High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with selected neurological and/or psychiatric disorders.
J Neurol. 2020-06-26; 267(11): 3371-3377
DOI: 10.1007/s00415-020-10020-4
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1. J Neurol. 2020 Nov;267(11):3371-3377. doi: 10.1007/s00415-020-10020-4. Epub 2020
Jun 26.
High diagnostic value of plasma Niemann-Pick type C biomarkers in adults with
selected neurological and/or psychiatric disorders.
Mandia D(1), Plaze M(2), Le Ber I(3)(4), Ewenczyk C(5), Morin A(4), Carle G(6),
Consoli A(7), Degardin A(8), Amad A(9), Moreau C(10), Anheim M(11)(12)(13),
Tranchant C(11)(12)(13), Mélé N(14), Roue-Jagot C(15), Lagarde J(15), Sarazin
M(15), Hamelin L(15), Ellul P(16), Pagan C(17), Pettazzoni M(17), Bekri S(18),
Belliard S(19), Goizet C(20), Wallon D(21), Lamari F(22), Nadjar Y(23).
Author information:
(1)Neurology Department, Reference Center for Lysosomal Diseases, Neurogenetics
and Metabolism Unit, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital,
75013, Paris, France.
(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.
(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.
(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.
(5)Département de Génétique Clinique, Hôpital Pitié-Salpêtrière, 47-83 boulevard
de l’Hôpital, 75013, Paris, France.
(6)Behavioral Neuropsychiatric Unit, Brain and Spine Institute, Pitié-Salpêtrière
Hospital, Paris, France.
(7)Department of Child and Adolescent Psychiatry, Pitié-Salpêtrière Hospital,
Sorbonne University, Paris, France.
(8)Department of Neurology, Guy Chatiliez Hospital, 59200, Tourcoing, France.
(9)CNRS, CHU LILLE, UMR9193-PsychiC-SCALab, Pôle de Psychiatrie, Univ. Lille,
59000, Lille, France.
(10)Department of Neurology, Expert Center for Parkinson’s Disease, CHU LILLE,
INSERM UMR_S 1171, LICEND, University of Lille, Lille, France.
(11)Département de Neurologie, Hôpital de Hautepierre, Hôpitaux Universitaires de
Strasbourg, Strasbourg, France.
(12)Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC),
INSERM-U964/CNRS-UMR7104, Université de Strasbourg, Illkirch, France.
(13)Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de
Strasbourg, Strasbourg, France.
(14)Service de Neurologie, Centre Hospitalier Sainte-Anne, Paris, France.
(15)Unité de Neurologie de la Mémoire et du Langage, GHU Paris Psychiatrie et
Neurosciences, Hôpital Sainte-Anne, Paris, France.
(16)Child and Adolescent Psychiatry Department, Robert Debré Hospital, APHP, 48
Boulevard Sérurier, 75019, Paris, France.
(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.
(18)Department of Metabolic Biochemistry, Rouen University Hospital, Rouen,
France.
(19)Centre Mémoire de Ressource et Recherche, CHU Rennes. INSERM U1077, EPHE,
Caen, France.
(20)Centre de Référence Maladies Rares Neurogénétique, Service de Génétique
Médicale, CHU Bordeaux and Laboratoire MRGM, INSERM U1211, Hôpital Pellegrin,
Univ. Bordeaux, Bordeaux, France.
(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.
(22)Département de Biochimie métabolique, UF Biochimie des Maladies
neurométaboliques, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital,
75013, Paris, France.
(23)Neurology Department, Reference Center for Lysosomal Diseases, Neurogenetics
and Metabolism Unit, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l’Hôpital,
75013, Paris, France. .
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.
DOI: 10.1007/s00415-020-10020-4
PMID: 32592146 [Indexed for MEDLINE]