{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T02:40:49Z","timestamp":1771728049113,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Diseases and Stroke (NINDS)","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}]},{"name":"National Institute of Neurological Diseases and Stroke (NINDS)","award":["EFF-D2860-C14\/17\/110"],"award-info":[{"award-number":["EFF-D2860-C14\/17\/110"]}]},{"name":"National Center for Advancing Translational Sciences (NCATS)","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}]},{"name":"National Center for Advancing Translational Sciences (NCATS)","award":["EFF-D2860-C14\/17\/110"],"award-info":[{"award-number":["EFF-D2860-C14\/17\/110"]}]},{"name":"National Institute of Child Health and Human Development (NICHD)","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}]},{"name":"National Institute of Child Health and Human Development (NICHD)","award":["EFF-D2860-C14\/17\/110"],"award-info":[{"award-number":["EFF-D2860-C14\/17\/110"]}]},{"name":"Rare Disorders Consortium Disease Network (RDCRN)","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}]},{"name":"Rare Disorders Consortium Disease Network (RDCRN)","award":["EFF-D2860-C14\/17\/110"],"award-info":[{"award-number":["EFF-D2860-C14\/17\/110"]}]},{"name":"KU Leuven internal C1 funding","award":["1U54NS115198-01"],"award-info":[{"award-number":["1U54NS115198-01"]}]},{"name":"KU Leuven internal C1 funding","award":["EFF-D2860-C14\/17\/110"],"award-info":[{"award-number":["EFF-D2860-C14\/17\/110"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Inherited metabolic disorders (IMDs) are genetic disorders that occur in as many as 1:2500 births worldwide. Nevertheless, they are quite rare individually and even more rare is the co-occurrence of two IMDs in one individual. To better understand the metabolic cross-talk between glycosylation changes and deficient energy metabolism, and its potential effect on outcomes, we evaluated patient fibroblasts with likely pathogenic variants in PGM1 and pathogenic variants in NDUFA13 derived from a patient who passed away at 16 years of age. The patient presented with characteristic of PGM1-CDG including bifid uvula, muscle involvement, abnormal glycosylation in blood, and elevated liver transaminases. In addition, hearing loss, seizures, elevated plasma and CSF lactate and a Leigh-like MRI brain pattern were present, which are commonly associated with Leigh syndrome. PGM1-CDG has been reported in about 70 individuals, while NDUFA13 deficiency has so far only been reported in 13 patients. As abundant energy is essential for glycosylation, and both PGM1 and NDUFA13 are linked to energy metabolism, we sought to better understand the underlying biochemical cause of the patient\u2019s clinical presentation. To do so, we performed extensive investigations including tracer metabolomics, lipidomics and enzymatic studies on the patient\u2019s fibroblasts. We found a profound depletion of UDP-hexoses, consistent with PGM1-CDG. Complex I enzyme activity and mitochondrial function were also impaired, corroborating complex I deficiency and Leigh syndrome. Further, lipidomics analysis showed similarities with both PGM1-CDG and OXPHOS-deficient patients. Based on our results, the patient was diagnosed with both PGM1-CDG and Leigh syndrome. In summary, we present the first case of combined CDG and Leigh syndrome, caused by (likely) pathogenic variants in PGM1 and NDUFA13, and underline the importance of considering the synergistic effects of multiple disease-causing variants in patients with complex clinical presentation, leading to the patient\u2019s early demise.<\/jats:p>","DOI":"10.3390\/cells14090638","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T06:10:13Z","timestamp":1745561413000},"page":"638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Complex Metabolomic Changes in a Combined Defect of Glycosylation and Oxidative Phosphorylation in a Patient with Pathogenic Variants in PGM1 and NDUFA13"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8190-7736","authenticated-orcid":false,"given":"Silvia","family":"Radenkovic","sequence":"first","affiliation":[{"name":"Laboratory of Applied Mass Spectrometry, Department of Molecular and Cellular Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium"},{"name":"Metabolomics Core Facility, Center for Cancer Biology, VIB, 3000 Leuven, Belgium"},{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Section Metabolic Diagnostics, Department of Genetics, UMC Utrecht, 3584 Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-6268","authenticated-orcid":false,"given":"Isabelle","family":"Adant","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Mass Spectrometry, Department of Molecular and Cellular Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium"},{"name":"Metabolomics Core Facility, Center for Cancer Biology, VIB, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3185-0780","authenticated-orcid":false,"given":"Matthew J.","family":"Bird","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Mass Spectrometry, Department of Molecular and Cellular Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium"},{"name":"Metabolomics Core Facility, Center for Cancer Biology, VIB, 3000 Leuven, Belgium"},{"name":"Clinical Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7720-5077","authenticated-orcid":false,"given":"Johannes V.","family":"Swinnen","sequence":"additional","affiliation":[{"name":"Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute and Leuven Institute for Single Cell Omics, Department of Oncology, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6154-0970","authenticated-orcid":false,"given":"David","family":"Cassiman","sequence":"additional","affiliation":[{"name":"Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium"},{"name":"Metabolic Center, University Hospitals Leuven, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5986-0468","authenticated-orcid":false,"given":"Sarah C.","family":"Gruenert","sequence":"additional","affiliation":[{"name":"Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1547-1705","authenticated-orcid":false,"given":"Bart","family":"Ghesqui\u00e8re","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Mass Spectrometry, Department of Molecular and Cellular Medicine, KU Leuven, 3000 Leuven, Belgium"},{"name":"Metabolomics Core Facility, Center for Cancer Biology, VIB, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55901, USA"},{"name":"Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"021102","DOI":"10.7189\/jogh.08.021102","article-title":"Global birth prevalence and mortality from inborn errors of metabolism: A systematic analysis of the evidence","volume":"8","author":"Waters","year":"2018","journal-title":"J. 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