Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy

Hannah F Jones; Marion Stoll; Gladys Ho; Dugald O'Neill; Velda X Han; Simon Paget; Kirsty Stewart; Jennifer Lewis; Kavitha Kothur; Christopher Troedson; Yanick J Crow; Russell C Dale; Shekeeb S Mohammad

doi:10.1016/j.braindev.2021.10.001

Autosomal dominant ADAR c.3019G>A (p.(G1007R)) variant is an important mimic of hereditary spastic paraplegia and cerebral palsy

Brain Dev. 2022 Feb;44(2):153-160. doi: 10.1016/j.braindev.2021.10.001. Epub 2021 Oct 24.

Authors

Affiliations

¹ Neurology Department, The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
² Molecular Medicine Laboratory, Concord Repatriation General Hospital, NSW Health Pathology, Australia.
³ Molecular Genetics Department, The Children's Hospital at Westmead, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia; Discipline of Genetic Medicine, University of Sydney, Sydney, New South Wales 2006, Australia.
⁴ Neurology Department, The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.
⁵ Khoo-Teck Puat-National University Children's Medical Institute, National University Health System, Singapore.
⁶ Kids Rehab, The Children's Hospital at Westmead, New South Wales, Australia.
⁷ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Laboratory of Neurogenetics and Neuroinflammation, Institute Imagine, Université de Paris, Paris, France.
⁸ Neurology Department, The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia.
⁹ Neurology Department, The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia; Discipline of Child & Adolescent Health, University of Sydney, Sydney, New South Wales 2006, Australia. Electronic address: shekeeb.mohammad@health.nsw.gov.au.

PMID: 34702576
DOI: 10.1016/j.braindev.2021.10.001

Abstract

Background: The type 1 interferonopathy, Aicardi-Goutières syndrome 6 (AGS6), is classically caused by biallelic ADAR mutations whereas dominant ADAR mutations are associated with dyschromatosis symmetrica hereditaria (DSH). The unique dominant ADAR c.3019G>A variant is associated with neurological manifestations which mimic spastic paraplegia and cerebral palsy (CP).

Case summaries: We report three cases of spastic paraplegia or CP diagnosed with AGS6 caused by the ADAR c.3019G>A variant. Two children inherited the variant from an asymptomatic parent, and each child had a different clinical course. The youngest case demonstrated relentless progressive symptoms but responded to immunomodulation using steroids and ruxolitinib.

Conclusion: The ADAR c.3019G>A variant has incomplete penetrance and is a likely underrecognized imitator of spastic paraplegia and dystonic CP. A high level of clinical suspicion is required to diagnose this form of AGS, and disease progression may be ameliorated by immunomodulatory treatment with selective Janus kinase inhibitors.

Keywords: ADAR; Aicardi-Goutières syndrome; Cerebral palsy; Hereditary spastic paraplegia; Interferonopathy; Janus kinase inhibitor; Neuroinflammation; Spastic diplegia; Striatal necrosis.

Publication types

Case Reports

MeSH terms

Adenosine Deaminase / genetics*
Autoimmune Diseases of the Nervous System / diagnosis*
Autoimmune Diseases of the Nervous System / drug therapy
Autoimmune Diseases of the Nervous System / genetics*
Cerebral Palsy / diagnosis
Child, Preschool
Diagnosis, Differential
Humans
Infant
Nervous System Malformations / diagnosis*
Nervous System Malformations / drug therapy
Nervous System Malformations / genetics*
RNA-Binding Proteins / genetics*
Spastic Paraplegia, Hereditary / diagnosis

Substances

RNA-Binding Proteins
ADAR protein, human
Adenosine Deaminase

Supplementary concepts

Aicardi-Goutieres syndrome