Abstract
Early diagnosis of Niemann-Pick disease type C (NPC) is crucial to slow the progression of neurological manifestations. Different tools were developed to aid diagnosis of NPC, but to date, no study has compared their performance. We aimed to compare the RADIAL algorithm, intended for the differential diagnosis of autosomal recessive cerebellar ataxias (ARCAs) and NPC-specific suspicion indices (SIs). This study was a retrospective analysis of data from 834 patients with molecularly confirmed ARCAs, including 57 NPC cases (RADIAL cohort). We aimed to compare the algorithm performance of RADIAL (Top 1 and Top 3) with that of four SIs (Original, Refined, 2/3 and 2/7) in discriminating NPC cases and non-NPC cases. We also identified ARCAs closely related to NPC as those with low specificity to detect non-NPC cases and described differential and overlapping features with NPC. Overall, excellent sensitivity and specificity (> 0.90) were achieved with both RADIAL and SI tools for NPC cases. The highest sensitivity was attained with the 2/7 SI, Refined SI and Top 3 RADIAL algorithms. Top 1 and Top 3 RADIAL were the most specific tools, followed by the Original SI. The individual comparison of each ARCA revealed that Wilson disease, PLA2G6-associated neurodegeneration, and hypomyelinating leukodystrophy (POLR3A) are frequent NPC false positives (PLA2G6 and POL3A only with the SIs). Both RADIAL and SI diagnostic approaches showed strong discriminatory potential and may be useful screening tools in different clinical contexts.
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References
Palau F, Espinós C. Autosomal recessive cerebellar ataxias. Orphanet J Rare Dis. 2006;1:47.
Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366:636–46.
Renaud M, Tranchant C, Martin JVT, Mochel F, Synofzik M, van de Warrenburg B, et al. A recessive ataxia diagnosis algorithm for the next generation sequencing era. Ann Neurol. 2017;82:892–9.
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;18:41–8.
Vanier MT. Niemann-pick disease type C. Orphanet J Rare Dis. 2010;5:16.
Zervas M, Somers KL, Thrall MA, Walkley SU. Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol. 2001;11:1283–7.
Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003;64:269–81.
Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F. Recommendations for the diagnosis and management of Niemann–Pick disease type C: an update. Mol Genet Metab. 2012;106:330–44.
Sévin 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.
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;8:1–10.
Schicks J, Vom Hagen JM, Bauer P, Beck-Wödl S, Biskup S, Krägeloh-Mann I, et al. Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy. Neurology. 2013;80:1169–70.
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.
Pineda M, Wraith JE, Mengel E, Sedel F, Hwu W-L, 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;98:243–9.
Patterson MC, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol. 2010;25:300–5.
Wraith JE, Vecchio D, Jacklin E, Abel L, Chadha-Boreham H, Luzy C, et al. Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab. 2010;99:351–7.
Miglustat (Zavesca) summary of product characteristics. Available at: https://www.ema.europa.eu/documents/product-information/zavesca-epar-product-information_en.pdf. Accessed December 10, 2018.
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. Neurol Clin Pract. 2017;106:1.
Sobrido M, Bauer P, de Koning T, Klopstock T, Nadjar Y, Patterson MC, et al. Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C? Orphanet J Rare Dis. 2019;14:20.
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;37:93–101.
Hendriksz CJ, Pineda M, Fahey M, Walterfang M, Runz H, Patterson MC, et al. The Niemann-Pick disease type C suspicion index : development of a new tool to aid diagnosis abstract. J Rare Disord Diagnosis Ther. 2015;1:1–9.
Pineda M, Mengel E, Jahnová H, Héron B, Imrie J, Lourenço CM, et al. A suspicion index to aid screening of early-onset Niemann-Pick disease type C (NP-C). BMC Pediatr. 2016;16:1–10.
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;78:1560–7.
Synofzik M, Fleszar Z, Schöls L, Just J, Bauer P, Torres Martin JV, et al. Identifying Niemann–Pick type C in early-onset ataxia: two quick clinical screening tools. J Neurol. 2016;263:1911–8.
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;33:877–90.
Anheim M, Lagha-Boukbiza O, Fleury-Lesaunier MC, Valenti-Hirsch MP, Hirsch E, Gervais-Bernard H, et al. Heterogeneity and frequency of movement disorders in juvenile and adult-onset Niemann-Pick C disease. J Neurol. 2014;261:174–9.
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;18:2–7.
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. Orphanet J Rare Dis. 2018;13:1–19.
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.
Verity CM, Winstone AM, Stellitano L, Will R, Nicoll A. The epidemiology of progressive intellectual and neurological deterioration in childhood. Arch Dis Child. 2010;95:361–4.
Anheim M, Fleury M, Monga B, Laugel V, Chaigne D, Rodier G, et al. Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, eastern France: implications for clinical management. Neurogenetics. 2010;11:1–12.
Kurian MA, Morgan NV, MacPherson L, Foster K, Peake D, Gupta R, et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008;70:1623–9.
Salih MA, Mundwiller E, Khan AO, AlDrees A, Elmalik SA, Hassan HH, et al. New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations. PLoS One. 2013;8:1–18.
Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, et al. Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive Hypomyelinating Leukodystrophy. Am J Hum Genet. 2011;89:415–23.
Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, et al. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab. 2015;114:501–15.
Daoud H, Tétreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, et al. Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J Med Genet. 2013;50:194–7.
Sakiyama Y, Narita A, Osawa S, Nanba E, Ohno K, Otsuka M. Abnormal copper metabolism in Niemann-Pick disease type C mimicking Wilson’s disease. Neurol Clin Neurosci. 2014;2:193–200.
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;8:1–11.
Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol. 2015;14:103–13.
Pineda M, Juríčková K, Karimzadeh P, Kolniková M, Malinová V, Torres J, et al. 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. Orphanet J Rare Dis. 2019;14:1–10.
Pineda M, Juríčková K, Karimzadeh P, Kolnikova M, Malinova V, Insua JL, et al. Disease characteristics, prognosis and miglustat treatment effects on disease progression in patients with Niemann-Pick disease type C: an international, multicenter, retrospective chart review. Orphanet J Rare Dis. 2019;14:1–10.
Acknowledgments
Carla Granados of Trialance SCCL provided medical writing assistance. RADIAL and SI algorithms are available upon request to the corresponding author.
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Medical writing assistance was funded by Syntax for Science SL.
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S.A.K. is an employee of Actelion Pharmaceuticals, a Pharmaceutical Company of Johnson & Johnson, Allschwil, Switzerland.
M.A. received honoraria and travel grants from Actelion, Johnson and Johnson, Teva, LVL, Orkyn, Aguettant, Merz, AbbVie.
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The RADIAL study was previously approved by the local ethics committee of Strasbourg University Hospital.
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Anheim, M., Torres Martin, J.V. & Kolb, S.A. Recessive Ataxia Differential Diagnosis Algorithm (RADIAL) Versus Specific Niemann-Pick Type C Suspicion Indices: A Retrospective Algorithm Comparison. Cerebellum 19, 243–251 (2020). https://doi.org/10.1007/s12311-020-01102-0
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DOI: https://doi.org/10.1007/s12311-020-01102-0