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.

Autor: Starosta RT; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA., Larson AA; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA., Meeks NJL; Department 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., Gracie S; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA., Friederich MW; Department 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., Gaughan SM; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA., Baker PR 2nd; Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA., Knupp KG; Department of Pediatrics, Section of Pediatric Neurology, University of Colorado, Aurora, CO, USA., Michel CR; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Reisdorph R; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Hock DH; Department 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., Stroud DA; Department 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., Wood T; Department 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., Van Hove JLK; Department 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.
Jazyk: angličtina
Zdroj: Mitochondrion [Mitochondrion] 2024 Nov; Vol. 79, pp. 101973. Date of Electronic Publication: 2024 Oct 15.
DOI: 10.1016/j.mito.2024.101973
Abstrakt: 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.
(Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
Databáze: MEDLINE
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