POLR3B is associated with a developmental and epileptic encephalopathy with myoclonic-atonic seizures and ataxia.

Katherine S Elliot, Julie S Cohen, Kristen L Park, Stewart Macleod, Martin Armstrong, Mary Callaghan, Georg Classen, Ioana Cutcutache, Jean-Madeleine de Sainte Agathe, David Dyment, Konrad Platzer, Shelagh Joss, Michael Marble, Marc Planes, Sylvia Redon, James Reese, Daniel Stobo, Christian Stockhaus, Marie-Laure Vuillaume, Emma L Wakeling, Kathleen Brown, Margarita Saenz, Arnaud Isapof, Joseph D Symonds, Matthew Osmond, Nicole I Wolf, Amy McTague, Julian C Knight, Matthew Page, Houman Ashrafian, Grace Yoon, Andreas Brunklaus, Cyril Mignot, Boris Keren, Sameer M Zuberi, Geneviève Bernard, Constance Smith-Hicks

Journal: Epilepsia 2024;65(11):3303-3323

PMID: 39348199

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Abstract

OBJECTIVE

POLR3B encodes the second largest subunit of RNA polymerase III, which is essential for transcription of small non-coding RNAs. Biallelic pathogenic variants in POLR3B are associated with an inherited hypomyelinating leukodystrophy. Recently, de novo heterozygous variants in POLR3B were reported in six individuals with ataxia, spasticity, and demyelinating peripheral neuropathy. Three of these individuals had epileptic seizures. The aim of this article is to precisely define the epilepsy phenotype associated with de novo heterozygous POLR3B variants.

METHODS

We used online gene-matching tools to identify 13 patients with de novo POLR3B variants. We systematically collected genotype and phenotype data from clinicians using two standardized proformas.

RESULTS

All 13 patients had novel POLR3B 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-atonic, atypical absence, or tonic-clonic seizures between the ages of six months and 4 years. Epilepsy was classified as epilepsy with myoclonic-atonic seizures (EMAtS) in seven patients and "probable EMAtS" in two more. Seizures were treatment resistant in all cases. Three patients became seizure-free. 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. 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). Additional features were ataxia/incoordination (8/13); microcephaly (7/13); peripheral neuropathy (4/13), and spasticity/hypertonia (6/13).

SIGNIFICANCE

POLR3B 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.

Address: Paediatric Neurosciences Research Group, School of Health and Wellbeing, University of Glasgow, Glasgow, UK.; Royal Hospital for Children, Glasgow, UK.; Children's Hospital Colorado, Anschutz Medical Campus, University of Colorado, Aurora, Colorado, USA.; Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière-Hôpital Trousseau, Sorbonne Université, Paris, France.; Royal Hospital for Children, Glasgow, UK.; UCB Pharma, Braine l'Alleud, Belgium.; Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.; Department of Experimental Therapeutics, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK.; Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.; Department Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.; Child Health and Human Development Program, Research, Institute of the McGill University Health Centre, Montreal, Quebec, Canada.; Department of Pediatrics, Section of Genetics and Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.; Department of Paediatrics, University Hospital Wishaw, Wishaw, UK.; Children's Center Bethel, University Bielefeld, Bielefeld, Germany.; Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, Maryland, USA.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; UCB Pharma, Slough, UK.; Department of Genetics, Pitié-Salpêtrière Hospital, APHP. Sorbonne Université, Paris, France.; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Service de Neuropédiatrie, Hôpital Trousseau, Sorbonne Université, Paris, France.; West of Scotland Regional Genetics Service, Queen Elizabeth University Hospitals, Glasgow, UK.; Division of Pediatric Genetics, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.; Developmental Neurosciences. Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK.; Service de Génétique Médicale et Biologie de la Reproduction, CHU de Brest, Brest, France.; Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.; Université Brest, Brest, France.; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Presbyterian Healthcare System, Albuquerque, New Mexico, USA.; Laboratoire de Biologie Médicale Multi-Sites SeqOIA, Paris, France.; UMR 1253, iBrain, University of Tours, Tours, France.; Genetics Department, University of Tours, Tours, France.; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma's Children's Hospital, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands.; North East Thames Regional Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.; Departments of Paediatrics and Molecular Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

DOI: 10.1111/epi.18115

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MeSH Terms: Humans, Female, Male, RNA Polymerase III, Child, Preschool, Epilepsies, Myoclonic, Infant, Ataxia, Child, Phenotype, Anticonvulsants