Deep Brain Stimulation in a Child with Aicardi‐Goutières Syndrome‐7 ( <scp>AGS7</scp> ): A Case Report and Literature Review

Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogeneous group of disorders with neurological and systemic findings. Some individuals present with early-onset encephalopathy, whereas others exhibit normal development followed by regression of milestones. Other signs include intellectual disability, irritability, spasticity, dystonia, acquired microcephaly, sterile pyrexia, chilblains, and hepatosplenomegaly.1 AGS is caused by homozygous variants in ADAR (OMIM: 146920), RNASEH2A (OMIM: 606034), RNASEH2B (OMIM: 610326), RNASEH2C (OMIM: 610330), SAMHD1 (OMIM; 606754), TREX1 (OMIM: 606609), RNU7-1 (OMIM: 617876), or LSM11 (OMIM: 617910) genes and heterozygous pathogenic variants in TREX1, ADAR, or IFIH1 (OMIM: 606951) genes.1, 2 Here we describe a child with AGS7 who had progressive dystonia and was managed with deep brain stimulation (DBS). An 8.5-year-old girl born to nonconsanguineous parents was referred for the management of progressive dystonia and regression of milestones. The mother reported fetal hypokinesia. The baby was born full term by vacuum-assisted delivery with a birth weight of 3150 g, and the neonatal transition was uneventful. Her motor milestones were mildly delayed from 6 months of age. She had a gradual regression of milestones from 18 months of age. Assessment at 21 months of age revealed normocephaly, spasticity of all four limbs, brisk deep tendon reflexes, bilateral ankle clonus, and dystonia of bilateral lower limbs. Brain magnetic resonance imaging (MRI) at 2 years of age (Fig. S1A–F) revealed hyperintense signal changes in dentate nuclei, dorsal pons, superior cerebellar peduncle, and periventricular and subcortical white matter. Plasma amino acids, urine organic acids, and acylcarnitine analysis were unyielding. Mild transaminitis was observed. Serum creatine kinase was normal. Trio-whole exome sequencing revealed a de novo heterozygous pathogenic variant c.2336G>A (p.Arg779His) in the exon 12 of IFIH1 gene. She was initiated on physiotherapy, occupational therapy, and speech therapy, following which she had a mild improvement in motor and a good improvement in her language skills. Dystonia was managed with trihexyphenidyl, baclofen, and botulinum toxin injections. Ophthalmology assessment revealed right-eye glaucoma. Echocardiography revealed normal pulmonary pressures. Baricitinib was initiated around 3 years of age.3 Though there was an initial stabilization of disease, a progressive worsening of limb dystonia (lower > upper limbs) was observed. Grade 2 severity was observed on the quality of muscle reaction assessed by modified Tardieu scale. She was referred to our center for consideration of DBS in view of progressive dystonia and loss of ambulation. Pre-DBS assessment revealed an alert child, spasticity of lower limbs more than upper limbs, and generalized dystonia. Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) assessment revealed a score of 29.5 on dystonia movement scale and 13 on disability scale. The total mean score in Pediatric Quality of Life Inventory (PedsQL) 4.0 generic core scales (parent-proxy report) was 30.43. DBS surgery was performed at 9 years and 11 months of age, with bilateral insertion of electrodes into the globus pallidus interna (GPi). No postsurgical complications were detected. The initial programming of deep brain stimulation includes right: C + 2−/1.5 mA/60 μs/125 Hz and left: C + 10−/1.5 mA/60 μs/125 Hz. Video 1 (segment 1) shows generalized dystonia prior to DBS and a mild reduction in the severity of dystonia at 6 and 14 months after DBS (Videos 2 and 3: segments 2 and 3). BFMDRS score at 14 months follow-up was 23 on dystonia movement scale and 11 on disability scale. The total mean score in PedsQL 4.0 generic core scales was 45.65. A clinically important change was detected in BFMDRS dystonia movement scale, disability scale, and PedsQL score.4 AGS7 is a rare disorder caused by gain-of-function mutations in interferon-induced helicase C domain-containing protein 1 (IFIH1) gene encoding for IFIH1 inappropriately detects endogenous nucleic acid as viral and is involved in the activation of type 1 interferon (IFN) signaling.5, 6 Therefore, gain-of-function mutation results in upregulation of IFN signaling and autoimmunity.5 The age at onset of symptoms may be fetal, neonatal, infantile, or early childhood. The neurological manifestations reported are acquired microcephaly, developmental delay, neuroregression, seizures, spasticity, dystonia, gait abnormalities, and polyneuropathy.5-7 Our patient had late-infantile onset symptoms with bipyramidal signs and progressive dystonia. The reported extraneurological manifestations include periodic fever, hepatosplenomegaly, skin lesions, glaucoma, pancreatitis, cholestasis, recurrent infection, pulmonary hypertension, anemia, and thrombocytopenia.6, 7 Glaucoma and mild transaminitis were observed in our proband. DBS is an established neuromodulation tool for the management of movement disorders in adults, whereas it is still an evolving tool for the management of refractory childhood dystonia. Our patient was managed with DBS as she had progressive dystonia despite appropriate medical management. A reduction in the severity of dystonia and an improvement in her functional status were observed after DBS. Similarly, Saraf et al. from India reported reduction in phasic movements and truncal dystonia following GPi-DBS in a young adult with AGS7.8 DBS of the subthalamic nucleus (STN) was found to be beneficial in a child with AGS due to variant in ADAR1 gene. Though there was a reduction in the frequency of dystonic crisis after DBS, only a mild reduction was observed in BFMDRS score.9 The outcome of individuals with AGS managed with DBS is shown in Table 1. In terms of safety, one of the patients died within 24 hours of electrode replacement, whereas another patient with AGS died about a year after the removal of DBS.10 Selection of an ideal candidate, surgical expertise, good postoperative care, and underlying etiology would determine the outcome of DBS in children. Patient 1: First DBS at 6.6 y of age DBS electrode replacement at 10.5 y NA NA Died within 24 h of DBS electrode replacement Respiratory arrest was documented Cause of death not identified on autopsy n = 1 AGS7 n = 1 AGS6 Reduction in frequency of dystonic crisis Mild reduction in BFMDRS score n = 1 AGS7 AGS7 is an interferonopathy with progressive neurological and extraneurological manifestations. With the recent advances targeting underlying pathophysiology in patients with AGS, DBS may be a good option in controlling progressive dystonia and improving the quality of life. (1) Research Project: A. Study Concept and Design, B. Organization, C. Data Acquisition; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Editing the Final Version. S.Y.: 1A, 1B, 1C, 3A. S.S., W.K.L., V.P.: 1B, 1C, 3A. S.V., A.L.M., S.B., A.D., A.F., G.M.I.: 1C, 3B. C.G.: 1A, 1B, 1C, 3B. Ethical Compliance Statement: Name of the institutional review board or ethics committee that approved the study: Research Ethics Board approval was not obtained for this case report. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: Dr. Asif Doja has received personal compensation for serving as an Expert Witness for the CMPA, Integra, and Connect Care. Dr. Alfonso Fasano has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion. He has received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer. Dr. George M Ibrahim is an advisory board member in Synergia, consultant in LivaNova, Medtronic, and Synergia, and advisory board member in Pediatric Epilepsy Surgery Alliance. Dr. Carolina Gorodetsky received consulting fees from Medtronic Inc and Ipsen, participated as an advisor at the advisory board meetings organized by Medtronic Inc. Written consent for publication was obtained from the parent. “We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.” The data that support the findings of this study are available from the corresponding author upon reasonable request. Fig. S1. (A–F) Sequential caudocranial axial fluid-attenuated inversion recovery (FLAIR) images at 2 years of age reveal abnormal hyperintense signal changes in the dentate nuclei (white arrows in A), dorsal pons (white arrow in B), and superior cerebellar peduncles (white arrow in C). Similar signal abnormality was seen in the cerebral white matter (white arrows in D–F) with a posterior predominance. There was no restricted diffusion or evidence of abnormal susceptibility (images not shown). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.