Malene Landbo Børresen

Background: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomized trials. The aim of the NEAT study is to evaluate the safety and efficacy of eDSP in children with ataxia telangiectasia.Methods: This international, multi-center, randomized, double-blind, placebo-controlled phase 3 study was conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, United Kingdom, and United States). Eligible participants were children aged 6 years or older weighing ≥15 kg with genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomized (1:1) to eDSP or placebo group via an independent Interactive Web Response System and were stratified by age (6–9 years or ≥10 years), gender, and region (US vs. other countries). All participants, investigators, sponsors, and raters were blinded to treatment assignments. eDSP was given intravenously every 21–30 days for six doses. All randomized participants were included in the intent-to-treat (ITT) and in the safety population, while the primary and secondary efficacy analyses were conducted in the ITT (6-9) population, which comprised 6-9-year-olds. The Rescored modified International Cooperative Ataxia Rating Scale (RmICARS) score was the primary efficacy endpoint, and a mixed-model-repeated-measures analysis was used. The trial was registered at Clinicaltrials.gov (NCT06193200) and is completed.Findings: Between June 24th, 2024, and December 17th, 2025, 105 participants were randomized into the eDSP group (N=51) or the placebo group (N=54) and received at least one dose of treatment. The 6-9-year-old population comprised 83 participants, 95% of which completed the trial. 40 were randomized to eDSP and 43 to placebo. Compared to the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in 6-9-year-old participants: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·0851). Adverse events were reported in 47 (92%) participants in the eDSP group and 50 (93%) of participants in the placebo group. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups.Interpretation: The primary efficacy endpoint was not achieved, as the impact of eDSP on neurological symptoms was modest. The treatment effect peaked at month 3 and appeared to diminish thereafter. Nevertheless, favorable safety profile of eDSP, validated in two large, randomized trials in ataxia telangiectasia, supports consideration of further studies in other disorders where glucocorticoids have proven clinical efficacy.Trial Registration: The trial was registered at Clinicaltrials.gov (NCT06193200) and is completed.Funding: Quince Therapeutics, Inc.Declaration of Interest: AP reports that his institution received payments from Quince Therapeutics to conduct the study. He received a travel grant from Quince Therapeutics for the investigators’ meeting. His institution has received funds from Vertex Ltd to undertake investigator-led studies in rare diseases, and he received funds from Vertex Ltd to attend and speak at an international meeting. AP is an unpaid member of the Action for A-T Scientific Advisory Committee. AS reports being a consultant to Quince Therapeutics and being compensated on an hourly basis for contributions to data analyses for this manuscript. He reports owning stock options from Quince Therapeutics. ASP reports receiving payments for lectures from the Oslo University Hospital Research Ethics and Governance Unit (REGUT) and serving as President of the Norwegian Society for Medical Genetics. BH reports being an employee of Quince and receiving payment, consulting fees and stock options from Quince. She is a Data Safety Monitoring Board member for an unrelated trial. BP reports holding stock options from Quince Therapeutics. CS reports being an employee of Quince Therapeutics, receiving consulting fees for advisory and development services from Quince Therapeutics and holding employee stock/stock option. She is also past president and board member of Inflammation Research Association. DGA reports grants from the Instituto de Salud Carlos III and Duchenne Parent Project Spain. He is also a principal investigator or sub-investigator on clinical trials run by Novartis, Italfarmaco, Pfizer, Union Chimique Belge (UCB) Pharma, Roche, DYNE Therapeutics, Solid Biosciences, and Satellos for other neurological disorders, and for Quince Therapeutics and Entrada Therapeutics for ataxia telangiectasia. He received consulting fees from Biogen and Astellas Gene Therapies, and his institution received consulting fees from Novartis, Sarepta, Entrada Therapeutics, and Santhera. He received payments for presentations from Alexion and Italfarmaco. He received support for attending investigators’ meetings from Novartis, Roche, Biogen, and Italfarmaco. He holds stock options from UCB Pharma. DGA is a member of the European Reference Network for Rare Neurological Diseases (Project ID No. 739510). DT reports being employed by Quince Therapeutics as Chief Medical Officer and Chief Executive Officer and receiving stock options as part of compensation. DZ reports no conflicts of interest. FP reports no conflicts of interest. HD reports no conflicts of interest. HL reports that his institution received payment from Quince Therapeutics for serving as a study site and that he received payments from Quince Therapeutics for membership on the Scientific Advisory...

Cerebellar mutism syndrome (CMS) is a well-known complication of posterior fossa (PF) tumour surgery. CMS has previously been reported in cases of non-tumour surgical aetiology in a limited number of publications. We report a case of a 10-year-old girl who suffered a cerebellar haemorrhage and subsequent CMS following surgical treatment of a ruptured arteriovenous malformation (AVM) in the cerebellar vermis. The AVM was removed acutely through a transvermian access, and hydrocephalus was treated with temporary external drainage. In the postoperative period, she suffered diffuse vasospasms of the anterior cerebral circulation and had a permanent shunt placed for hydrocephalus. Her mutism resolved after 45 days but severe ataxia persisted. To our knowledge, this is the first reported case of CMS related to a vermian haemorrhagic stroke with postoperative diffuse vasospasms. Based on this case, we present a literature review on CMS of non-tumour surgical origin in children.

Background We aimed to determine school performance and psychiatric comorbidity in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic–clonic seizures (GTCS) alone. Methods All children (< 18 years) fulfilled International League Against Epilepsy criteria after review of their medical records. Control groups were the pediatric background population or children with non-neurological chronic disease. Outcomes were on school performance and psychiatric comorbidity. We compared mean grade point averages using linear regression and estimated hazard ratios using Cox regression in the remaining analyses. We adjusted for the child’s sex, age, and year of birth; and parental highest education, receipt of cash benefits or early retirement. Results We included 92 JAE, 190 JME, 27 GTCS alone, 15,084 non-neurological chronic disease controls, and population controls. JAE had two times increased hazard for special needs education compared with age-matched population controls (hazard ratio 2.2, 95% CI = 1.1‒4.6, p = 0.03); this was not seen in JME. Compared with population controls, both JAE and JME had lower grade point average in secondary and high school (JME: 9th grade: – 0.5 points, 95% CI = −0.9 to −0.06, p = 0.03; high school: – 0.6 points, 95% CI = −1.3 to −0.1, p = 0.04), and 8% fewer JME and 15% fewer JAE attended high school. Both JME and JAE had higher hazard for redeeming sleep medication compared with non-neurological chronic disease; additionally, JAE had increased hazard for ADHD medicine redemptions. Conclusions Both JAE and JME had marginally poorer school performance; performance seemed worse in JAE than in JME. Both JAE and JME had increased use of sleep medication.

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro—a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

A disproportionate number of Greenland's Inuit population are chronically infected with Hepatitis B virus (HBV; 5–10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4 × 10⁻⁵[95% HPD 8.8 × 10⁻⁶, 2.0 × 10⁻⁵] and a time to the most recent common ancestor of 629 CE [95% HPD 37–1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese sequences. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2 and ~97% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be considered a novel quasi-subgenotype.

A disproportionate amount of Greenland’s Inuit population is chronically infected with Hepatitis B virus (HBV; 5-10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4×10 ⁻⁵ [95% HPD 8.8×10 ⁻⁶ , 2.0×10 ⁻⁵ ] and a time to the most recent common ancestor of 629 CE [95% HPD 37-1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese samples. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2, and approximately 98% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be a novel subgenotype.