Summary Background Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. Methods In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. Findings 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14–20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57–1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=−0·604; serum, r=−0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. Interpretation AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. Funding European Union’s Seventh Framework Programme; European Research Council.

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.

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A written protocol will be developed based on evidence and feedback incorporating any changes to the CO-OP intervention for children and young people with HMD, as per the Medical Research Council's Framework for Complex Interventions.

OBJECTIVE Deep brain stimulation (DBS) is an established treatment for pediatric dystonia. The accuracy of electrode implantation is multifactorial and remains a challenge in this age group, mainly due to smaller anatomical targets in very young patients compared to adults, and also due to anatomical abnormalities frequently associated with some etiologies of dystonia. Data on the accuracy of robot-assisted DBS surgery in children are limited. The aim of the current paper was to assess the accuracy of robot-assisted implantation of DBS leads in a series of patients with childhood-onset dystonia. METHODS Forty-five children with dystonia undergoing implantation of DBS leads under general anesthesia between 2017 and 2019 were included. Robot-assisted stereotactic implantation of the DBS leads was performed. The final position of the electrodes was verified with an intraoperative 3D scanner (O-arm). Coordinates of the planned electrode target and actual electrode position were obtained and compared, looking at the radial error, depth error, absolute error, and directional error, as well as the euclidean distance. Functional assessment data prospectively collected by a multidisciplinary pediatric complex motor disorders team were analyzed with regard to motor skills, individualized goal achievement, and patients’ and caregivers’ expectations. RESULTS A total of 90 DBS electrodes were implanted and 48.5% of the patients were female. The mean age was 11.0 ± 0.6 years (range 3–18 years). All patients received bilateral DBS electrodes into the globus pallidus internus. The median absolute errors in x-, y-, and z-axes were 0.85 mm (range 0.00–3.25 mm), 0.75 mm (range 0.05–2.45 mm), and 0.75 mm (range 0.00–3.50 mm), respectively. The median euclidean distance from the target to the actual electrode position was 1.69 ± 0.92 mm, and the median radial error was 1.21 ± 0.79. The robot-assisted technique was easily integrated into the authors’ surgical practice, improving accuracy and efficiency, and reducing surgical time significantly along the learning curve. No major perioperative complications occurred. CONCLUSIONS Robot-assisted stereotactic implantation of DBS electrodes in the pediatric age group is a safe and accurate surgical method. Greater accuracy was present in this cohort in comparison to previous studies in which conventional stereotactic frame-based techniques were used. Robotic DBS surgery and neuroradiological advances may result in further improvement in surgical targeting and, consequently, in better clinical outcome in the pediatric population.