D 1615 OULU 2021 D 1615 UNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA DMEDICA Oula Knuutinen Oula Knuutinen University Lecturer Tuomo Glumoff CHILDHOOD-ONSET University Lecturer Santeri Palviainen GENETIC WHITE MATTER Postdoctoral researcher Jani Peräntie DISORDERS OF THE BRAIN IN NORTHERN FINLAND University Lecturer Anne Tuomisto University Lecturer Veli-Matti Ulvinen Planning Director Pertti Tikkanen Professor Jari Juga Associate Professor (tenure) Anu Soikkeli University Lecturer Santeri Palviainen UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; Publications Editor Kirsti Nurkkala MEDICAL RESEARCH CENTER OULU; OULU UNIVERSITY HOSPITAL ISBN 978-952-62-2933-1 (Paperback) ISBN 978-952-62-2934-8 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) ACTA UNIVERSITATIS OULUENSIS D Medica 1615 OULA KNUUTINEN CHILDHOOD-ONSET GENETIC WHITE MATTER DISORDERS OF THE BRAIN IN NORTHERN FINLAND Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium 12 of Oulu University Hospital (Kajaanintie 50), on 21 May 2021, at 12 noon UNIVERSITY OF OULU, OULU 2021 Copyright © 2021 Acta Univ. Oul. D 1615, 2021 Supervised by Professor Johanna Uusimaa Docent Päivi Vieira Docent Maria Suo-Palosaari Reviewed by Docent Maija Castrén Doctor Hannele Koillinen Opponent Docent Tarja Linnankivi ISBN 978-952-62-2933-1 (Paperback) ISBN 978-952-62-2934-8 (PDF) ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) Cover Design Raimo Ahonen PUNAMUSTA TAMPERE 2021 Knuutinen, Oula, Childhood-onset genetic white matter disorders of the brain in Northern Finland. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; Medical Research Center Oulu; Oulu University Hospital Acta Univ. Oul. D 1615, 2021 University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland Abstract Genetic white matter disorders (GWMD), leukodystrophies and genetic leukoencephalopathies, are a major cause of neurodevelopmental disorders. Over a hundred related genes are recognised. The recent implementation of next-generation sequencing has facilitated the frequent characterisation of novel disorders seen today. This study was intended to evaluate the current epidemiology, genetic aetiologies, clinical phenotypes, and natural history of childhood-onset GWMDs. Additional aims were to characterise novel and rare phenotypes and to examine the effect of Finnish disease heritage on the distribution of specific disorders. This population-based cohort study consisted of 80 children diagnosed with a genetically defined white matter disorder in Northern Finland between 1990 and 2019. The cumulative childhood incidence was 30/100,000 live births, and it was higher in the later study period. In total, 49 distinct disorders were identified, of which 20% were leukodystrophies and 80% were genetic leukoencephalopathies. Mitochondrial aetiology was noted in 21% of the cases. Disorders belonging to the Finnish disease heritage constituted 10% of the cases. Motor developmental delay (79%), intellectual disability (56%), hypotonia (60%), and spasticity (49%) were the most frequent clinical findings. The study identified 20 disorders that were either recently characterised or not previously associated with white matter abnormalities. These included a novel TAF1C related phenotype. Additionally, a rare neonatal Alexander disease with a novel GFAP variant was described, consolidating the recently proposed neonatal phenotype. These findings provide comprehensive data on the current epidemiology and clinical features of GWMDs, benefitting future clinical trials. In addition to enabling genetic counselling, genetic phenotype data guide clinicians and researchers studying the pathomechanisms of GWMDs. Keywords: brain MRI, children, genetics, intellectual disability, leukodystrophy, white matter Knuutinen, Oula, Lapsuusiän geneettiset valkean aivoaineen sairaudet Pohjois- Suomessa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Medical Research Center Oulu; Oulun yliopistollinen sairaala Acta Univ. Oul. D 1615, 2021 Oulun yliopisto, PL 8000, 90014 Oulun yliopisto Tiivistelmä Geneettiset valkean aivoaineen sairaudet, leukodystrofiat ja geneettiset leukoenkefalopatiat, ovat merkittäviä neurologisten kehityshäiriöiden aiheuttajia. Taudinaiheuttajageenejä tunnetaan yli sata, ja eksomi- ja genomisekvensoinnin yleistyminen on mahdollistanut uusien tautien löytämi- sen aiempaa tehokkaammin. Tämän tutkimuksen tavoitteena oli selvittää lapsuusiän geneettisten valkean aivoaineen saira- uksien epidemiologiaa, geneettisiä etiologioita, kliinisiä ilmiasuja ja tautien luonnollista kulkua. Lisäksi tavoitteena oli löytää uusia ja harvinaisia fenotyyppejä sekä tarkastella suomalaisen tau- tiperinnön vaikutusta tautikirjoon. Tämän väestöpohjaisen kohortti-tutkimuksen aineistona oli 80 Pohjois-Suomessa asunutta lasta, joilla diagnosoitiin geneettinen valkean aivoaineen sairaus vuosina 1990–2019. Tautien kumulatiivinen ilmaantuvuus lapsuudessa oli 30/100 000 elävänä syntynyttä lasta, ja insidenssi oli suurempi myöhempinä vuosikymmeninä. Löydetyistä 49 taudista 20 % oli leukodystrofioita ja 80 % geneettisiä enkefalopatioita. Mitokondriaalinen tausta liittyi 21 %:iin tapauksista. Kym- menellä prosentilla oli suomalaiseen tautiperintöön kuuluva sairaus. Yleisimpiä kliinisiä löydök- siä olivat motoriikan kehityshäiriöt (49 %), älyllinen kehitysvammaisuus (56 %), heikko lihas- jäntevyys (60 %) ja spastisuus (49 %). Aineistoon kuului 20 viime vuosina löydettyä sairautta tai sairautta, joita ei ole aiemmin pidetty valkean aivoaineen sairauksina. Yksi näistä oli aiemmin kuvaamaton TAF1C-geeniin liittyvä neurologinen sairaus. Toisessa osatyössä kuvattiin uusi GFAP-geenin muutos ja harvinainen Alexanderin taudin vastasyntyneisyyskauden tautimuoto, mikä tukee tämän olemassaoloa muista ikäkausista erillisenä tautimuotona. Tutkimustulokset muodostavat kokonaisvaltaisen kuvauksen geneettisten valkean aivoai- neen sairauksien epidemiologiasta ja kliinisistä piirteistä. Löydökset auttavat tulevaisuudessa kliinisten tutkimusten suunnittelua ja perinnöllisyysneuvontaa sekä ohjaavat tautien parissa työs- kenteleviä kliinikkoja ja tutkijoita. Asiasanat: aivojen magneettikuvaus, lapset, leukodystrofia, perinnölliset sairaudet, valkea aivoaine, älyllinen kehitysvammaisuus Ostinato rigore RIGORE 8 Acknowledgements This work was carried out in the Clinic for Children and Adolescents, Oulu University Hospital, and in the PEDEGO Research Unit at the University of Oulu during 2015–2021. The work was funded by the Arvo and Lea Ylppö Foundation; Stiftelsen Alma och K. A. Snellman Säätiö; Oulun Lääketieteellinen Tutkimussäätiö; Academy of Finland; the Finnish Medical Foundation; the Pediatric Research Foundation; Special State Grants for Health Research in the Clinic of Paediatrics and Adolescents, Oulu University Hospital, Finland; the University of Oulu Graduate School; Folkhälsan Research Foundation; the Newton Fund; the Medical Research Council; the Wellcome Investigator Award; the Lily Foundation UK; and the Evelyn Trust. First, I would like to thank my supervisors, Professor Johanna Uusimaa, MD, PhD; Adjunct Professor Päivi Vieira, MD, PhD; and Adjunct Professor Maria Suo- Palosaari, MD, PhD. Johanna welcomed me into her research group as a buoyant medical student interested in the brain. Her unrelenting vigour, enthusiasm, and optimism broke through several barriers and smoothed the path during the project. This project would truly never have come into being without her. Päivi exemplified a constant thoroughness in science and medicine that I wish to imitate, and she taught me much of scientific writing. Maria’s clinical work in the radiology of genetic white matter disorders truly embodies da Vinci’s obstinate rigor, turning every stone, searching every nook. She supported me in adversity, and without her kind words I might have cut myself off this project and moved to other work. I wish to thank Reetta Hinttala, MSc, PhD, who warmly welcomed me to the research group and made arrangements for me to learn the basics of laboratory work (something I never really employed, being drawn into clinical work). For her patience in this endeavour, I want to thank our lovely laboratory technician, Pirjo Keränen. I am truly grateful to Salla Kangas, MSc, PhD, for patiently teaching me about genetic databases, among other things. I thank all the rest of the paediatric neurology research group members. I also owe special thanks to Dr. Jaakko Oikarainen, MD, who not only reviewed countless brain MRI scans but also discussed research problems as a fellow PhD student. I am grateful for the effortless collaboration between numerous co-authors in Oulu, Helsinki, the United Kingdom, and Jordan. Professor Anna-Elina Lehesjoki, MD, PhD, Professor Rita Horvath, MD, PhD, and Dr. Angela Pyle, PhD, deserve special appreciation for making the collaboration across several organisations possible. I thank Associate Professor Tawfiq Froukh, PhD, and Dr. Latifa Marawa, MD, for their collaboration and 9 contribution in characterising the TAF1C related disorder. Adjunct Professor Jukka Moilanen introduced me to the in silico prediction studies that were later applied in all studies in this thesis. Dr. Elisa Rahikkala, MD, PhD, greatly helped in the collection of cohort genetic data. I thank Professor Vesa