Summary
Niemann–Pick disease type C (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder that leads to variable symptoms that include cognitive decline, ataxia, dystonia, cataplexy, vertical supranuclear gaze palsy, and seizures. Currently, there is no specific treatment for NPC other than palliative care. Substrate reduction therapy represents a potential strategy for treating this debilitating neurodegenerative disorder. Miglustat (Zavesca) is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyses the first step in the biosynthesis of most glycosphingolipids. Miglustat has pharmacokinetic properties that allow it to cross the blood–brain barrier, thus making it a potential therapeutic agent for treating neurological symptoms in NPC patients. We present here a case report of a Brazilian child treated with miglustat. Before treatment, the patient presented with difficulties walking and swallowing, slurred speech, moderate cognitive impairments, ataxia, ptosis, and vertical supranuclear ophthalmoplegia. On a disability scale, the patient obtained a score of 15 before treatment and 8 after treatment. Following 12 months of treatment, the patient remained stable with improvements in speech, ptosis, ophthalmoplegia, ataxia, hypotonia and seizures. The Child Behavior Checklist (CBCL) was used to assess psychopathological, behavioural and social problems before and after treatment. The CBCL showed that indices for depression, affective and attention problems were all in the normal range following treatment. Thus, for this individual miglustat was an effective, well-tolerated and efficacious medication for treatment of NPC symptoms. Follow-up maintenance studies are vital to establish whether both the efficacy and safety of miglustat persist with time.
Similar content being viewed by others
Abbreviations
- CBCL:
-
Child behavior checklist
- MRI:
-
Magnetic resonance imaging
- NPC:
-
Niemann–Pick disease type C
- q.d.:
-
every day
- t.i.d:
-
three times a day
References
Achenbach TM (1991) Manual for the Child Behavior Checklist/4-18 and 1991 Profile. Burlington, VT: University of Vermont Department of Psychiatry.
Achenbach TM, Ruffle TM (2000) The Child Behavior Checklist and related forms for assessing behavioral/emotional problems and competencies. Pediatr Rev 21: 265–271. doi:10.1542/pir.21-8-265.
Chien YH, Lee NC, Tsai LK, et al (2007) 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 30: 826–833. doi:10.1007/s10545-007-0630-y.
Erickson RP, Garver WS, Camargo F, et al (2000) Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann–Pick C mice. J Inherit Metab Dis 23: 54–62. doi:10.1023/A:1005650930330.
Imrie J, Dasgupta S, Besley GT, et al (2007) The natural history of Niemann–Pick disease type C in the UK. J Inherit Metab Dis 30: 51–59. doi:10.1007/s10545-006-0384-7.
Iturriaga C, Pineda M, Fernandez-Valero EM, et al (2006) Niemann–Pick C disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci 249: 1–6. doi:10.1016/j.jns.2006.05.054.
Lachmann RH, te Vruchte D, Lloyd-Evans E, et al (2004) Treatment with miglustat reverses the lipid-trafficking defect in Niemann–Pick disease type C. Neurobiol Dis 16: 654–658. doi:10.1016/j.nbd.2004.05.002.
Paciorkowski AR, Westwell M, Ounpuu S, et al (2008) Motion analysis of a child with Niemann–Pick disease type C treated with miglustat. Mov Disord 23: 124–128. doi:10.1002/mds.21779.
Patterson MC, Di Bisceglie AM, Higgins JJ, et al (1993) The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann–Pick disease type C. Neurology 43: 61–64.
Patterson MC, Vanier MT, Suzuki K, et al (2001) Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th Edn. New York: McGraw-Hill, 3611–3633.
Patterson MC, Vecchio D, Prady H, et al (2007) Miglustat for treatment of Niemann–Pick C disease: a randomised controlled study. Lancet Neurol 6: 765–772. doi:10.1016/S1474-4422(07)70194-1.
Saunier B, Kilker RD Jr, Tkacz JS, et al (1982) Inhibition of N-linked complex oligosaccharide formation by 1-deoxynojirimycin, an inhibitor of processing glucosidases. J Biol Chem 257: 14155–14161.
Sevin M, Lesca G, Baumann N, et al (2007) The adult form of Niemann–Pick disease type C. Brain 130(Pt 1): 120–133. doi:10.1093/brain/awl260.
Treiber A, Morand O, Clozel M (2007) The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. Xenobiotica 37: 298–314. doi:10.1080/00498250601094543.
Vanier MT, Millat G (2003) Niemann–Pick disease type C. Clin Genet 64: 269–281. doi:10.1034/j.1399-0004.2003.00147.x.
Wadzinski J, Franks R, Roane D, et al (2007) Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med 20: 499–502. doi:10.3122/jabfm.2007.05.070062.
Walkley SU, Suzuki K (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 1685: 48–62.
Zervas M, Somers KL, Thrall MA, et al (2001) Critical role for glycosphingolipids in Niemann–Pick disease type C. Curr Biol 11: 1283–1287. doi:10.1016/S0960-9822(01)00396-7.
Acknowledgements
We thank Dr Cameron B. Gundersen for critical reading of the manuscript, and Jaqueline Kolberg for assistance with the illustrations. M. L. C. gratefully acknowledges support from Mr Norbert Gehr. We also thank the patient’s family for allowing this publication.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicating editor: Guy Besley
Competing interests: None declared
Rights and permissions
About this article
Cite this article
Santos, M.L.F., Raskin, S., Telles, D.S. et al. Treatment of a child diagnosed with Niemann–Pick disease type C with miglustat: A case report in Brazil. J Inherit Metab Dis 31 (Suppl 2), 357–361 (2008). https://doi.org/10.1007/s10545-008-0923-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-008-0923-9