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      Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations

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          Abstract

          Objective

          The Suspicion Index (SI) screening tool was developed to identify patients suspected of having Niemann-Pick disease type C (NP-C). The SI provides a risk prediction score (RPS) based on NP-C manifestations within and across domains (visceral, neurological, and psychiatric). The aim of these subanalyses was to further examine the discriminatory power of the SI by age and manifestation–associations by NP-C suspicion-level and leading manifestations.

          Methods

          The original retrospectively collected data were split into three patient age groups, where NP-C-positive cases were >16 years ( n = 30), 4–16 years ( n = 18), and <4 years ( n = 23), and patients’ RPS were analyzed by logistic regression. Co-occurrence of manifestations within groups of suspicion level (low, medium, high) and leading manifestations (presence/absence of ataxia, cognitive decline, psychosis, and splenomegaly) were analyzed descriptively.

          Results

          NP-C-positive cases versus controls showed strong discriminatory power of RPS. Area under the receiver operating characteristic curve was 0.964 (>16 years) and 0.981 (4–16 years) but weaker 0.562 for infants (<4 years). Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement, suggestive of a preneurological phase of the disease. In patients >4 years, prominent leading manifestation–associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline. Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment-resistant psychiatric symptoms.

          Conclusions

          The SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants <4 years. The SI is also informative regarding the association and co-occurrence of manifestations in patients with NP-C.

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          Most cited references2

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          Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial.

          A randomized, controlled trial of miglustat indicated that miglustat (Zavesca) stabilized neurological disease over 12 months in adult and juvenile patients with Niemann-Pick disease type C (NP-C). We report data from a non-controlled, open-label extension to this initial randomized trial. All patients completing the randomized trial were allowed to continue treatment in a 12-month, non-controlled open-label extension. Those completing 12 months of extension therapy could continue further on miglustat in a 'continued extension' phase. From a total of 29 patients in the randomized phase (mean [+/-SD] age 24.6+/-9.1 ears; 52% female), 21 completed 12 months of therapy with miglustat (17 of whom received miglustat in the initial randomized phase, and four in the extension phase), and 15 patients (all from the miglustat-randomized group) completed 24 months on miglustat. Mean horizontal saccadic eye movement velocity (HSEM-alpha) indicated improvement in the 12-month miglustat group, and stabilization in the 24-month group; swallowing was improved or stable in 86% and in up to 93%, respectively. Ambulation was stabilized in both the 12- and 24-month groups. In an exploratory disease stability analysis of prospective data on key parameters of disease progression (HSEM-alpha, swallowing, ambulation and cognition), 13/19 (68%) patients receiving >or= 12 months' miglustat therapy had stable disease. Among all patients receiving >or= 1 dose of miglustat (n=28), the most frequent adverse events were diarrhoea, weight decrease, flatulence and tremor. Overall, these data suggest that long-term miglustat therapy stabilizes neurological disease and is well tolerated in adult and juvenile patients with NP-C. Copyright 2009 Elsevier Inc. All rights reserved.
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            Is Open Access

            New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

            Niemann-Pick disease type C (NP-C) is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®), a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years) and in juveniles and adults (12 years and older), compared with those diagnosed in early childhood (younger than 6 years). Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder.
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              Author and article information

              Contributors
              +44-161-206 4365 , +44-161-206 4036 , chris.hendriksz@srft.nhs.uk
              Journal
              J Inherit Metab Dis
              J. Inherit. Metab. Dis
              Journal of Inherited Metabolic Disease
              Springer Netherlands (Dordrecht )
              0141-8955
              1573-2665
              21 June 2013
              21 June 2013
              2014
              : 37
              : 93-101
              Affiliations
              [ ]Genetic Medicine, St. Mary’s Hospital, Oxford Road, Manchester, M13 9WL UK
              [ ]Department of Neurology and Reference Center for Lysosomal Diseases, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France
              [ ]Fundació, Hospital Sant Joan de Déu, Centre for Biomedical Research on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain
              [ ]Department of Paediatrics, Academic Medical Center, University of Amsterdam, 11005 AZ Amsterdam, The Netherlands
              [ ]Manchester Academic Health Science Centre (MAHSC), Salford Royal Hospital NHS Foundation Trust, University of Manchester, Brunswick Street, Manchester, M13 9PL UK
              [ ]Department of Paediatrics, Monash University, Clayton, Victoria Australia
              [ ]Department of Neuropsychiatry, Royal Melbourne Hospital and Melbourne Neuropsychiatry Center, University of Melbourne, 3050 Melbourne, Victoria Australia
              [ ]Division of Child and Adolescent Neurology, Mayo Clinic, Rochester, MN 55905 USA
              [ ]Actelion Pharmaceuticals Ltd, 4123 Allschwil, Switzerland
              Author notes

              Communicated by: Olaf Bodamer

              Article
              9626
              10.1007/s10545-013-9626-y
              3889645
              23793527
              c5955724-35b8-4d1e-8783-6e5e3d7eb6b4
              © The Author(s) 2013

              Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

              History
              : 20 December 2012
              : 24 May 2013
              : 28 May 2013
              Categories
              Original Article
              Custom metadata
              © SSIEM and Springer Science+Business Media Dordrecht 2014

              Internal medicine
              Internal medicine

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