Recommendations for the detection and diagnosis of Niemann-Pick disease type C

Purpose of review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. Recent findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Mayo Clinic (MCP), Rochester, MN; UCL Great Ormond Street Institute of Child Health (PC, PG), London, UK; Great Ormond Street Hospital (PG), London, UK; Département de Neurologie (MA), Hôpital de Hautepierre, CHU de Strasbourg; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) (MA), INSERM-U964/CNRSUMR7104/Université de Strasbourg, Illkirch; Fédération de Médecine Translationnelle de Strasbourg (FMTS) (MA), Université de Strasbourg, France; Institute of Medical Genetics and Applied Genomics (PB), University Hospital of Tübingen; Centogene AG (PB), Rostock, Germany; Universitaire de Psychiatrie de l’Enfant et de l’Adolescent (OB), CHU de Nantes, France; Regional Coordinator Centre for Rare Diseases (AD), University Hospital Santa Maria della Misericordia, Udine, Italy; Division of Metabolism, Bambino Gesù Children’s Hospital (CD-V), Rome, Italy; Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie der Universität Regensburg am Bezirksklinikum (HHK), Regensburg, Germany; Hospices Civils de Lyon–Centre de Biologie et Pathologie Est (PL), Bron, France; University of São Paulo (HCFMRP-USP) (CML), Ribeirão Preto, SP, Brazil; Department of Medicine (DSO), Washington University, St Louis, MO; Child Development Centre (AP), Addenbrooke’s Hospital, Cambridge, UK; University of Zaragoza (MP), IIS Aragon, Spain; Department of Neurology and German Center for Vertigo and Balance Disorders (MS), University Hospital Munich, Germany; Laboratoire Gillet-Mérieux (MTV), Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, Bron, France; Department of Neuropsychiatry (MW), Royal Melbourne Hospital & University of Melbourne, Australia; and Universitätsklinikum Münster (TM), Germany. Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp. The Article Processing Charge was funded by Actelion Pharmaceuticals Ltd. No statistical analyses were required for preparation of this manuscript. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Correspondence to: [email protected] Neurology: Clinical Practice ||| December 2017 Neurology.org/cp 499 Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified. Summary: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists. Neurol Clin Pract 2017;7:499–511 N iemann-Pick disease type C (NP-C) is a rare neurovisceral lysosomal disorder caused by autosomal recessive mutations in NPC1 or NPC2 (95% and ;4% of patients). Analysis of 4 independent exome sequencing databases gave a conservative estimated incidence of 1/92,104 for NP-C1 and 1/2,858,998 for NP-C2, in agreement with recent clinical data. After accounting for 2 common NPC1 variants, the incidence was estimated to be potentially 1/19,000–1/36,000 for late-onset forms, suggesting that previous prevalence estimates may be too low. NP-C diagnosis is typically delayed by a mean of 4.1 years from first onset of neurologic symptoms, narrowing the therapeutic window. The first international recommendations for clinical management of NP-C were prepared in 2009 based on a literature review and consensus among an expert panel with updates in 2012 after a second meeting of an NP-C Guidelines Working Group. Recent advances in the field of NP-C screening technologies (e.g., biomarkers) and diagnostic techniques (e.g., molecular genetics) justify an update of these recommendations. The development and availability of simple, rapid, and reliable biomarkers (oxysterols, lysosphingomyelin derivatives, and bile acids) will likely increase detection of patients with NP-C. Increased availability of next-generation sequencing (NGS) (e.g., phenotype-specific gene panels) may widen the application of genetic testing in clinical practice, particularly in at-risk patient cohorts. Previous recommendations focused on identifying individual patients with a high clinical suspicion of NP-C. Technologic developments may facilitate patient identification based on clinical suspicion or within larger cohorts via broad genetic or biomarker screening, which ultimately may improve patient outcomes. Development of the updated NP-C diagnostic recommendations The NP-C Diagnostic Recommendations Expert Panel met in May 2016 to assess the impact of recently published data and to reach consensus on the best approaches to diagnosing NP-C. The following sections of the previous recommendations were updated: differential diagnosis and initial detection, diagnosis, and the NP-C diagnostic algorithm. Three approaches to the detection and diagnosis of patients with NP-C were established: clinical assessment, biomarker testing, and genetic analysis. Differential diagnosis and initial detection • All patients with suspicion of NP-C require rigorous and detailed clinical assessment, as described in the 2012 diagnostic recommendations. • All undiagnosed patients with any manifestation of NP-C should be referred to regional or national centers specializing in inherited metabolic disorders. • Visceral, neurologic, ophthalmologic, and psychiatric manifestations should be explored in depth. • Details of the signs, symptoms, and disease stages of NP-C are covered extensively elsewhere. Advances in psychiatric assessments • Psychiatric symptoms and cognitive disorders were observed in 45% and 61%, respectively, of patients with late-onset NP-C, and psychiatric symptoms in 86% of patients in another small cohort; however, no specific neuropsychiatric profile was observed. Patients with NP-C, particularly adults, can present with a range of psychiatric symptoms, 500 Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Marc C. Patterson et al.