TY - JOUR
T1 - Application of N-palmitoyl-O-phosphocholineserine for diagnosis and assessment of response to treatment in Niemann-Pick type C disease
AU - Sidhu, Rohini
AU - Kell, Pamela
AU - Dietzen, Dennis J.
AU - Farhat, Nicole Y.
AU - Do, An Ngoc Dang
AU - Porter, Forbes D.
AU - Berry-Kravis, Elizabeth
AU - Vite, Charles H.
AU - Reunert, Janine
AU - Marquardt, Thorsten
AU - Giugliani, Roberto
AU - Lourenço, Charles M.
AU - Bodamer, Olaf
AU - Wang, Raymond Y.
AU - Plummer, Ellen
AU - Schaffer, Jean E.
AU - Ory, Daniel S.
AU - Jiang, Xuntian
N1 - Funding Information:
This work was supported by grants from the NIH Grant # UL1 TR000448 (X.J.), the University of Pennsylvania Orphan Disease Center ( MDBR-17-124-NPC , X.J.), Dana's Angels Research Trust (D.S.O. and N.M.Y.), Ara Parseghian Medical Research Foundation (D.S.O. and N.M.Y.), Support of Accelerated Research for NPC Disease (D.S.O.), Hope for Hayley and Samantha's Search for the Cure Funds (E.B.K.), Referral Center for Animal Models of Human Genetic Disease ( P40 OD010939 , C.H.V.), the Liferay Foundation and the Campbell Foundation of Caring (R.Y.W.), and by NIH grants R01 NS081985 (D.S.O. and J.E.S.), P41-GM103422 (F-F.H), and 2R01DK067859 (M.H.G.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.), a Bench to Bedside award from the Office of Rare Diseases (F.D.P. and D.S.O.), and National Center for Advancing Translational Sciences grant 1ZIATR000014 (F.D.P.). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579 ). We are grateful to the National Niemann-Pick Disease Foundation for their assistance in obtaining samples from NPC1 and NPC1 carrier subjects. The authors express their appreciation to the families and patients who participated in this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
This work was supported by grants from the NIH Grant # UL1 TR000448 (X.J.), the University of Pennsylvania Orphan Disease Center (MDBR-17-124-NPC, X.J.), Dana's Angels Research Trust (D.S.O. and N.M.Y.), Ara Parseghian Medical Research Foundation (D.S.O. and N.M.Y.), Support of Accelerated Research for NPC Disease (D.S.O.), Hope for Hayley and Samantha's Search for the Cure Funds (E.B.K.), Referral Center for Animal Models of Human Genetic Disease (P40 OD010939, C.H.V.), the Liferay Foundation and the Campbell Foundation of Caring (R.Y.W.), and by NIH grants R01 NS081985 (D.S.O. and J.E.S.), P41-GM103422 (F-F.H), and 2R01DK067859 (M.H.G.). This study was also supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F.D.P.), a Bench to Bedside award from the Office of Rare Diseases (F.D.P. and D.S.O.), and National Center for Advancing Translational Sciences grant 1ZIATR000014 (F.D.P.). This work was performed in the Metabolomics Facility at Washington University (NIH P30 DK020579). We are grateful to the National Niemann-Pick Disease Foundation for their assistance in obtaining samples from NPC1 and NPC1 carrier subjects. The authors express their appreciation to the families and patients who participated in this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/4
Y1 - 2020/4
N2 - Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPβCD treatment. In an intravenous (IV) HPβCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPβCD treatment.
AB - Niemann-Pick type C (NPC) disease is a rare lysosomal storage disorder caused by mutations in either the NPC1 or the NPC2 gene. A new class of lipids, N-acyl-O-phosphocholineserines were recently identified as NPC biomarkers. The most abundant species in this class of lipid, N-palmitoyl-O-phosphocholineserine (PPCS), was evaluated for diagnosis of NPC disease and treatment efficacy assessment with 2-hydroxypropyl-β-cyclodextrin (HPβCD) in NPC. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated to measure PPCS in human plasma and cerebrospinal fluid (CSF). A cutoff of 248 ng/mL in plasma provided a sensitivity of 100.0% and specificity of 96.6% in identifying NPC1 patients from control and NPC1 carrier subjects. PPCS was significantly elevated in CSF from NPC1 patients, and CSF PPCS levels were significantly correlated with NPC neurological disease severity scores. Plasma and CSF PPCS did not change significantly in response to intrathetical (IT) HPβCD treatment. In an intravenous (IV) HPβCD trial, plasma PPCS in all patients was significantly reduced. These results demonstrate that plasma PPCS was able to diagnose NPC1 patients with high sensitivity and specificity, and to evaluate the peripheral treatment efficacy of IV HPβCD treatment.
KW - 2-Hydroxypropyl-β-cyclodextrin
KW - Diagnosis
KW - LysoSM-509
KW - N-palmitoyl-O-phosphocholineserine
KW - Niemann-Pick disease type C
KW - Treatment assessment
UR - http://www.scopus.com/inward/record.url?scp=85078845231&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2020.01.007
DO - 10.1016/j.ymgme.2020.01.007
M3 - Article
C2 - 32033912
AN - SCOPUS:85078845231
VL - 129
SP - 292
EP - 302
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 4
ER -