title: Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia.
abstract: BACKGROUND
  Hereditary spastic paraplegia is a neurodegenerative phenotype characterized by a progressive loss of corticospinal motor tract function. In a majority of affected individuals the pathogenesis remains undetermined.
  
  
  METHODS
  We identified a series of patients with a phenotype of nonsyndromic spastic paraplegia in whom no diagnosis had been reached before exome sequencing. We measured the expression of interferon stimulated genes (ISGs) in peripheral blood from these patients.
  
  
  RESULTS
  Five patients from four families with previously unexplained spastic paraplegia were identified with mutations in either ADAR1 (one patient), IFIH1 (one patient), or RNASEH2B (three patients from two families). All patients were developmentally normal before the onset of features beginning in the second year of life. All patients remain of normal intellect. Four patients demonstrated normal neuroimaging, while a single patient had features of nonspecific dysmyelination. The patients with ADAR1 and IFIH1-related disease showed a robust interferon signature. The patients with mutations in RNASEH2B demonstrated no (two patients) or a minimal (one patient) upregulation of ISGs compared with controls.
  
  
  CONCLUSIONS
  Mutations in ADAR1, IFIH1, and RNASEH2B can cause a phenotype of spastic paraplegia with normal neuroimaging, or in association with nonspecific dysmyelination. Although the presence of an interferon signature can be helpful in interpreting the significance of gene variants in this context, patients with pathogenic mutations in RNASEH2B may demonstrate no upregulation of ISGs in peripheral blood. However, it remains possible that type I interferons act as a neurotoxin in the context of all genotypes.
authors.affiliation: INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.
authors.forename: Yanick J
authors.initials: YJ
authors.lastname: Crow
authors.affiliation: Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Center, Cairo, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Division of Human Genetics and Genome Research, Department of Medical Genetics, National Research Center, Cairo, Egypt.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Center, Cairo, Egypt.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abdel-Salam
authors.affiliation: National Reference Center for Rare Diseases "leukodystrophies," INSERM U676, Université Paris Diderot, Sorbonne Paris Cité Université, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Department of Paediatrics, Rainbow House NHS Ayrshire & Arran, Irvine, Scotland, United Kingdom.
authors.forename: Nuno J V
authors.initials: NJ
authors.lastname: Cordeiro
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, United States.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Kaiser Permanente Los Angeles Medical Center, Los Angeles, California, United States.
authors.forename: Nirmala Rani
authors.initials: NR
authors.lastname: Gowrinathan
authors.affiliation: Pediatric Neurology, Strasbourg-Hautepierre University Hospital, Avenue Moliere, Strasbourg, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laugel
authors.affiliation: Centre de Référence des Leucodystrophies, Service de Neuropédiatrie et Maladies Métaboliques; Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Renaldo
authors.affiliation: Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: Department of Paediatric Neurology, F Floor Martin Wing, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
authors.forename: John H
authors.initials: JH
authors.lastname: Livingston
authors.affiliation: Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, United Kingdom.
authors.forename: Gillian I
authors.initials: GI
authors.lastname: Rice
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics*; D000328:Adult; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008297:Male; D009154:Mutation; D016601:RNA-Binding Proteins / Q000235:genetics*; D016914:Ribonuclease H / Q000235:genetics*; D035781:Siblings; D015419:Spastic Paraplegia, Hereditary / Q000097:blood / Q000235:genetics*
chemical_list: D007370:Interferon Type I; D016601:RNA-Binding Proteins; C091139:ribonuclease HII; D016914:Ribonuclease H; C000595356:ADAR protein, human; D000243:Adenosine Deaminase; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1