Neuropediatrics 2014; 45(06): 386-391
DOI: 10.1055/s-0034-1389161
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Mutations in ADAR1, IFIH1, and RNASEH2B Presenting As Spastic Paraplegia

Yanick J. Crow
1   INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France
2   Paris Descartes–Sorbonne Paris Cité University, Paris, France
3   Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, United Kingdom
,
Maha S. Zaki
4   Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Center, Cairo, Egypt
,
Mohamed S. Abdel-Hamid
5   Division of Human Genetics and Genome Research, Department of Medical Genetics, National Research Center, Cairo, Egypt
,
Ghada Abdel-Salam
4   Division of Human Genetics and Genome Research, Department of Clinical Genetics, National Research Center, Cairo, Egypt
,
Odile Boespflug-Tanguy
6   National Reference Center for Rare Diseases “leukodystrophies,” INSERM U676, Université Paris Diderot, Sorbonne Paris Cité Université, Paris, France
7   Pediatric Neurology and Metabolic Disease Service, Hôpital Robert Debré, Paris, France
,
Nuno J. V. Cordeiro
8   Department of Paediatrics, Rainbow House NHS Ayrshire & Arran, Irvine, Scotland, United Kingdom
,
Joseph G. Gleeson
9   Department of Neurosciences, University of California, San Diego, La Jolla, California, United States
,
Nirmala Rani Gowrinathan
10   Kaiser Permanente Los Angeles Medical Center, Los Angeles, California, United States
,
Vincent Laugel
11   Pediatric Neurology, Strasbourg–Hautepierre University Hospital, Avenue Moliere, Strasbourg, France
,
Florence Renaldo
12   Centre de Référence des Leucodystrophies, Service de Neuropédiatrie et Maladies Métaboliques; Hôpital Robert Debré, AP-HP, Paris, France
13   Centre de Référence des maladies Neurogénétiques de l'enfant à l'adulte, Service de Neuropédiatrie, Hôpital Armand Trousseau, AP-HP, Paris, France
14   UMR 1141; Physiopathologie et neuroprotection des atteintes du cerveau en développement/Pathophysiology and neuroprotection of perinatal brain lesions; Université Paris Diderot, Paris, France
,
Diana Rodriguez
15   Service de Neuropédiatrie, Hôpital Armand Trousseau, Paris, France
,
John H. Livingston
16   Department of Paediatric Neurology, F Floor Martin Wing, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
,
Gillian I. Rice
3   Manchester Academic Health Science Centre, University of Manchester, Genetic Medicine, Manchester, United Kingdom
› Author Affiliations
Further Information

Publication History

22 May 2014

28 July 2014

Publication Date:
22 September 2014 (online)

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.

Supplementary Material

 
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