Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.

Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.

Complications and visual outcomes following surgical resection of pediatric optic pathway/hypothalamic gliomas: a systematic review and meta-analysis.

Pediatric optic pathway/hypothalamic gliomas (OPHG) pose challenges in treatment due to their location and proximity to vital structures. Surgical resection plays a key role in the management of OPHG especially when the tumor exhibits mass effect and causes symptoms. However, data regarding outcomes and complications of surgical resection for OPHG remains heterogenous. The authors performed a systematic review on pediatric OPHG in four databases: PubMed, EMBASE, Cochrane Library, and Google Scholar. We included studies that reported on the visual outcomes and complications of OPHG resection. A meta-analysis was performed and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 26 retrospective studies were included. Seven hundred ninety-seven pediatric patients with OPHG undergoing surgical resection were examined. A diagnosis of NF1 was confirmed in 9.7%. Gross total resection was achieved in 36.7%. Intraorbital optic pathway gliomas showed a significantly higher gross total resection rate compared to those located in the chiasmatic/hypothalamic region (75.8% vs. 9.6%). Postoperatively, visual acuity improved in 24.6%, remained unchanged in 68.2%, and worsened in 18.2%. Complications included hydrocephalus (35.4%), anterior pituitary dysfunction (19.6%), and transient diabetes insipidus (29%). Tumor progression post-resection occurred in 12.8%, through a mean follow-up of 53.5 months. Surgical resection remains an essential strategy for treating symptomatic and large pediatric OPHG and can result in favorable vision outcomes in most patients. Careful patient selection is critical. Patients should be monitored for hydrocephalus development postoperatively and followed up to assess for tumor progression and adjuvant treatment necessity.

Endoscopic endonasal approach for resection of odontoid process, decompression of the cervicomedullary junction spinal cord, and resection of pannus.

Odontoid pannus is an abnormal collection of degenerative or inflammatory tissue on the C1-dens joint that can result in severe spinal cord compression myelopathy. Treatment options vary depending on severity and etiology. In cases of severe cord compression, surgical management could be either through a purely posterior approach or in combination with an anterior decompression via endoscopic endonasal approach (EEA). This case presents a 77-year-old female who underwent posterior cervical fixation for odontoid pannus causing dramatic cervical myelopathy who failed to improve over a 6-month period and required anterior transodontoid pannus resection and decompression via EEA. The video can be found here: https://stream.cadmore.media/r10.3171/2024.1.FOCVID23176.

Clinical Characteristics of Adolescents With Juvenile Idiopathic Arthritis Transitioning to Adult Rheumatology Care in Canada: Results From the CAPRI Registry.

OBJECTIVE: Using Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) juvenile idiopathic arthritis (JIA) registry data, we describe (1) clinical characteristics of patients with JIA transitioning to adult care, (2) prevalence of disease-related damage and complications, and (3) changes in disease activity during the final year prior to transfer. METHODS: Registry participants who turned 17 years between February 2017 and November 2021 were included. Clinical characteristics and patient-reported outcomes (PROs) at the last recorded pediatric rheumatology visit, and changes observed in the year prior to that visit were analyzed. Physicians completed an additional questionnaire characterizing cumulative disease-related damage and adverse events by age 17 years. RESULTS: At their last visit, 88 of 131 participants (67%) had inactive and 42 (32%) had active disease. Overall, 96 (73%) were on medications and 41 (31%) were on biologic disease-modifying antirheumatic drugs. Among 80 participants for whom the additional questionnaire was completed, 26% had clinically detected joint damage, 31% had joint damage on imaging, 14% had uveitis, and 7.5% had experienced at least 1 serious adverse event. During the final year, 44.2% of patients were in remission, 28.4% attained inactive disease, and 27.4% became or remained active. Mean scores of PROs were stable overall during that last year, but a minority reported marked worsening. CONCLUSION: A substantial proportion of youth with JIA transitioning to adult care in Canada had a high disease burden, which was reflected by their degree of disease activity, joint damage, or ongoing medication use. These results will inform pediatric and adult providers of anticipated needs during transition of care.

Probabilistic coverage of the frontal aslant tract in young adults: Insights into individual variability, lateralization, and language functions.

The frontal aslant tract (FAT) is a crucial neural pathway of language and speech, but little is known about its connectivity and segmentation differences across populations. In this study, we investigate the probabilistic coverage of the FAT in a large sample of 1065 young adults. Our primary goal was to reveal individual variability and lateralization of FAT and its structure-function correlations in language processing. The study utilized diffusion MRI data from 1065 subjects obtained from the Human Connectome Project. Automated tractography using DSI Studio software was employed to map white matter bundles, and the results were examined to study the population variation of the FAT. Additionally, anatomical dissections were performed to validate the fiber tracking results. The tract-to-region connectome, based on Human Connectome Project-MMP parcellations, was utilized to provide population probability of the tract-to-region connections. Our results showed that the left anterior FAT exhibited the most substantial individual differences, particularly in the superior and middle frontal gyrus, with greater variability in the superior than the inferior region. Furthermore, we found left lateralization in FAT, with a greater difference in coverage in the inferior and posterior portions. Additionally, our analysis revealed a significant positive correlation between the left FAT inferior coverage area and the performance on the oral reading recognition (p = .016) and picture vocabulary (p = .0026) tests. In comparison, fractional anisotropy of the right FAT exhibited marginal significance in its correlation (p = .056) with Picture Vocabulary Test. Our findings, combined with the connectivity patterns of the FAT, allowed us to segment its structure into anterior and posterior segments. We found significant variability in FAT coverage among individuals, with left lateralization observed in both macroscopic shape measures and microscopic diffusion metrics. Our findings also suggested a potential link between the size of the left FAT's inferior coverage area and language function tests. These results enhance our understanding of the FAT's role in brain connectivity and its potential implications for language and executive functions.

Exoscope-based supracerebellar infratentorial approach for a pineal meningioma in the prone position.

The supracerebellar infratentorial (SCIT) approach is a well-described corridor to lesions in the quadrigeminal cistern, pineal gland, and dorsal midbrain. It can be performed in the prone or sitting position. The sitting position offers the benefit of gravity retraction of the cerebellum but comes at the expense of nonergonomic hand positioning and the potential risk of air embolism. The 3D exoscope is an alternative to the operating microscope and permits the SCIT approach in the prone position with excellent visualization. This video demonstrates exoscope-based SCIT approach for resection of a pineal meningioma in the prone position. The video can be found here: https://stream.cadmore.media/r10.3171/2023.10.FOCVID23155.

Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children.

PURPOSE: In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS: Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS: Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION: After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.

A decade of progress in juvenile idiopathic athritis treatments and outcomes in Canada: results from ReACCh-Out and the CAPRI registry.

OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

Reductions in Bone Mineral Density Are Apparent Early in Children With Prevalent Osteonecrosis Lesions Following Leukemia Therapy.

Osteonecrosis (ON) is a serious complication of childhood acute lymphoblastic leukemia. We determined the prevalence of osteonecrotic lesions in our patient population by a one-time multisite magnetic resonance imaging (MRI) more than 1 year following leukemia therapy. MRI findings were evaluated in relationship to clinical factors (including longitudinal changes in bone mineral density [BMD]). Eighty-six children enrolled in the Steroid Associated Osteoporosis in the Pediatric Population (STOPP) study were evaluated for ON at 3.1 ± 1.3 years following therapy. Thirty children had a total of 150 confirmed ON lesions (35%). Lumbar spine (LS) BMD Z-scores (mean ± SD) were low at diagnosis and similar between patients with and without ON (-1.09 ± 1.53 versus -1.27 ± 1.25, p = 0.549). LS BMD Z-scores declined from baseline to 12 months in children with ON (-0.31 ± 1.02) but not in those without (0.13 ± 0.82, p = 0.035); the hip BMD Z-scores from baseline to 24 months declined in both groups, but to a greater extent in those with ON (-1.77 ± 1.22) compared to those without (-1.03 ± 1.07, p = 0.045). At the time of the MRI, mean total hip and total body (TB) BMD Z-scores were lower in children with ON (hip -0.98 ± 0.95 versus -0.28 ± 1.06, p = 0.010; TB -1.36 ± 1.10 versus -0.48 ± 1.50, p = 0.018). Pain occurred in 11/30 (37%) with ON versus 20/56 (36%) without, p = 0.841. In multivariable models, older age at diagnosis (odds ratio [OR] 1.57; 95% confidence interval [CI], 1.15-2.13; p = 0.004), and hip BMD Z-score at MRI (OR 2.23; 95% CI, 1.02-4.87; p = 0.046) were independently associated with ON. Overall, one-third of children demonstrated ON after leukemia therapy. Those with ON had greater reductions in spine and hip BMD Z-scores in the first 1 and 2 years of therapy, respectively. Older age and lower hip BMD Z-scores at MRI were significantly associated with prevalent, off-therapy ON. These data assist in identifying children at risk of ON. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Stereotactic Radiosurgery for Meningiomas in Children and Adolescents: An International Multi-Institutional Study.

BACKGROUND AND OBJECTIVES: Meningiomas in children are uncommon, with distinct characteristics that set them apart from their adult counterparts. The existing evidence for stereotactic radiosurgery (SRS) in this patient population is limited to only case series. The objective of this study was to evaluate the safety and efficacy of SRS in managing pediatric meningiomas. METHODS: Children and adolescents who had been treated for meningioma with single-fraction SRS were included in this retrospective, multicenter study. The assessment included local tumor control, any complications related to the tumor or SRS, and the emergence of new neurological deficits after SRS. RESULTS: The cohort included 57 patients (male-to-female ratio 1.6:1) with a mean age of 14.4 years who were managed with single-fraction SRS for 78 meningiomas. The median radiological and clinical follow-up periods were 69 months (range, 6-268) and 71 months (range, 6-268), respectively. At the last follow-up, tumor control (tumor stability and regression) was achieved in 69 (85.9%) tumors. Post-SRS, new neurological deficits occurred in 2 (3.5%) patients. Adverse radiation effects occurred in 5 (8.8%) patients. A de novo aneurysm was observed in a patient 69 months after SRS. CONCLUSION: SRS seems to be a safe and effective up-front or adjuvant treatment option for surgically inaccessible, recurrent, or residual pediatric meningiomas.

Anterior Thoracic Discectomy and Fusion for Symptomatic Ventral Bone Spur Associated Type I Cerebrospinal Fluid Leak: A Technical Report and Operative Video.

STUDY DESIGN: Technical Report. OBJECTIVE: Cerebrospinal fluid (CSF) leak secondary to anterior osteophytes at the cervico-thoracic junction is a rare cause of intracranial hypotension. In this article we describe a technique for anterior repair of spontaneous ventral cerebrospinal fluid leaks in the upper thoracic spine. METHODS: In this technical report and operative video, we describe a 23-year-old male who presented with positional headaches and bilateral subdural hematoma. Dynamic CT myelography demonstrated a high flow ventral cerebrospinal fluid leak associated with a ventral osteophyte at the level of the T1-T2 disc space. Targeted blood patch provided only temporary improvement in symptoms. An anterior approach was chosen to remove the offending spur and micro-surgically repair the dural defect. RESULTS: The patient had complete resolution of his preoperative symptoms after primary repair. CONCLUSIONS: In select cases, an anterior approach to the upper thoracic spine is effective to repair Type 1 cerebrospinal fluid leaks.

Elevated ADA2 Enzyme Activity at the Onset of Chronic Graft-versus-Host Disease in Children.

Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Association Between HLA-DPB1 and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Children.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients. METHODS: We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls). RESULTS: We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P = 1.5 × 10-8 , odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3-ANCA positivity than in children with myeloperoxidase-ANCA positivity. Among the HLA alleles, the HLA-DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow-up adult AAV cohort (P = 2.6 × 10-4 , OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort. CONCLUSION: The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.

The endoscopic anterior transmaxillary temporal pole approach for mesial temporal lobe epilepsies: a feasibility study.

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the ideal surgical approach to achieve seizure freedom and minimize morbidity is an unsolved question. Selective approaches to mesial temporal structures often result in suboptimal seizure outcomes. The authors report the results of a pilot study intended to evaluate the clinical feasibility of using an endoscopic anterior transmaxillary (eATM) approach for minimally invasive management of MTLEs. METHODS: The study is a prospectively collected case series of four consecutive patients who underwent the eATM approach for the treatment of MTLE and were followed for a minimum of 12 months. All participants underwent an epilepsy workup and surgical care at a tertiary referral comprehensive epilepsy center and had medically refractory epilepsy. The noninvasive evaluations and intracranial recordings of these patients confirmed the presence of anatomically restricted epileptogenic zones located in the mesial temporal structures. Data on seizure freedom at 1 year, neuropsychological outcomes, diffusion tractography, and adverse events were collected and analyzed. RESULTS: By applying the eATM technique and approaching the far anterior temporal lobe regions, mesial-basal resections of the temporal polar areas and mesial temporal structures were successfully achieved in all patients (2 with left-sided approaches, 2 with right-sided approaches). No neurological complications or neuropsychological declines were observed. All 4 patients achieved Engel class Ia outcome up to the end of the follow-up period (19, 15, 14, and 12 months). One patient developed hypoesthesia in the left V2 distribution but there were no other adverse events. The low degree of white matter injury from the eATM approach was analyzed using high-definition fiber tractography in 1 patient as a putative mechanism for preserving neuropsychological function. CONCLUSIONS: The described series demonstrates the feasibility and potential safety profile of a novel approach for medically refractory MTLE. The study affirms the feasibility of performing efficacious mesial temporal lobe resections through an eATM approach.

Surgical Limitations of the Microscopic Transciliary Supraorbital Keyhole Approach to the Anterior and Middle Skull Base.

BACKGROUND: The microscopic transciliary SupraOrbital keyhole (mtSO) approach has been used for a wide variety of anterior and middle fossa pathologies, including aneurysms, meningiomas, craniopharyngiomas, and other skull-base tumors. Several clinical series have proven its efficacy and safety, but detailed anatomical demarcations of the anterior and middle cranial base exposure are lacking. Our aim was to define the surgical limitations of the mtSO approach to the ipsilateral and contralateral anterior and middle skull base. METHODS: Five cadaveric specimens (10 sides) were studied with image guidance to illustrate the limits of the surgical exposure. In addition, 30 dry skulls were used to measure the working distances between the craniotomy and key bony landmarks of the mtSO approach. RESULTS: Surgical exposure at the anterior skull base covered the area between the medial half of the contra- and the medial two-thirds of the ipsilateral sphenoid wing including both optic nerves and interoptic space. The anterior limit at the midline was the sphenoethmoidal suture. Ipsilateral anterior clinoidectomy permitted exposure of the superior orbital fissure, which defined the anteromedial limit at the middle fossa, whereas the anterolateral limit was defined by the ophthalmic branch of the trigeminal nerve. Moreover, the posteromedial and posterolateral limits were the posterior clinoid process and the petrous ridge, respectively. CONCLUSIONS: Our findings define the surgical limitations of the mtSO approach for the treatment of anterior and middle cranial base pathologies. These limits can be reliably identified on imaging studies allowing assessment of exposure to guide preoperative case selection.

Pathogenic variant c.1052T>A (p.Leu351Gln) in adenosine deaminase 2 impairs secretion and elevates type I IFN responsive gene expression.

Background: Adenosine deaminase 2 (ADA2) is a homodimeric, extracellular enzyme and putative growth factor that is produced by cells of the myeloid lineage and, catalytically, deaminates extracellular adenosine to inosine. Loss-of-(catalytic)-function variants in the ADA2 gene are associated with Deficiency of ADA2 (DADA2), an autosomal recessive disease associated with an unusually broad range of inflammatory manifestations including vasculitis, hematological defects and cytopenia. Previous work by our group led to the identification of ADA2 variants of novel association with DADA2, among which was a unique c.1052T>A (p.Leu351Gln; herein referred to as L351Q) variant located in the catalytic domain of the protein. Methods: Mammalian (Flp-IN CHO) cells were engineered to stably express wild-type ADA2 and ADA2 protein variants, including the pathogenic L351Q variant identified in DADA2 patients. An enzyme assay and immunoblotting were used to assess ADA2 catalytic activity and secretion, respectively, and the outcome of experimentally induced inhibition of protein processing (Golgi transport and N-linked glycosylation) was assessed. Reverse transcription quantitative real-time PCR (RT-qPCR) was applied to determine the relative expression of Type I Interferon stimulated genes (ISGs), IFIT3 and IRF7. Results: In addition to abrogating catalytic activity, the L351Q variant impaired secretion of L351Q ADA2 resulting in an intracellular accumulation of L351Q ADA2 protein that was not observed in cells expressing wild-type ADA2 or other ADA2 protein variants. Retention of L351Q ADA2 was not attributable to impaired glycosylation on neighboring asparagine residues and did not impact cell growth or integrity. Constitutive expression of Type I ISGs IFIT3 and IRF7 was observed in cells expressing L351Q ADA2. Conclusions: The impaired secretion of L351Q ADA2 may be an important factor leading to the severe phenotype observed in patients with this variant further emphasizing the importance of assessing impacts beyond catalytic activity when evaluating genotype-phenotype relationships in DADA2.

Differential tractography as a dynamic imaging biomarker: A methodological pilot study for Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Due to its diverse manifestations, the scientific community has long recognized the need for sensitive, objective, individualized, and dynamic disease assessment tools. We examined the feasibility of Differential Tractography as a biomarker to evaluate correlation of symptom severity and of HD progression at the individual level. Differential tractography is a novel tractography modality that maps pathways with axonal injury characterized by a decrease of anisotropic diffusion pattern. We recruited sixteen patients scanned at 0-, 6-, and 12-month intervals by diffusion MRI scans for differential tractography assessment and correlated its volumetric findings with the Unified Huntington's Disease Rating Scale (UHDRS). Deterministic fiber tracking algorithm was applied. Longitudinal data was modeled using the generalized estimating equation (GEE) model and correlated with UHDRS scores, in addition to Spearman correlation for cross-sectional data. Our results show that volumes of affected pathways revealed by differential tractography significantly correlated with UHDRS scores in longitudinal data (p-value < 0.001), and chronological changes in differential tractography also correlated with the changes in UHDRS (p-value < 0.001). This technique opens new clinical avenues as a clinical translational tool to evaluate presymptomatic and symptomatic gene positive individuals. Our results provide support that differential tractography has the potential to be used as a dynamic imaging biomarker to assess at the individual level in a non-invasive manner, disease progression in HD. Critically important, differential tractography proves to be a quantitative tool for following degeneration in presymptomatic patients, with potential applications in clinical trials.

Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study.

OBJECTIVES: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes. METHODS: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids. RESULTS: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes. CONCLUSIONS: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.