DOCSLIB.ORG

Childhood-Onset Genetic White Matter Disorders of the Brain in Northern Finland

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Childhood-Onset Genetic White Matter Disorders of the Brain in Northern Finland 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
Load more

Recommended publications
  • KIF1A-Related Autosomal Dominant Spastic Paraplegias (SPG30) in Russian Families G
    Rudenskaya et al. BMC Neurology (2020) 20:290 https://doi.org/10.1186/s12883-020-01872-4 RESEARCH ARTICLE Open Access KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families G. E. Rudenskaya1 , V. A. Kadnikova1* , O. P. Ryzhkova1 , L. A. Bessonova1, E. L. Dadali1 , D. S. Guseva1 , T. V. Markova1 , D. N. Khmelkova2 and A. V. Polyakov1 Abstract Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course.
    [Show full text]
  • 2020.07.27.20162974V1.Full.Pdf
    medRxiv preprint doi: https://doi.org/10.1101/2020.07.27.20162974; this version posted July 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 1 Title: Genotype and defects in microtubule-based motility correlate with clinical severity in 2 KIF1A Associated Neurological Disorder 3 Authors: Lia Boyle,1 Lu Rao,2 Simranpreet Kaur,3 Xiao Fan,1,4 Caroline Mebane,1 Laura 4 Hamm,5 Andrew Thornton,6 Jared T Ahrendsen,7 Matthew P Anderson,7,8 John Christodoulou,3 5 Arne Gennerich,2 Yufeng Shen,4,9 Wendy K Chung1,10 6 7 Abstract: KIF1A Associated Neurological Disorder (KAND) encompasses a recently identified 8 group of rare neurodegenerative conditions caused by variants in KIF1A, a member of the 9 kinesin-3 family of microtubule (MT) motor proteins. Here we characterize the natural history of 10 KAND in 117 individuals using a combination of caregiver or self-reported medical history, a 11 standardized measure of adaptive behavior, clinical records, and neuropathology. We developed 12 a heuristic severity score using a weighted sum of common symptoms to assess disease severity. 13 Focusing on 100 individuals, we compared the average clinical severity score for each variant 14 with in silico predictions of deleteriousness and location in the protein. We found increased 15 severity is strongly associated with variants occurring in regions involved with ATP and MT- 16 binding: the P-loop, switch I, and switch II.
    [Show full text]
  • Mackenzie's Mission Gene & Condition List
    Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child.
    [Show full text]
  • Homozygous TAF1C Variants Are Associated with a Novel Childhood-Onset
    Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype Running title: TAF1C Associated Neurological Phenotype Oula Knuutinen, M.D.a,b*; Angela Pyle, Ph.D.c*; Maria Suo-Palosaari, M.D., Ph.D.b,d†; Jennifer Duff, Ph.D.c†; Tawfiq Froukh, Ph.D.e; Anna-Elina Lehesjoki, M.D., Ph.D.f; Salla M. Kangas, Ph.D.a,b,g; James Cassidy, M.Sc.c; Latifa Maraqa, M.D.h; Riikka Keski-Filppula, M.D., Ph.Da,b,i; Hannaleena Kokkonen, Ph.D.j; Johanna Uusimaa, M.D., Ph.D.a,b,k; Rita Horvath, M.D., Ph.D.c§; Päivi Vieira, M.D., Ph.D.a,b,k§ aPEDEGO Research Unit, University of Oulu, Finland bMedical Research Center, University of Oulu, Finland cWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, UK dDepartment of Diagnostic Radiology, Research Unit of Medical Imaging, Physics and Technology, Oulu University Hospital and University of Oulu, Finland eDepartment of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan f Folkhälsan Research Center and Medicum, University of Helsinki, Finland gBiocenter Oulu, University of Oulu, Finland hPKU & Genetic Consultation Clinic, Amman, Jordan iDepartment of Clinical Genetics, Oulu University Hospital, Finland jNorthern Finland Laboratory Centre NordLab, Oulu University Hospital, Finland kClinic for Children and Adolescents, Oulu University Hospital, Finland *†§Equal contribution. Corresponding author: Päivi Vieira, Clinic for Children and Adolescents, Oulu University Hospital, PO Box 23, 90029 Oulu, Finland. [email protected]. Acknowledgements This work was supported by the Arvo and Lea Ylppö Foundation, Stiftelsen Alma och K. A. Snellman Säätiö, and Oulun Lääketieteellinen Tutkimussäätiö.
    [Show full text]
  • KIF1A-Related Disorders in Children: a Wide Spectrum of Central And
    KIF1A-related disorders in children: a wide spectrum of central and peripheral nervous system involvement Authors: Tarishi Nemani*,1 Dora Steel*,1,2 Marios Kaliakatsos,1 Catherine DeVile,1 Athina Ververi,3 Richard Scott,3 Spas Getov,5 Sniya Sudhakar,6 Alison Male,3 Kshitij Mankad,6 Genomics England Research Consortium,7 Francesco Muntoni,1,2 Mary M Reilly,4 Manju A Kurian,1,2 Lucinda Carr,1 Pinki Munot1 * Joint first authors 1. Department of Paediatric Neurology, Great Ormond Street Hospital, London, UK 2. UCL Great Ormond Street Institute of Child, London, UK 3. Department of Clinical Genetics, Great Ormond Street Hospital, London, UK 4. UCL Queen Square Institute of Neurology, London, UK 5. Department of Neurophysiology, Great Ormond Street Hospital, London, UK 6. Department of Radiology, Great Ormond Street Hospital, London, UK 7. Genomics England, Queen Mary University of London, UK Running Title: Spectrum of KIF1A disorders in children Word Count: 2145 1 Abstract Background and Aims KIF1A-related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological and radiological features which may occur in childhood-onset KRD. Methods We report on all the children and young people seen at a single large tertiary centre. Data was collected through a retrospective case-notes review. Results 12 individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress.
    [Show full text]
  • A Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2 Mutations, Comparison to Previously Published Patients and Clinical Distinction from PEHO Syndrome
    Journal Pre-proof A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome Viivi Nevanlinna, Svetlana Konovalova, Berten Ceulemans, Mikko Muona, Anni Laari, Taru Hilander, Katarin Gorski, Leena Valanne, Anna-Kaisa Anttonen, Henna Tyynismaa, Carolina Courage, Anna-Elina Lehesjoki PII: S1769-7212(18)30943-1 DOI: https://doi.org/10.1016/j.ejmg.2019.103766 Reference: EJMG 103766 To appear in: European Journal of Medical Genetics Received Date: 21 December 2018 Revised Date: 15 September 2019 Accepted Date: 15 September 2019 Please cite this article as: V. Nevanlinna, S. Konovalova, B. Ceulemans, M. Muona, A. Laari, T. Hilander, K. Gorski, L. Valanne, A.-K. Anttonen, H. Tyynismaa, C. Courage, A.-E. Lehesjoki, A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome, European Journal of Medical Genetics (2019), doi: https://doi.org/10.1016/j.ejmg.2019.103766. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Masson SAS.
    [Show full text]
  • 1 a Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2
    1 1 2 3 1 A Patient with Pontocerebellar Hypoplasia Type 6: Novel RARS2 Mutations, Comparison to 4 5 6 2 Previously Published Patients and Clinical Distinction from PEHO Syndrome 7 8 3 9 10 4 Viivi Nevanlinnaa,b, Svetlana Konovalovac, Berten Ceulemansd, Mikko Muonaa,1, Anni Laaria,c, Taru 11 12 5 Hilanderc, Katarin Gorskia,c, Leena Valannee, Anna-Kaisa Anttonena,f,g, Henna Tyynismaac, f, h, 13 14 a,c a,c,f,* 15 6 Carolina Courage , Anna-Elina Lehesjoki 16 17 7 18 19 8 aFolkhälsan Research Center, Helsinki, Finland 20 21 9 bFaculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland 22 23 c 24 10 Research Programs Unit, Molecular Neurology, University of Helsinki, Finland 25 26 11 dDepartment of Pediatric Neurology, Antwerp University Hospital, University of Antwerp, Belgium 27 28 12 eDepartment of Radiology, Hospital District of Helsinki and Uusimaa Medical Imaging Center, 29 30 13 31 University of Helsinki and Helsinki University Hospital, Helsinki, Finland 32 f 33 14 Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Finland 34 35 15 gLaboratory of Genetics, Helsinki University Hospital, Helsinki, Finland 36 37 16 hNeuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland 38 39 17 1 40 Present address: Blueprint Genetics, Helsinki, Finland 41 42 18 *Corresponding author. Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, 43 44 19 00290, Helsinki, Finland; tel: +358 2941 25072; email: [email protected] 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 61 62 20 Abstract 63 64 65 21 Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy 66 67 22 caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase 68 69 23 enzyme (mtArgRS).
    [Show full text]
  • SPTAN1 Encephalopathy: Distinct Phenotypes and Genotypes
    Journal of Human Genetics (2015) 60, 167–173 & 2015 The Japan Society of Human Genetics All rights reserved 1434-5161/15 www.nature.com/jhg REVIEW SPTAN1 encephalopathy: distinct phenotypes and genotypes Jun Tohyama1,2, Mitsuko Nakashima3, Shin Nabatame4,Ch’ng Gaik-Siew5, Rie Miyata6, Zvonka Rener-Primec7, Mitsuhiro Kato8, Naomichi Matsumoto3 and Hirotomo Saitsu3 Recent progress in genetic analysis reveals that a significant proportion of cryptogenic epileptic encephalopathies are single-gene disorders. Mutations in numerous genes for early-onset epileptic encephalopathies have been rapidly identified, including in SPTAN1, which encodes α-ΙΙ spectrin. The aim of this review is to delineate SPTAN1 encephalopathy as a distinct clinical syndrome. To date, a total of seven epileptic patients with four different in-frame SPTAN1 mutations have been identified. The major clinical features of SPTAN1 mutations include epileptic encephalopathy with hypsarrhythmia, no visual attention, acquired microcephaly, spastic quadriplegia and severe intellectual disability. Brainstem and cerebellar atrophy and cerebral hypomyelination, as observed by magnetic resonance imaging, are specific hallmarks of this condition. A milder variant is characterized by generalized epilepsy with pontocerebellar atrophy. Only in-frame SPTAN1 mutations in the last two spectrin repeats in the C-terminal region lead to dominant negative effects and these specific phenotypes. The last two spectrin repeats are required for α/β spectrin heterodimer associations and the mutations can alter heterodimer formation between the two spectrins. From these data we suggest that SPTAN1 encephalopathy is a distinct clinical syndrome owing to specific SPTAN1 mutations. It is important that this syndrome is recognized by pediatric neurologists to enable proper diagnostic work-up for patients.
    [Show full text]