Evidence map›Paper›PMID 42711551›Full record

ArticleEMBO molecular medicine2026

Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease.

Johan L K Van Hove, Marisa W Friederich, Roxanne A Van Hove, Jessica C Lee, Kaz M Knight, Tonia E Donovan, Lori Silveira, Rebecca D Ganetzky, Michio Hirano, Jose Abdenur and 36 more

Abstract read
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In one paragraph

Article in EMBO molecular medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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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

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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

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0 citing papers in PubMed.

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4 · The record

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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

46 authors.

Johan L K Van Hove *Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA. Johan.Vanhove@childrenscolorado.org.ORCID http://orcid.org/0000-0003-2850-3294
Marisa W Friederich *Department of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA. Marisa.Friederich@childrenscolorado.org.ORCID http://orcid.org/0000-0003-0902-5565
Roxanne A Van HoveDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Jessica C LeeDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.
Kaz M KnightDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-3184-3620
Tonia E DonovanDepartment of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, CO, USA.
Lori SilveiraDepartment of Pediatrics, Section of Pediatric Endocrinology, University of Colorado, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-2826-7036
Rebecca D GanetzkyDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Michio HiranoDepartment of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Jose AbdenurDivision of Metabolic Disorders, Rady's Children's Health Orange County, Orange, CA, USA.
Merlin G ButlerDepartments of Psychiatry & Behavioral Sciences and Pediatrics, Kansas University Medical Center, Kansas City, KS, USA.ORCID http://orcid.org/0000-0002-2911-0524
David CassimanDepartment of Gastroenterology-Hepatology and Metabolic Center, Catholic University Leuven, Leuven, Belgium.ORCID http://orcid.org/0000-0002-6154-0970
Bruce H CohenDepartment of Pediatrics, Akron Children's Hospital, Akron, OH, USA.ORCID http://orcid.org/0000-0003-2253-8955
Sarah H ElseaDepartment of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.ORCID http://orcid.org/0000-0002-1400-8519
Gregory M EnnsDepartment of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
William A GahlUndiagnosed Diseases Program, Section on Biochemical Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Ralitza GavrilovaDepartments of Neurology and Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Gabrielle C GeddesDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Emma E GlamuzinaAdult and Paediatric National Metabolic Service, Starship Children's Hospital, Te Whatu Ora Health New Zealand, Auckland, New Zealand.
Amy GoldsteinDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Richard H HaasDepartments of Neurology and Pediatrics, University of California San Diego, La Jolla, CA, USA.
Aneal KhanMAGIC Clinic, Calgary, Canada.ORCID http://orcid.org/0000-0001-8131-7947
Kimberly A KrippsDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Austin A LarsonDepartment of Pediatrics, Section of Clinical Genetics and Metabolism, University of Colorado, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-2079-6929
April N LehmanDepartment of Pediatrics, Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH, USA.ORCID http://orcid.org/0009-0007-8543-4033
Uta Lichter-KoneckiDepartment of Pediatrics, University of Pittsburgh, UPMC Children's Hospital, Pittsburgh, PA, USA.
Johannes A MayrUniversity Children's Hospital, Paracelsus Medical University, Salzburg, Austria.ORCID http://orcid.org/0000-0001-6970-336X
Eva MoravaDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
James T PetersonDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Russell P SanetoDepartment of Neurology, Division of Pediatric Neurology, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
Fernando ScagliaDepartment of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Emily ShelkowitzDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Mariella SimonDivision of Metabolic Disorders, Rady's Children's Health Orange County, Orange, CA, USA.ORCID http://orcid.org/0000-0002-8200-3277
Joél E G SmetDepartment of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University, Gent, Belgium.ORCID http://orcid.org/0000-0002-9551-6282
Wendy E SmithDivision of Genetics, Maine Health, Main Medical Center, Bangor, ME, USA.
Claudia Soler-AlfonsoCook Children's Genetics Center, Cook Children's Hospital, Forth Worth, TX, USA.
Mark TarnopolskyDivision of Neuromuscular and Neurometabolic Disorders, Department of Pediatrics, McMasters University, Hamilton, ON, Canada.ORCID http://orcid.org/0000-0003-0312-3746
Rudy N A Van CosterDepartment of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University, Gent, Belgium.
Arnaud V VanlanderDepartment of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University, Gent, Belgium.
Pieter VermeerschClinical Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium.
Jerry VockleyDepartment of Pediatrics, University of Pittsburgh, UPMC Children's Hospital, Pittsburgh, PA, USA.
Kristen WigbyRady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, USA.
Lynne A WolfeUndiagnosed Diseases Program, Section on Biochemical Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-7628-5741
Saskia B WortmannUniversity Children's Hospital, Paracelsus Medical University, Salzburg, Austria.ORCID http://orcid.org/0000-0002-1968-8103
Jennifer H YangDepartment of Neurosciences, University of California San Diego, San Diego, CA, USA.

Funding

The North American Mitochondrial Disease Consortium (NAMDC)U54NS078059 · NINDS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI HIRANO, MICHIO · 2011 to 2023
$17.5M
HHS | NIH | National Center for Advancing Translational Sciences (NCATS) U54NS078059NINDS NIH HHS U54 NS078059
6 · The paper itself

Abstract

Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.

Indexed as

FibroblastsMitochondrial DiseasesDNA, MitochondrialFemaleHumansSensitivity and SpecificityDNA, Mitochondrial

Identifiers

PMID42711551
PMCPMC13658156

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