Evidence map›Paper›PMID 39413893›Full record

ArticleMitochondrion2024

An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis.

Rodrigo T Starosta, Austin A Larson, Naomi J L Meeks, Sara Gracie, Marisa W Friederich, Sommer M Gaughan, Peter R Baker, Kelly G Knupp, Cole R Michel, Richard Reisdorph and 4 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Mitochondrion, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Review
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Rodrigo T StarostaDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Austin A LarsonDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Naomi J L MeeksDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
Sara GracieDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Marisa W FriederichDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
Sommer M GaughanDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Peter R BakerDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Kelly G KnuppDepartment of Pediatrics, Section of Pediatric Neurology, University of Colorado, Aurora, CO, USA.
Cole R MichelDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Richard ReisdorphDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Daniella H HockDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
David A StroudDepartment of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3052, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC 3052, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
Tim WoodDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
Johan L K Van HoveDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA; Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA. Electronic address: Johan.Vanhove@childrenscolorado.org.

Funding

The North American Mitochondrial Disease Consortium (NAMDC)U54NS078059 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI VAN HOVE, JOHAN L · 2011 to 2023
$17.5M
Fusion Lumos Orbitrap System for Quantitative Proteomics and Metabolomics ApplicationsS10OD028538 · OD · UNIVERSITY OF COLORADO DENVER · PI REISDORPH, NICHOLE A · 2021 to 2021
$1.3M
NIH HHS S10 OD028538NINDS NIH HHS U54 NS078059
6 · The paper itself

Abstract

The diagnosis of mitochondrial disorders is complex. Rapid whole genome sequencing is a first line test for critically ill neonates and infants allowing rapid diagnosis and treatment. Standard genomic technology and bioinformatic pipelines still have an incomplete diagnostic yield requiring complementary approaches. There are currently limited options for rapid additional tests to continue a diagnostic work-up after a negative rapid whole-genome sequencing result, reflecting a gap in clinical practice. Multi-modal integrative diagnostic approaches derived from systems biology including proteomics and transcriptomics show promise in suspected mitochondrial disorders. In this article, we report the case of a neonate who presented with severe lactic acidosis on the second day of life, for whom an initial report of ultra-rapid genome sequencing was negative. The patient was started on dichloroacetate as an emergency investigational new drug (eIND), with a sharp decline in lactic acid levels and clinical stabilization. A proteomics-based approach identified a complete absence of PDHX protein, leading to a re-review of the genome data for the PDHX gene in which a homozygous deep intronic pathogenic variant was identified. Subsequent testing in the following months confirmed the diagnosis with deficient pyruvate dehydrogenase enzyme activity, reduced protein levels of E3-binding protein, and confirmed by mRNA sequencing to lead to the inclusion of a cryptic exon and a premature stop codon. This case highlights the power of rapid proteomics in guiding genomic analysis. It also shows a promising role for dichloroacetate treatment in controlling lactic acidosis related to PDHX-related pyruvate dehydrogenase complex deficiency.

Indexed as

Acidosis, LacticDichloroacetic AcidCritical IllnessHumansInfant, NewbornIntronsMaleMultiomicsProteomicsPyruvate Dehydrogenase (Lipoamide)Dichloroacetic AcidPyruvate Dehydrogenase (Lipoamide)DichloroacetateHereditary orotic aciduriaLactic acidosisProteomicsPyruvate dehydrogenaseWhole genome sequencing

Identifiers

PMID39413893
PMCPMC11578067

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.