{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:05:18Z","timestamp":1792591518365,"version":"4.5.0"},"reference-count":49,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"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":["Epilepsia"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:italic>POLR3B<\/jats:italic> encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non\u2010coding RNAs. Biallelic pathogenic variants in <jats:italic>POLR3B<\/jats:italic> are associated with an inherited hypomyelinating leukodystrophy. Recently, <jats:italic>de novo<\/jats:italic> heterozygous variants in <jats:italic>POLR3B<\/jats:italic> were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures.<\/jats:p><jats:p>The aim of this article is to precisely define the epilepsy phenotype associated with <jats:italic>de novo<\/jats:italic> heterozygous <jats:italic>POLR3B<\/jats:italic> variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used online gene\u2010matching tools to identify 13 patients with <jats:italic>de novo<\/jats:italic> <jats:italic>POLR3B<\/jats:italic> variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All 13 patients had novel <jats:italic>POLR3B<\/jats:italic> variants. Twelve of 13 variants were classified as pathogenic or likely pathogenic as per American College of Medical Genetics (ACMG) criteria. Patients presented with generalized myoclonic, myoclonic\u2010atonic, atypical absence, or tonic\u2010clonic seizures between the ages of six months and 4\u2009years. Epilepsy was classified as epilepsy with myoclonic\u2010atonic seizures (EMAtS) in seven patients and \u201cprobable EMAtS\u201d in two more.<\/jats:p><jats:p>Seizures were treatment resistant in all cases. Three patients became seizure\u2010free. All patients had some degree of developmental delay or intellectual disability. In most cases developmental delay was apparent before the onset of seizures. Three of 13 cases were reported to have developmental stagnation or regression in association with seizure onset.<\/jats:p><jats:p>Treatments for epilepsy that were reported by clinicians to be effective were: sodium valproate, which was effective in five of nine patients (5\/9) who tried it; rufinamide (2\/3); and ketogenic diet (2\/3).<\/jats:p><jats:p>Additional features were ataxia\/incoordination (8\/13); microcephaly (7\/13); peripheral neuropathy (4\/13), and spasticity\/hypertonia (6\/13).<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p><jats:italic>POLR3B<\/jats:italic> is a novel genetic developmental and epileptic encephalopathy (DEE) in which EMAtS is the predominant epilepsy phenotype. Ataxia, neuropathy, and hypertonia may be variously observed in these patients.<\/jats:p><\/jats:sec>","DOI":"10.1111\/epi.18115","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T15:55:29Z","timestamp":1727711729000},"page":"3303-3323","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["<i>POLR3B<\/i> is associated with a developmental and epileptic encephalopathy with myoclonic\u2010atonic seizures and ataxia"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2141-4216","authenticated-orcid":false,"given":"Joseph D.","family":"Symonds","sequence":"first","affiliation":[{"name":"Paediatric Neurosciences Research Group, School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen L.","family":"Park","sequence":"additional","affiliation":[{"name":"Children's Hospital Colorado, Anschutz Medical Campus University of Colorado  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Mignot","sequence":"additional","affiliation":[{"name":"D\u00e9partement de G\u00e9n\u00e9tique, Groupe Hospitalier Piti\u00e9\u2010Salp\u00eatri\u00e8re\u2010H\u00f4pital Trousseau Sorbonne Universit\u00e9  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart","family":"Macleod","sequence":"additional","affiliation":[{"name":"Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Armstrong","sequence":"additional","affiliation":[{"name":"UCB Pharma  Braine l'Alleud Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houman","family":"Ashrafian","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine John Radcliffe Hospital  Oxford UK"},{"name":"Department of Experimental Therapeutics, Radcliffe Department of Medicine John Radcliffe Hospital  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Bernard","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics McGill University  Montreal Quebec Canada"},{"name":"Department Specialized Medicine, Division of Medical Genetics McGill University Health Centre  Montreal Quebec Canada"},{"name":"Child Health and Human Development Program, Research Institute of the McGill University Health Centre  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Section of Genetics and Children's Hospital Colorado University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-6903","authenticated-orcid":false,"given":"Andreas","family":"Brunklaus","sequence":"additional","affiliation":[{"name":"Paediatric Neurosciences Research Group, School of Health and Wellbeing University of Glasgow  Glasgow UK"},{"name":"Royal Hospital for Children  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Callaghan","sequence":"additional","affiliation":[{"name":"Department of Paediatrics University Hospital Wishaw  Wishaw UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Classen","sequence":"additional","affiliation":[{"name":"Children's Center Bethel University Bielefeld  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Neurology and Developmental Medicine Kennedy Krieger Institute  Baltimore Maryland USA"},{"name":"Department of Neurology Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioana","family":"Cutcutache","sequence":"additional","affiliation":[{"name":"UCB Pharma  Slough UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Madeleine","family":"de Sainte\u00a0Agathe","sequence":"additional","affiliation":[{"name":"Department of Genetics, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital APHP. 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