Summary of Study ST002934

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001825. The data can be accessed directly via it's Project DOI: 10.21228/M8T714 This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002934
Study TitleMetabolic profiling of newborn DBS samples associated with transit and false elevation of glutarylcarnitine (C5DC)
Study SummaryBackground: Glutaric aciduria type-1 (GA-1) is a rare autosomal recessive metabolic disorder caused by a glutaryl coenzyme A dehydrogenase (GCDH) deficiency, affecting approximately 1 in 110,000 individuals globally. This enzymatic deficiency leads to abnormal elevations of glutaryl-CoA and its derivatives, specifically glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), and glutarylcarnitine (C5DC). Clinical manifestations encompass macrocephaly, developmental delays, and movement disorders. Early detection via genetic testing and newborn screening (NBS), utilizing GA-1 biomarkers in dried blood spot (DBS) samples, is vital for prompt intervention. Despite the NBS system, transit-elevated C5DC-containing DBS samples from falsely suspected GA-1 newborns sometimes yield normal results, posing diagnostic sensitivity and specificity challenges. Consequently, there is a growing need for alternative diagnostic tools. Comprehensive mass spectrometry-based untargeted metabolomics offers promise in identifying additional informative biomarkers for distinguishing falsely suspected GA-1 newborns from healthy counterparts. Methodology: In this prospective study, we obtained DBS samples with transit-elevated C5DC levels from falsely suspected GA-1 newborns (n=47) and matched control DBS samples from healthy newborns (n=47) through the NBS program. Metabolites were extracted and analyzed via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Subsequent multivariate and univariate statistical analyses and feature annotation enabled biomarker and pathway investigations for significantly altered metabolites. Results: Untargeted metabolomics analysis revealed alterations in 582 upregulated and 546 downregulated metabolites. The commonly used GA-1 biomarkers, including C5DC, exhibited no significant changes in the falsely suspected GA-1 DBS samples. Conversely, 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-Palmitoylcysteine, 3-hydroxylinoleoylcarnitine, Heptacarboxyporphyrin, and MG (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient and falsely elevated C5DC levels in DBS samples. Conclusions: Our untargeted metabolomics investigation unveiled distinct metabolic pathways and biomarkers linked to the transient C5DC elevation in DBS samples from falsely suspected GA-1 newborns. These findings can enhance GA-1 diagnosis by serving as predictive indicators during NBS analysis. Validation studies are warranted to confirm the presence of these newly identified metabolic pathways and biomarkers in confirmed GA-1 cases.
Institute
King Faisal Specialist Hospital and Research Centre (KFSHRC)
Last NameAl Mogren
First NameMaha
AddressZahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
Emailmahamogren@gmail.com
Phone966541205332
Submit Date2023-09-11
Raw Data AvailableYes
Raw Data File Type(s)raw(Waters)
Analysis Type DetailLC-MS
Release Date2024-04-02
Release Version1
Maha Al Mogren Maha Al Mogren
https://dx.doi.org/10.21228/M8T714
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001825
Project DOI:doi: 10.21228/M8T714
Project Title:Metabolic profiling of newborn DBS samples associated with transit and false elevation of glutarylcarnitine (C5DC)
Project Summary:Background: Glutaric aciduria type-1 (GA-1) is a rare autosomal recessive metabolic disorder caused by a glutaryl coenzyme A dehydrogenase (GCDH) deficiency, affecting approximately 1 in 110,000 individuals globally. This enzymatic deficiency leads to abnormal elevations of glutaryl-CoA and its derivatives, specifically glutaric acid (GA), 3-hydroxyglutaric acid (3OHGA), and glutarylcarnitine (C5DC). Clinical manifestations encompass macrocephaly, developmental delays, and movement disorders. Early detection via genetic testing and newborn screening (NBS), utilizing GA-1 biomarkers in dried blood spot (DBS) samples, is vital for prompt intervention. Despite the NBS system, transit-elevated C5DC-containing DBS samples from falsely suspected GA-1 newborns sometimes yield normal results, posing diagnostic sensitivity and specificity challenges. Consequently, there is a growing need for alternative diagnostic tools. Comprehensive mass spectrometry-based untargeted metabolomics offers promise in identifying additional informative biomarkers for distinguishing falsely suspected GA-1 newborns from healthy counterparts. Methodology: In this prospective study, we obtained DBS samples with transit-elevated C5DC levels from falsely suspected GA-1 newborns (n=47) and matched control DBS samples from healthy newborns (n=47) through the NBS program. Metabolites were extracted and analyzed via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). Subsequent multivariate and univariate statistical analyses and feature annotation enabled biomarker and pathway investigations for significantly altered metabolites. Results: Untargeted metabolomics analysis revealed alterations in 582 upregulated and 546 downregulated metabolites. The commonly used GA-1 biomarkers, including C5DC, exhibited no significant changes in the falsely suspected GA-1 DBS samples. Conversely, 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-Palmitoylcysteine, 3-hydroxylinoleoylcarnitine, Heptacarboxyporphyrin, and MG (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient and falsely elevated C5DC levels in DBS samples. Conclusions: Our untargeted metabolomics investigation unveiled distinct metabolic pathways and biomarkers linked to the transient C5DC elevation in DBS samples from falsely suspected GA-1 newborns. These findings can enhance GA-1 diagnosis by serving as predictive indicators during NBS analysis. Validation studies are warranted to confirm the presence of these newly identified metabolic pathways and biomarkers in confirmed GA-1 cases.
Institute:King Faisal Specialist Hospital and Research Centre (KFSHRC)
Last Name:Al Mogren
First Name:Maha
Address:Zahrawi Street, Al Maather, Riyadh 11211, Saudi Arabia
Email:mahamogren@gmail.com
Phone:966541205332

Subject:

Subject ID:SU003047
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Male and female
Species Group:Mammals

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Factor
SA31830820830117_CControl
SA31830920820305_CControl
SA31831020809384_CControl
SA31831120830418_CControl
SA31831220818595_CControl
SA31831320851147_CControl
SA31831420859945_CControl
SA31831520859015_CControl
SA31831620851217_CControl
SA31831720808613_CControl
SA31831820839215_CControl
SA31831920808598_CControl
SA31832020688815_CControl
SA31832120688684_CControl
SA31832220649302_CControl
SA31832320419817_CControl
SA31832420771984_CControl
SA31832520799041_CControl
SA31832620859954_CControl
SA31832720799980_CControl
SA31832820799892_CControl
SA31832920799050_CControl
SA31833020808604_CControl
SA31833120864956_CControl
SA31833221554366_CControl
SA31833321554348_CControl
SA31833421501966_CControl
SA31833521492242_CControl
SA31833621558089_CControl
SA31833721610033_CControl
SA31833821753462_CControl
SA31833921703814_CControl
SA31834021670026_CControl
SA31834121610051_CControl
SA31834221484386_CControl
SA31834321462162_CControl
SA31834420902618_CControl
SA31834520890216_CControl
SA31834620884792_CControl
SA31834720882846_CControl
SA31834820940654_CControl
SA31834920975067_CControl
SA31835021077520_CControl
SA31835121073931_CControl
SA31835221027899_CControl
SA31835319534501_CControl
SA31835419281533_CControl
SA31835520407797_GAGA
SA31835620334941_GAGA
SA31835720312851_GAGA
SA31835820310303_GAGA
SA31835920488455_GAGA
SA31836020492412_GAGA
SA31836120639226_GAGA
SA31836220624808_GAGA
SA31836320537584_GAGA
SA31836420525109_GAGA
SA31836520308928_GAGA
SA31836620249546_GAGA
SA31836719762935_GAGA
SA31836819568043_GAGA
SA31836919558785_GAGA
SA31837019533094_GAGA
SA31837119785967_GAGA
SA31837219844611_GAGA
SA31837320249412_GAGA
SA31837419929105_GAGA
SA31837519885751_GAGA
SA31837619864732_GAGA
SA31837720735858_GAGA
SA31837820749860_GAGA
SA31837921437087_GAGA
SA31838021371994_GAGA
SA31838121368884_GAGA
SA31838221355783_GAGA
SA31838321443088_GAGA
SA31838421444935_GAGA
SA318385MOH00027361087_GAGA
SA318386MOH00027354847_GAGA
SA318387MOH00027340288_GAGA
SA318388MOH00027337062_GAGA
SA31838921349010_GAGA
SA31839021294251_GAGA
SA31839120788142_GAGA
SA31839220780043_GAGA
SA31839320777340_GAGA
SA31839420774404_GAGA
SA31839520830630_GAGA
SA31839620854922_GAGA
SA31839721033438_GAGA
SA31839820927291_GAGA
SA31839920876340_GAGA
SA31840020855976_GAGA
SA31840118862900_GAGA
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Collection:

Collection ID:CO003040
Collection Summary:The Institutional Review Boards at King Faisal Specialist Hospital and Research Centre (KFSHRC) in Riyadh, Saudi Arabia (RAC # 2160 027) reviewed and approved this study and its related procedures. DBS samples were obtained from the metabolomics section laboratory, Clinical Genomics Department (CGD) in the Center for Genomic Medicine (CGM) at KFSHRC as leftover material from the newborn screening program. To identify predictive metabolic profiling, newborn DBS samples found to have transit elevation of C5DC, showing normal C5DC level in the follow-up NBS testing, were used (n=47), and DBS samples from healthy controls (n=47) were included in this study for comparison purposes to predict different metabolic profiling. The two groups were age- and gender-matched, where non-newborn samples with ages more than 4 weeks or diagnosed with other inborn errors of metabolism (IMD) were excluded from this study.
Collection Protocol Filename:GA_Sample Collection
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR003056
Treatment Summary:None

Sample Preparation:

Sampleprep ID:SP003053
Sampleprep Summary:Metabolites were extracted from DBS using a standard procedure reported elsewhere (14). Briefly, one punch, a size of 3.2 mm, was collected from each DBS, and then metabolites were extracted by adding 250 ul (40:40:20) (methanol: acetonitrile: dH2O) and mixing in a plate shaker for 2 h at RT. Meanwhile, another set of punches from each sample was collected and pooled as QC samples, which were prepared to control the system's stability. After that, the extracts from the study and QC samples were dried using SpeedVac (Thermo Fischer, Christ, Germany). The dried samples were reconstituted in 90 ul using (1:1) mobile phase A: B (A: 0.1% Formic acid in dH2O, B: 0.1% Formic acid in 50% MeOH and ACN) and 10 µl of internal standard mixture for metabolomics analysis.
Sampleprep Protocol ID:GA_Metabolites extraction

Combined analysis:

Analysis ID AN004812 AN004813
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Waters Acquity Waters Acquity
Column Waters Acquity UPLC XSelect HSS C18 (100 × 2.1mm, 2.5um) Waters Acquity UPLC XSelect HSS C18 (100 × 2.1mm, 2.5um)
MS Type ESI ESI
MS instrument type QTOF QTOF
MS instrument name Waters Xevo-G2-S Waters Xevo-G2-S
Ion Mode POSITIVE NEGATIVE
Units Peak Area Peak Area

Chromatography:

Chromatography ID:CH003637
Chromatography Summary:The Waters Acquity UPLC system coupled with a Xevo G2-S QTOF mass spectrometer equipped with an electrospray ionization source (ESI) was used to analyze the samples. The extracted metabolites were chromatographed using an ACQUITY UPLC using XSelect (100×2.1mm, 2.5 μm) column (Waters Ltd., Elstree, UK), the mobile phase composed of 0.1% formic acid in dH2O as solvent A, and B consists of 0.1% formic acid in 50% ACN: MeOH. A gradient elution schedule was run as follows: 0-16 min 95- 5% A, 16-19 min 5% A, 19-20 min 5-95% A, 20-22 min 95- 95% A, at 300 µL/min flow rate. MS spectra were acquired under positive and negative electrospray ionization modes (ESI+, ESI-). MS conditions were as follows: source temperature was 150◦C, the desolvation temperature was 500◦C (ESI+) or 140 (ESI−), the capillary voltage was 3.20 kV (ESI+) or 3 kV (ESI−), cone voltage was 40 V, desolvation gas flow was 800.0 L/h, cone gas flow was 50 L/h. The collision energies of low and high functions were set at off and 10 V to 50 V, respectively, in MSE mode. The mass spectrometer was calibrated with 100–1200 Da sodium formate in both ionization modes. The lock mass compound, leucine-enkephalin (an external reference to the ion m/z 556.2771 in (ESI+) and 554.2615 (ESI-)), was infused continuously, switching between the sample and the reference every 45 and 60 s for ESI+ and ESI-, respectively, for a 0.5 s scan time, a flow rate of 10 µL/min, a cone voltage of 30 V, and collision energy of 4 V. Data were collected in continuum mode with Masslynx™ V4.1 workstation (Waters Inc., Milford, Massachusetts, USA). The samples were acquired randomly, and a QC sample was injected after each 10 study samples to control the system’s variations. A mixture of several internal standards with a final concentration of 10 µg/ml was added to each sample, serving as a reference compound to help correct any variations that may occur during sample preparation and analysis.
Methods Filename:GA_LCMS Metabolomics
Instrument Name:Waters Acquity
Column Name:Waters Acquity UPLC XSelect HSS C18 (100 × 2.1mm, 2.5um)
Column Temperature:55
Flow Gradient:0–16 min 95%–5% A, 16–19 min 5% A, 19–20 min 5%–95% A, and 20–22 min, 95%– 95% A
Flow Rate:300 μl/min.
Solvent A:0.1% formic acid in dH2O
Solvent B:0.1% formic acid in 50% MeOH and ACN
Chromatography Type:Reversed phase

MS:

MS ID:MS004558
Analysis ID:AN004812
Instrument Name:Waters Xevo-G2-S
Instrument Type:QTOF
MS Type:ESI
MS Comments:The DIA data were collected with a Masslynx™ V4.1 workstation in continuum mode (Waters Inc., Milford, MA, USA). The raw MS data were processed following a standard pipeline using the Progenesis QI v.3.0 software.
Ion Mode:POSITIVE
  
MS ID:MS004559
Analysis ID:AN004813
Instrument Name:Waters Xevo-G2-S
Instrument Type:QTOF
MS Type:ESI
MS Comments:The DIA data were collected with a Masslynx™ V4.1 workstation in continuum mode (Waters Inc., Milford, MA, USA). The raw MS data were processed following a standard pipeline using the Progenesis QI v.3.0 software.
Ion Mode:NEGATIVE
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