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.


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


  • RNA-Binding Proteins
  • ADAR protein, human
  • Adenosine Deaminase

Supplementary concepts

  • Aicardi-Goutieres syndrome