BACKGROUND: Niemann-Pick disease Type C (NP-C) is a lysosomal lipid storage disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales. METHODS: This retrospective, observational chart review included patients with NP-C from five expert NP-C centers. Patient disability scores were recorded using three published NP-C disability scales, and a unified disability scale was developed to allow comparison of data from each scale. Disease progression was represented by scores on the unified NP-C disability scale. Patients were stratified as infantile (< 4 years), juvenile (≥ 4 - < 16 years), and adult (≥ 16 years) based on age at diagnosis, and treated ≥1 year and non-treated/treated < 1 year based on the duration of miglustat treatment. RESULTS: The analysis included 63 patients; the majority (61.9%) were on miglustat therapy for ≥1 year. Ataxia and clumsiness/frequent fall were the most common neurologic symptoms across age groups, whereas, hypotonia and delayed developmental milestones were specific to infantile patients. In both infantile and juvenile patients, visceral signs preceded diagnosis and neurologic signs were noted at or shortly after diagnosis. Adult patients presented with a range of visceral, neurologic, and psychiatric signs in years preceding diagnosis. Patients on miglustat therapy for ≥1 year had a lower mean annual disease progression compared with those untreated/treated < 1 year (1.32 vs 3.54 points/year). A significant reduction in annual disease progression in infantile patients, and a trend towards reduced disease progression in juvenile patients after ≥1 year of miglustat treatment, translated into higher age at last contact or death in these groups. CONCLUSIONS: The type and onset of symptoms varied across age groups and were consistent with descriptions of NP-C within the literature. Miglustat treatment was associated with a reduced rate of disability score worsening in infantile and juvenile patients, both in agreement with increased age at last contact.

Actelion Pharmaceuticals Ltd Allschwil Switzerland

Department of Child Neurology Comenius University Medical School and National Institute of Children's Diseases Bratislava Slovakia

Department of Paediatric Neurology Paediatric Neurology Research Centre Shahid Beheshti University of Medical Sciences Mofid Children Hospital Tehran Iran

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pediatrics Centre for Inborn Errors of Metabolism Comenius University Children's Hospital Bratislava Slovakia

Hospital Sant Joan de Deu Passeig de Sant Joan de Deu 2 Esplugues de Llobregat 08950 Barcelona Spain

Syntax for Science SL Mallorca Spain

Zobrazit více v PubMed

Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, et al. Consensus clinical management guidelines for Niemann-pick disease type C. Orphanet J Rare Dis. 2018;13(1):50. doi: 10.1186/s13023-018-0785-7. PubMed DOI PMC

Mengel E, Pineda M, Hendriksz CJ, Walterfang M, Torres JV, Kolb SA. Differences in Niemann-pick disease type C symptomatology observed in patients of different ages. Mol Genet Metab. 2017;120(3):180–189. doi: 10.1016/j.ymgme.2016.12.003. PubMed DOI

Vanier MT. Niemann-pick disease type C. Orphanet J Rare Dis. 2010;5:16. doi: 10.1186/1750-1172-5-16. PubMed DOI PMC

Patterson M. Niemann-Pick Disease Type C. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2019 PubMed

Wassif CA, Cross JL, Iben J, Sanchez-Pulido L, Cougnoux A, Platt FM, et al. High incidence of unrecognized visceral/neurological late-onset Niemann-pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med. 2016;18(1):41–48. doi: 10.1038/gim.2015.25. PubMed DOI PMC

Vance JE. Lipid imbalance in the neurological disorder, Niemann-pick C disease. FEBS Lett. 2006;580(23):5518–5524. doi: 10.1016/j.febslet.2006.06.008. PubMed DOI

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):330–344. doi: 10.1016/j.ymgme.2012.03.012. PubMed DOI

Pineda M, Mengel E, Jahnova H, Heron B, Imrie J, Lourenco CM, et al. A suspicion index to aid screening of early-onset Niemann-pick disease type C (NP-C) BMC Pediatr. 2016;16:107. doi: 10.1186/s12887-016-0641-7. PubMed DOI PMC

Wraith JE, Sedel F, Pineda M, Wijburg FA, Hendriksz CJ, Fahey M, et al. Niemann-pick type C suspicion index tool: analyses by age and association of manifestations. J Inherit Metab Dis. 2014;37(1):93–101. doi: 10.1007/s10545-013-9626-y. PubMed DOI PMC

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. doi: 10.1186/1750-1172-8-12. PubMed DOI PMC

Patterson MC, Clayton P, Gissen P, Anheim M, Bauer P, Bonnot O, et al. Recommendations for the detection and diagnosis of Niemann-pick disease type C: an update. Neurol Clin Pract. 2017;7(6):499–511. PubMed PMC

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: Iranian pediatric case series. J Child Neurol. 2013;28(12):1599–1606. doi: 10.1177/0883073812464526. PubMed DOI

Pineda M, Wraith JE, Mengel E, Sedel F, Hwu WL, Rohrbach M, et al. Miglustat in patients with Niemann-pick disease type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab. 2009;98(3):243–249. doi: 10.1016/j.ymgme.2009.07.003. PubMed DOI

Pineda M, Perez-Poyato MS, O'Callaghan M, Vilaseca MA, Pocovi M, Domingo R, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-pick disease type C: a case series. Mol Genet Metab. 2010;99(4):358–366. doi: 10.1016/j.ymgme.2009.11.007. PubMed DOI

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):1–6. doi: 10.1016/j.jns.2006.05.054. PubMed DOI

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(1):132–140. PubMed PMC

Fecarotta S, Romano A, Della Casa R, Del Giudice E, Bruschini D, Mansi G, et al. Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-pick disease type C. Orphanet J Rare Dis. 2015;10:22. doi: 10.1186/s13023-015-0240-y. PubMed DOI PMC

Sedel F, Chabrol B, Audoin B, Kaphan E, Tranchant C, Burzykowski T, et al. Normalisation of brain spectroscopy findings in Niemann-pick disease type C patients treated with miglustat. J Neurol. 2016;263(5):927–936. doi: 10.1007/s00415-016-8051-1. PubMed DOI PMC

Mengel E, Klunemann HH, Lourenco 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. doi: 10.1186/1750-1172-8-166. PubMed DOI PMC

Evaluation of different suspicion indices in identifying patients with Niemann-Pick disease Type C in clinical practice: a post hoc analysis of a retrospective chart review