ, Fahey M, Walterfang M, et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology. 2012;78(20):1560–7.

    CAS  PubMed  Google Scholar 

  65. 65.

    Mengel E, Klünemann HH, Lourenço CM, Hendriksz CJ, Sedel F, Walterfang M, et al. Niemann-Pick disease type C symptomatology: an expert-based clinical description. Orphanet J Rare Dis. 2013;8:166.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Wraith JE, Baumgartner MR, Bembi B, Covanis A, Levade T, Mengel E, et al. Recommendations on the diagnosis and management of Niemann-Pick disease type C. Mol Genet Metab. 2009;98:152–65.

    CAS  PubMed  Google Scholar 

  67. 67.

    Pineda M, Walterfang M, Patterson MC. Miglustat in Niemann-Pick disease type C patients: a review. Orphanet J Rare Dis. 2018;13:140.

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Bonney DK, O’Meara A, Shabani A, Imrie J, Bigger BW, Jones S, et al. 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;3:171–3.

    Google Scholar 

  69. 69.

    Senirli RT, Kuşçu O, Akyol U, Topçu M, Yiğit Ö, Aksoy S, et al. Otorhinolaryngological, audiovestibular and swallowing manifestations of patients with Niemann–Pick disease type C. Int J Pediatr Otorhinolaryngol. 2016;80:1–4.

    PubMed  Google Scholar 

  70. 70.

    Yanjanin NM, Velez JI, Gropman A, King K, Bianconi SE, Conley SK, et al. Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:132–40.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    King KA, Gordon-Salant S, Yanjanin N, Zalewski C, Houser A, Porter FD, et al. Auditory phenotype of Niemann-Pick disease, type C1. Ear Hear. 2014;35(1):110–7.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Guo W, He A, Boer M. Elevated plasma chitotriosidase activity in various Lysosomal storage disorders. J Inherit Metab Dis. 1995;18(6):717–22.

    CAS  PubMed  Google Scholar 

  73. 73.

    Ward S, O’Donnell P, Fernandez S, et al. 2-Hydroxypropyl-β-Cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res. 2010;68(1):52–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Belmatoug N, Burlina A, Giraldo P, Hendriksz CJ, Kuter DJ, Mengel E, et al. Gastrointestinal disturbances and their management in miglustat-treated patients. J Inherit Metab Dis. 2011;34(5):991–1001.

    CAS  PubMed  Google Scholar 

  75. 75.

    Copetti S D, Santos G N. Feeding for patients with neurodegenerative disoders as a focus on Niemann type C Pick disease (Npd). Nov Tech Nutri Food Sci. 2(2). NTNF.000535. 2018.

  76. 76.

    Coisne C, Tilloy S, Monflier E, Wils D, Fenart L, Gosselet F. Cyclodextrins as emerging therapeutic tools in the treatment of cholesterol-associated vascular and neurodegenerative diseases. Molecules. 2016;21:E1748.

    PubMed  Google Scholar 

  77. 77.

    Och U, Fischer T, Marquardt T. Dietary carbohydrate modification in Niemann-Pick type C. Case series of dietary treatment during miglustat (Zavesca®) therapy. Ernährungs Umschau. 2019;66(03):36–44.

    Google Scholar 

  78. 78.

    Papandreou A, Gissen P. Diagnostic workup and management of patients with suspected Niemann-Pick type C disease. Ther Adv Neurol Disord. 2016;9(3):216–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Telles-Correia D, Barbosa-Rocha N, Gama-Marques J, Moreira AL, Alves-Moreira C, Saraiva S, et al. Validation of the Portuguese version of the Psychotic Symptom Rating Scales (PSYRATS). Actas Esp Psiquiatr. 2017;45(2):56–61.

    PubMed  Google Scholar 

  80. 80.

    Vessoni AL. Adaptação e estudo de confiabilidade da escala de avaliação das síndromes positiva e negativa para a esquizofrenia no Brasil [dissertação]. São Paulo: Escola Paulista de Medicina; 1993.

  81. 81.

    Bressan RA, Chaves AC, Shirakawa I, de Mari J. Validity study of the Brazilian version of the Calgary Depression Scale for Schizophrenia. Schizophr Res. 1998;32(1):41–9.

    CAS  PubMed  Google Scholar 

  82. 82.

    Arciniegas DB. Psychosis. Continuum (Minneap Minn). 2015;21(3 Behavioral Neurology and Neuropsychiatry)2015;21(3):715-736.

  83. 83.

    Bertolazi AN, Fagondes SC, Hoff LS, Pedro VD, Menna Barreto SS, Johns MW. Portuguese-language version of the Epworth sleepiness scale: validation for use in Brazil. J Bras Pneumol. 2009;35(9):877–83.

    PubMed  Google Scholar 

  84. 84.

    Bertolazi AN, Fagondes SC, Hoff LS, Dartora EG, Miozzo IC, de Barba ME, et al. Validation of the Brazilian Portuguese version of the Pittsburgh Sleep Quality Index. Sleep Med. 2011;12(1):70–5.

    PubMed  Google Scholar 

  85. 85.

    Masuko AH, Carvalho LB, Machado MA, Morais JF, Prado LB, Prado GF. Translation and validation into the Brazilian Portuguese of the restless legs syndrome rating scale of the International Restless Legs Syndrome Study Group. Arq Neuropsiquiatr. 2008;66(4):832–6.

    PubMed  Google Scholar 

  86. 86.

    da Silva TI, Alonso NB, Azevedo AM, Westphal-Guitti AC, Migliorini RCVP, Marques CM, et al. Tradução e adaptação cultural da Seizure Severity Questionnaire: resultados preliminares. J Epilepsy Clin Neurophysiol. 2006;12(1):41–7.

    Google Scholar 

  87. 87.

    Bowman EA, Walterfang M, Abel L, Desmond P, Fahey M, Velakoulis D. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat. J Neurol. 2015;262:2106–14.

    CAS  PubMed  Google Scholar 

  88. 88.

    Szakszon K, Szegedi I, Magyar Á, Oláh É, Andrejkovics M, Balla P, et al. Complete recovery from psychosis upon miglustat treatment in a juvenile Niemann-Pick C patient. Eur J Paediatr Neurol. 2014;18:75–8.

    PubMed  Google Scholar 

  89. 89.

    Santos MLF, Raskin S, Telles DS, Löhr Junior A, Liberalesso PBN, Vieira SC, et al. Treatment of a child diagnosed with Niemann-Pick disease type C with miglustat: a case report in Brazil. J Inherit Metab Dis. 2008;31:357–61.

    Google Scholar 

  90. 90.

    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;6:765–72.

    CAS  PubMed  Google Scholar 

  91. 91.

    Liu B. Therapeutic potential of cyclodextrins in the treatment of Niemann-Pick type C disease. Clin Lipidol. 2012;7:289–301.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Berry-Kravis E, Chin J, Hofmann A, Winston A, Stoner R, LaGorio L, et al. Long-term treatment of Niemann-Pick type C1 disease with intrathecal 2-hydroxypropyl-β-cyclodextrin. Pediatr Neurol. 2018;80:24–34.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Megías-Vericat JE, García-Robles A, Company-Albir MJ, Fernández-Megía MJ, Pérez-Miralles FC, López-Briz E, et al. Early experience with compassionate use of 2 hydroxypropyl-beta-cyclodextrin for Niemann-Pick type C disease: review of initial published cases. Neurol Sci. 2017;38:727–43.

    PubMed  Google Scholar 

  94. 94.

    Kirkegaard T, Gray J, Priestman DA, et al. Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016;8(355):355ra118.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Subramanian K, Hutt DM, Scott SM, Gupta V, Mao S, Balch WE. Correction of Niemann-Pick type C1 trafficking and activity with the histone deacetylase inhibitor valproic acid. J Biol Chem. 2020:jbc.RA119.010524.

  96. 96.

    Bremova T, Malinová V, Amraoui Y, Mengel E, Reinke J, Kolníková M, et al. Acetyl-dl-leucine in Niemann-Pick type C: a case series. Neurology. 2015;85(16):1368–75.

    CAS  PubMed  Google Scholar 

  97. 97.

    Schultz ML, Krus KL, Lieberman AP. Lysosome and endoplasmic reticulum quality control pathways in Niemann-Pick type C disease. Brain Res. 1649;2016:181–8.

    Google Scholar 

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Conception and design of the work: DMR and PBN. SSOC: literature search; acquisition, analysis, or interpretation of data for the work: DMR, MASN, and PBN. Drafting the work: DMR, JLP, MASN, and PBN. All authors were involved in critical revision of the manuscript for important intellectual content.

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Correspondence to Pedro Braga-Neto.

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Rangel, D.M., Melo, M.C.A., Pedroso, J.L. et al. Beyond the Typical Syndrome: Understanding Non-motor Features in Niemann-Pick Type C Disease. Cerebellum (2020).

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  • Niemann-Pick type C
  • Non-motor symptoms
  • Sleep
  • Dementia
  • Psychosis
  • Autonomic findings
  • Epilepsy
  • Systemic features