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High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with selected neurological and/or psychiatric disorders

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Abstract

Late-onset Niemann-Pick type C (NP-C) is a rare, underdiagnosed lysosomal disease with neurological manifestations. A specific treatment, miglustat, can stabilize the disease if given early. Recently, three plasma screening biomarkers (PSBs) were developed [cholestane3β,5α,6βtriol (C-triol), 7-ketocholesterol (7-KC), and lysosphingomyelin-509 (LSM-509)], allowing a simpler and quite robust screening of patients suitable for genetic testing. The objective of our study was to evaluate practical utility and feasibility of large-scale PSB screening for NP-C in selected adult patients. Patients were prospectively enrolled if they showed, starting from 12 years of age, at least one of the three initial neuro-psychiatric manifestations described in NP-C: (1) gait disorder (cerebellar and/or dystonic); (2) cognitive decline with frontal lobe syndrome; (3) atypical psychosis. PSBs were measured in plasma of all patients and, if positive (LSM-509 and/or C-triol + 7-KC elevated), sequencing of NPC1 and NPC2 genes was performed. A total of 251 patients [136 males, 115 females; median age 42.1 (range 12.2–85.6) years] were screened. Six patients had positive PSBs. Two were confirmed to have NP-C (0.8% diagnostic yield, both with all three PSBs highly increased, especially LSM-509). False-positive rate was 1.2%, which was identical if only considering LSM-509. By contrast, false-positive rates were 8.1% and 5.7% for 7-KC and C-triol, respectively. We showed that selecting patients with neurologic and/or psychiatric symptoms consistent with NP-C for large-scale PSB screening is a simple and valid strategy to identify new adult NP-C patients, and would probably lead to earlier diagnosis and treatment administration if widely applied.

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Acknowledgements

We thank Actelion pharmaceutical and Claudia Bertonati for the financial support of this study.

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Authors and Affiliations

  1. Neurology Department, Reference Center for Lysosomal Diseases, Neurogenetics and Metabolism Unit, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013, Paris, France

    Daniele Mandia & Yann Nadjar

  2. Inserm U894, Institute of Psychiatry and Neurosciences of Paris, University Paris Descartes, Service Hospitalo‐Universitaire de Psychiatrie GHU Paris Psychiatrie et Neurosciences, Paris, France

    Marion Plaze

  3. Inserm U1127, CNRS UMR 7225, Institut du Cerveau et la Moelle épinière (ICM), Sorbonne Universités, UPMC Université Paris 6, Hôpital Pitié-Salpêtrière, Paris, France

    Isabelle Le Ber

  4. National reference center for rare or early dementias, Institute of Memory and Alzheimer’s Disease (IM2A), Department of Neurology, AP-HP-Hôpital Pitié-Salpêtrière, Paris, France

    Isabelle Le Ber & Alexandre Morin

  5. Département de Génétique Clinique, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013, Paris, France

    Claire Ewenczyk

  6. Behavioral Neuropsychiatric Unit, Brain and Spine Institute, Pitié-Salpêtrière Hospital, Paris, France

    Guilhem Carle

  7. Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France

    Angèle Consoli

  8. Department of Neurology, Guy Chatiliez Hospital, 59200, Tourcoing, France

    Adrian Degardin

  9. CNRS, CHU LILLE, UMR9193-PsychiC-SCALab, Pôle de Psychiatrie, Univ. Lille, 59000, Lille, France

    Ali Amad

  10. Department of Neurology, Expert Center for Parkinson’s Disease, CHU LILLE, INSERM UMR_S 1171, LICEND, University of Lille, Lille, France

    Caroline Moreau

  11. Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Mathieu Anheim & Christine Tranchant

  12. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104, Université de Strasbourg, Illkirch, France

    Mathieu Anheim & Christine Tranchant

  13. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France

    Mathieu Anheim & Christine Tranchant

  14. Service de Neurologie, Centre Hospitalier Sainte-Anne, Paris, France

    Nicolas Mélé

  15. Unité de Neurologie de la Mémoire et du Langage, GHU Paris Psychiatrie et Neurosciences, Hôpital Sainte-Anne, Paris, France

    Carole Roue-Jagot, Julien Lagarde, Marie Sarazin & Lorraine Hamelin

  16. Child and Adolescent Psychiatry Department, Robert Debré Hospital, APHP, 48 Boulevard Sérurier, 75019, Paris, France

    Pierre Ellul

  17. Unité Maladies Héréditaires du Métabolisme, Service de Biochimie et Biologie Moléculaire Grand Est, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron cedex, France

    Cécile Pagan & Magali Pettazzoni

  18. Department of Metabolic Biochemistry, Rouen University Hospital, Rouen, France

    Soumeya Bekri

  19. Centre Mémoire de Ressource et Recherche, CHU Rennes. INSERM U1077, EPHE, Caen, France

    Serge Belliard

  20. Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, CHU Bordeaux and Laboratoire MRGM, INSERM U1211, Hôpital Pellegrin, Univ. Bordeaux, Bordeaux, France

    Cyril Goizet

  21. Inserm Department of Neurology and CNR-MAJNormandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, U1245 and Rouen University Hospital, 76000, Rouen, France

    David Wallon

  22. Département de Biochimie métabolique, UF Biochimie des Maladies neurométaboliques, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital, 75013, Paris, France

    Foudil Lamari

Authors
  1. Daniele Mandia
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  2. Marion Plaze
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  3. Isabelle Le Ber
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  4. Claire Ewenczyk
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  5. Alexandre Morin
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  6. Guilhem Carle
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  7. Angèle Consoli
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  8. Adrian Degardin
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  9. Ali Amad
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  10. Caroline Moreau
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  11. Mathieu Anheim
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  12. Christine Tranchant
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  13. Nicolas Mélé
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  14. Carole Roue-Jagot
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  15. Julien Lagarde
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  16. Marie Sarazin
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  17. Lorraine Hamelin
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  18. Pierre Ellul
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  19. Cécile Pagan
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  20. Magali Pettazzoni
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  21. Soumeya Bekri
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  22. Serge Belliard
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  23. Cyril Goizet
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  24. David Wallon
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  25. Foudil Lamari
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  26. Yann Nadjar
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Contributions

DM contributed to acquisition and analysis of data and drafting of the most part of manuscript and figures. MP, ILB, CE, AM, GC, AC, AD, AA, CM, MA, CT, NM, CRJ, JL, MS, LH, PE, SB, CG, DW, CP, MP, SB, and FL contributed to acquisition and analysis of data. YN contributed to conception and design of the study, acquisition and analysis of data, and drafting a significant portion of manuscript and figures.

Corresponding author

Correspondence to Yann Nadjar.

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Conflicts of interest

Dr Marion Plaze, Mathieu Anheim, Cécile Pagan, Cyril Goizet, and Yann Nadjar received travel grants and/or honoraria from Actelion Pharmaceuticals, which manufactures the drug Miglustat, used in NP-C; Mathieu Anheim also received honoraria and/or grants from Johnson and Johnson which is now part of Actelion Pharmaceuticals. Dr Daniele Mandia, Caroline Moreau, Isabelle Le Ber, Claire Ewenczyk, Alexandre Morin, Guilhem Carle, Angèle Consoli, Adrian Degardin, Ali Amad, Mathieu Anheim, Christine Tranchant, Nicolas Mélé, Carole Roue Jagot, Julien Lagarde, Marie Sarazin, Lorraine Hamelin, Pierre Ellul, Soumeya Bekri, Serge Belliard, David Wallon, and Foudil Lamari report no conflicts of interests relevant to this manuscript.

Ethical standards

This study has been approved by the appropriate ethics committee.

Informed consent

All patients gave their informed consent prior to their inclusion in the study.

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Mandia, D., Plaze, M., Le Ber, I. et al. High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with selected neurological and/or psychiatric disorders. J Neurol 267, 3371–3377 (2020). https://doi.org/10.1007/s00415-020-10020-4

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  • DOI: https://doi.org/10.1007/s00415-020-10020-4

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