{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:07:57Z","timestamp":1779379677122,"version":"3.53.1"},"reference-count":19,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NeuroSci"],"abstract":"<jats:p>Periventricular nodular heterotopia (PVNH) is a genetically heterogeneous malformation of cortical development with variable neurological outcomes. Among recessive forms, ARFGEF2-related disorder is uniquely characterised by the association of diffuse PVNH and progressive microcephaly. We describe a two-year-old boy born to consanguineous parents who presented with severe developmental delay, hypotonia, progressive microcephaly, and infantile-onset epileptic spasms with developmental regression. Brain MRI showed extensive bilateral PVNH associated with callosal hypoplasia and ventriculomegaly. EEG revealed dysmature background activity with multifocal epileptiform discharges and runs of asynchronous fast activity during sleep. Genetic testing identified a novel homozygous nonsense variant in ARFGEF2. The clinical course was characterised by drug-resistant epilepsy and multisystemic involvement, including feeding difficulties and recurrent respiratory infections. To contextualise this case, we performed a comprehensive review of previously reported patients, further delineating the clinical, neuroradiological, and electroclinical spectrum of ARFGEF2-related disorder. This case highlights progressive microcephaly as a key distinguishing feature of ARFGEF2-related PVNH and underscores the importance of early genetic diagnosis to guide targeted surveillance for extra-CNS complications and multidisciplinary care.<\/jats:p>","DOI":"10.3390\/neurosci7030063","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:02:27Z","timestamp":1779375747000},"page":"63","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ARFGEF2-Related Periventricular Nodular Heterotopia: A Case Report and Literature Review"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6685-3134","authenticated-orcid":false,"given":"Luca","family":"Andreoli","sequence":"first","affiliation":[{"name":"Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"},{"name":"Department of Humanities and Life Sciences, University School for Advanced Studies, Istituto Universitario di Studi Superiori\u2014IUSS, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8505-3894","authenticated-orcid":false,"given":"Davide","family":"Caputo","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neuroscience, European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio M.","family":"Doniselli","sequence":"additional","affiliation":[{"name":"Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5889-2342","authenticated-orcid":false,"given":"Giuliana","family":"Messina","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Granocchio","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-3041","authenticated-orcid":false,"given":"Barbara","family":"Castellotti","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2293-8687","authenticated-orcid":false,"given":"Elena","family":"Freri","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neuroscience, European Reference Network EPIcare, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/s41582-020-0395-6","article-title":"International consensus recommendations on the diagnostic work-up for malformations of cortical development","volume":"16","author":"Oegema","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1212\/01.WNL.0000055898.00349.02","article-title":"Autosomal recessive form of periventricular heterotopia","volume":"60","author":"Sheen","year":"2003","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/ng1276","article-title":"Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex","volume":"36","author":"Sheen","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"53","DOI":"10.4161\/bioa.28516","article-title":"Filamin A and Big2: A shared endocytic pathway","volume":"4","author":"Sheen","year":"2014","journal-title":"Bioarchitecture"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.ejpn.2013.05.002","article-title":"Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: Case study and literature review","volume":"17","author":"Verhelst","year":"2013","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s10048-009-0192-2","article-title":"Movement disorder and neuronal migration disorder due to ARFGEF2 mutation","volume":"10","author":"Halley","year":"2009","journal-title":"Neurogenetics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1136\/jmedgenet-2013-101752","article-title":"West syndrome, microcephaly, grey matter heterotopia and hypoplasia of corpus callosum due to a novel ARFGEF2 mutation","volume":"50","author":"Banne","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.pediatrneurol.2014.05.008","article-title":"Periventricular nodular heterotopia and dystonia due to an ARFGEF2 mutation","volume":"51","year":"2014","journal-title":"Pediatr. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.braindev.2015.06.004","article-title":"The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder","volume":"38","author":"Yilmaz","year":"2016","journal-title":"Brain Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.24911\/JBCGenetics\/183-1531469195","article-title":"Recessive ARFGEF2 mutation causes progressive microcephaly, epilepsy, and a distinct MRI pattern","volume":"1","author":"Alojair","year":"2018","journal-title":"JBCGenetics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"11","DOI":"10.11648\/j.ijgg.20180601.13","article-title":"A Systematic Genetic Assessment of ARFGEF2 Mutations in Periventricular Heterotopia","volume":"6","author":"Kenana","year":"2018","journal-title":"Int. J. Genet. Genom."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/cge.14637","article-title":"Recognisable Neuroradiological Findings in Five Neurogenetic Disorders","volume":"107","author":"Rosenblum","year":"2025","journal-title":"Clin. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Vogelezang, S., Bradfield, J.P., Grant, S.F.A., Felix, J.F., and Jaddoe, V.W.V. (2022). Genetics of early-life head circumference and genetic correlations with neurological, psychiatric and cognitive outcomes. BMC Med. Genom., 15.","DOI":"10.1186\/s12920-022-01281-1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.1528-1167.2006.00374.x","article-title":"Periventricular nodular heterotopia: Classification, epileptic history, and genesis of epileptic discharges","volume":"47","author":"Battaglia","year":"2006","journal-title":"Epilepsia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3934","DOI":"10.1007\/s00415-023-11724-z","article-title":"The phenotypic spectrum of epilepsy associated with periventricular nodular heterotopia","volume":"270","author":"Paliotti","year":"2023","journal-title":"J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.sleep.2017.11.1138","article-title":"Different maturational changes of fast and slow sleep spindles in the first four years of life","volume":"42","author":"Novelli","year":"2018","journal-title":"Sleep Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1111\/j.1528-1167.2012.03466.x","article-title":"Abnormal structural and functional brain connectivity in grey matter heterotopia","volume":"53","author":"Christodoulou","year":"2012","journal-title":"Epilepsia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/cne.20806","article-title":"Overlapping expression of ARFGEF2 and Filamin A in the neuroependymal lining of the lateral ventricles: Insights into the cause of periventricular heterotopia","volume":"494","author":"Lu","year":"2006","journal-title":"J. Comp. Neurol."}],"container-title":["NeuroSci"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2673-4087\/7\/3\/63\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T15:39:58Z","timestamp":1779377998000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2673-4087\/7\/3\/63"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,21]]},"references-count":19,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["neurosci7030063"],"URL":"https:\/\/doi.org\/10.3390\/neurosci7030063","relation":{},"ISSN":["2673-4087"],"issn-type":[{"value":"2673-4087","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,21]]}}}