{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:12:05Z","timestamp":1787497925865,"version":"build-2736575974"},"reference-count":24,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T00:00:00Z","timestamp":1675987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Luxembourg National Research Fund (FNR)","award":["C18\/BM\/12661133"],"award-info":[{"award-number":["C18\/BM\/12661133"]}]},{"name":"Luxembourg National Research Fund (FNR)","award":["GNT1136197"],"award-info":[{"award-number":["GNT1136197"]}]},{"name":"Luxembourg National Research Fund (FNR)","award":["GNT20097321140851"],"award-info":[{"award-number":["GNT20097321140851"]}]},{"name":"Luxembourg National Research Fund (FNR)","award":["GNT1164479"],"award-info":[{"award-number":["GNT1164479"]}]},{"name":"National Health and Medical Research Council (NHMRC) of Australia Senior Research Fellowship","award":["C18\/BM\/12661133"],"award-info":[{"award-number":["C18\/BM\/12661133"]}]},{"name":"National Health and Medical Research Council (NHMRC) of Australia Senior Research Fellowship","award":["GNT1136197"],"award-info":[{"award-number":["GNT1136197"]}]},{"name":"National Health and Medical Research Council (NHMRC) of Australia Senior Research Fellowship","award":["GNT20097321140851"],"award-info":[{"award-number":["GNT20097321140851"]}]},{"name":"National Health and Medical Research Council (NHMRC) of Australia Senior Research Fellowship","award":["GNT1164479"],"award-info":[{"award-number":["GNT1164479"]}]},{"name":"Australian National Health and Medical Research Council","award":["C18\/BM\/12661133"],"award-info":[{"award-number":["C18\/BM\/12661133"]}]},{"name":"Australian National Health and Medical Research Council","award":["GNT1136197"],"award-info":[{"award-number":["GNT1136197"]}]},{"name":"Australian National Health and Medical Research Council","award":["GNT20097321140851"],"award-info":[{"award-number":["GNT20097321140851"]}]},{"name":"Australian National Health and Medical Research Council","award":["GNT1164479"],"award-info":[{"award-number":["GNT1164479"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A&gt;G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.<\/jats:p>","DOI":"10.3390\/ijms24043582","type":"journal-article","created":{"date-parts":[[2023,2,10]],"date-time":"2023-02-10T06:43:23Z","timestamp":1676011403000},"page":"3582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6768-3665","authenticated-orcid":false,"given":"Nicole J.","family":"Van Bergen","sequence":"first","affiliation":[{"name":"Brain and Mitochondrial Research Group, Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital, Melbourne, VIC 3002, Australia"},{"name":"Department of Paediatrics, University of Melbourne, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Gunanayagam","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-4548","authenticated-orcid":false,"given":"Adam M.","family":"Bournazos","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, The Children\u2019s Hospital at Westmead, Westmead, NSW 2145, Australia"},{"name":"The Children\u2019s Medical Research Institute, 214 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adhish S.","family":"Walvekar","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc O.","family":"Warmoes","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana N.","family":"Semcesen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Pharmacology, Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Lunke","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, University of Melbourne, Melbourne, VIC 3002, Australia"},{"name":"Victorian Clinical Genetics Services, Royal Children\u2019s Hospital, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shobhana","family":"Bommireddipalli","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, The Children\u2019s Hospital at Westmead, Westmead, NSW 2145, Australia"},{"name":"The Children\u2019s Medical Research Institute, 214 Hawkesbury Road, Westmead, Sydney, NSW 2145, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Sikora","sequence":"additional","affiliation":[{"name":"Brain and Mitochondrial Research Group, Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4795-0834","authenticated-orcid":false,"given":"Myrto","family":"Patraskaki","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Hobart Hospital, Hobart, TAS 7000, Australia"},{"name":"School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denisse","family":"Garza","sequence":"additional","affiliation":[{"name":"Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8929-6957","authenticated-orcid":false,"given":"Dale","family":"Sebire","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Gooley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-5727","authenticated-orcid":false,"given":"Catriona A.","family":"McLean","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Alfred Hospital, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parm","family":"Naidoo","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugil","family":"Rajasekaran","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging, Royal Hobart Hospital, Hobart, TAS 7000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2048-3383","authenticated-orcid":false,"given":"David A.","family":"Stroud","sequence":"additional","affiliation":[{"name":"Brain and Mitochondrial Research Group, Murdoch Children\u2019s Research Institute, Royal Children\u2019s Hospital, Melbourne, VIC 3002, Australia"},{"name":"Department of Biochemistry & Pharmacology, Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Melbourne, VIC 3002, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7143-0719","authenticated-orcid":false,"given":"Carole L.","family":"Linster","sequence":"additional","affiliation":[{"name":"Enzymology and Metabolism Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4367 Belvaux, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Wallis","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Tasmania, Hobart, TAS 7000, Australia"},{"name":"Tasmanian Clinical Genetics Service, Royal Hobart 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Australia"},{"name":"Victorian Clinical Genetics Services, Royal Children\u2019s Hospital, Melbourne, VIC 3002, Australia"},{"name":"Discipline of Child and Adolescent Health, Faculty of Health and Medicine, University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1002\/jimd.12541","article-title":"Clinical and biochemical distinctions for a metabolite repair disorder caused by NAXD or NAXE deficiency","volume":"45","author":"Walvekar","year":"2022","journal-title":"J. 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