{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:58:52Z","timestamp":1777395532578,"version":"3.51.4"},"reference-count":40,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Pathogenic variants in <jats:italic>AIFM1<\/jats:italic> have been associated with a wide spectrum of disorders, spanning from CMT4X to mitochondrial encephalopathy. Here we present a novel phenotype and review the existing literature on <jats:italic>AIFM1<\/jats:italic>\u2010related disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed EEG recordings, brain MRI and MR Spectroscopy, metabolic screening, echocardiogram, clinical exome sequencing (CES) and family study. Effects of the variant were established on cultured fibroblasts from skin punch biopsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The patient presented with drug\u2010resistant, electro\u2010clinical, multifocal seizures 6\u2009h after birth. Brain MRI revealed prominent brain swelling of both hemispheres and widespread signal alteration in large part of the cortex and of the thalami, with sparing of the basal nuclei. CES analysis revealed the likely pathogenic variant c.5T&gt;C; p.(Phe2Ser) in the <jats:italic>AIFM1<\/jats:italic> gene. The affected amino acid residue is located in the mitochondrial targeting sequence. Functional studies on cultured fibroblast showed a clear reduction in AIFM1 protein amount and defective activities of respiratory chain complexes I, III and IV. No evidence of protein mislocalization or accumulation of precursor protein was observed. Riboflavin, Coenzyme Q10 and thiamine supplementation was therefore given. At 6\u2009months of age, the patient exhibited microcephaly but did not experience any further deterioration. He is still fed orally and there is no evidence of muscle weakness or atrophy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This is the first <jats:italic>AIFM1<\/jats:italic> case associated with neonatal seizures and diffuse white matter involvement with relative sparing of basal ganglia, in the absence of clinical signs suggestive of myopathy or motor neuron disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51876","type":"journal-article","created":{"date-parts":[[2023,8,30]],"date-time":"2023-08-30T06:44:57Z","timestamp":1693377897000},"page":"1844-1853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expanding the spectrum of neonatal\u2010onset AIFM1\u2010associated disorders"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6539-5360","authenticated-orcid":false,"given":"Alberto A.","family":"Zambon","sequence":"first","affiliation":[{"name":"Unit of Neurology San Raffaele Scientific Institute  Milan Italy"},{"name":"Neuromuscular Repair Unit, Institute of Experimental Neurology (InSpe), Division of Neuroscience IRCCS Ospedale San Raffaele  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6564-3766","authenticated-orcid":false,"given":"Daniele","family":"Ghezzi","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"},{"name":"Department of Pathophysiology and Transplantation University of Milan  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Baldoli","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianni","family":"Cutillo","sequence":"additional","affiliation":[{"name":"Unit of Neurology San Raffaele Scientific Institute  Milan Italy"},{"name":"Neurophysiology Service San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katia","family":"Fontana","sequence":"additional","affiliation":[{"name":"Department of Neonatology San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Sofia","sequence":"additional","affiliation":[{"name":"Department of Neonatology San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Grazia","family":"Patricelli","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Clinical Genetics San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessia","family":"Nasca","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Vinci","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivana","family":"Spiga","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Clinical Genetics San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Lamantea","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna F.","family":"Fanelli","sequence":"additional","affiliation":[{"name":"Neurophysiology Service San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Grazia Natali","family":"Sora","sequence":"additional","affiliation":[{"name":"Unit of Neurology San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosanna","family":"Rovelli","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Poloniato","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Carrera","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Clinical Genetics San Raffaele Scientific Institute  Milan Italy"},{"name":"Unit of Genomics for Human Disease Diagnosis San Raffaele Scientific Institute  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-0479","authenticated-orcid":false,"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Unit of Neurology San Raffaele Scientific Institute  Milan Italy"},{"name":"Neurophysiology Service San Raffaele Scientific Institute  Milan Italy"},{"name":"Vita\u2010Salute San Raffaele University  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graziano","family":"Barera","sequence":"additional","affiliation":[{"name":"Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/17135"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104231"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022110784"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.170"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.03.002"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.10.008"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000001613"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2018.05.008"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/jns.12348"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2017.09.004"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet\u20102014\u2010102961"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12792"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010017\u20100520\u2010x"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.25.23.10261\u201010272.2005"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2011.09.020"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.141"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a006081"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436\u2010019\u20100666\u2010z"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2004.09.006"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23033"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcps050929"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.111.2.351"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601276"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2106950118"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1155\/2010\/737385"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.7184"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600461"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01034"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.889089"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1101\/mcs.a001560"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2021.101272"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2015.01.001"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320200214"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010017\u20100524\u20106"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13452"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1212\/nxg.0000000000000420"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62072"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.05.013"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2016.05.004"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.51876","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T20:06:20Z","timestamp":1697486780000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.51876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/acn3.51876"],"URL":"https:\/\/doi.org\/10.1002\/acn3.51876","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,29]]},"assertion":[{"value":"2023-06-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}