Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program.

BACKGROUND: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of ß-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII. METHODS: This disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022. RESULTS: As of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and - 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died. CONCLUSIONS: To date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Expedited Exome Reanalysis Following Deep Phenotyping and Muscle Biopsy in Suspected Mitochondrial Disorder.

BACKGROUND: Exome sequencing (ES) is a useful tool in diagnosing suspected mitochondrial disease but can miss pathogenic variants for several reasons. Additional testing, such as muscle biopsy or biochemical testing, can be helpful in exome-negative cases. METHODS: We report a patient who presented with repeated episodes of lactic acidosis and failure to thrive. RESULTS: ES and mitochondrial sequencing were initially negative but clinical suspicion for mitochondrial disease remained high. After muscle biopsy showed evidence of mitochondrial dysfunction, the ES was reanalyzed and revealed novel variants in AARS2. CONCLUSION: This case demonstrates the importance of muscle biopsy and biochemical testing in evaluating patients with a high suspicion of mitochondrial disease, even in the genomics era. Closed-loop communication between molecular genetics laboratories and clinical geneticists is an important step to help establish diagnosis in unsolved cases.

De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

Mucopolysaccharidosis type VII (Sly syndrome) - What do we know?

Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare, life-threatening, progressive disease caused by genetic mutations that affect lysosomal storage/function. MPS VII has an estimated prevalence of <1:1,000,000 and accounts for <3% of all MPS diagnoses. Given the rarity of MPS VII, comprehensive information on the disease is limited and we present a review of the current understanding. In MPS VII, intracellular glycosaminoglycans accumulate due to a deficiency in the lysosomal enzyme that is responsible for their degradation, ß-glucuronidase, which is encoded by the GUSB gene. MPS VII has a heterogeneous presentation. Features can manifest across multiple systems and can vary in severity, age of onset and progression. The single most distinguishing clinical feature of MPS VII is non-immune hydrops fetalis (NIHF), which presents during pregnancy. MPS VII usually presents within one month of life and become more prominent at 3 to 4 years of age; key features are skeletal deformities, hepatosplenomegaly, coarse facies, and cognitive impairment, although phenotypic variation is a hallmark. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy with vestronidase alfa. Care should be individualized for each patient. Development of consensus guidelines for MPS VII management and treatment is needed, as consolidation of expert knowledge and experience (for example, through the MPS VII Disease Monitoring Program) may provide a significant positive impact to patients.

Implementation of a tier system for IVIG indications to address IVIG shortage at a tertiary care pediatric medical center.

BACKGROUND: Drug shortages are a common issue that healthcare systems face and can result in adverse health outcomes for patients requiring inferior alternate treatment. The United States recently experienced a national drug shortage of intravenous immunoglobulin (IVIG). Several reported strategies to address the IVIG and other drug shortages have been proposed; however, there is a lack of evidence-based methods for protocol development and implementation. OBJECTIVE: To evaluate the efficacy of introducing a multidisciplinary task force and tier system of indications and to minimize adverse effects during a shortage of IVIG. METHODS: Faculty members across disciplines with expertise in IVIG use were invited to participate in a task force to address the shortage and ensure adequate supply for emergent indications. A tier system of IVIG indications was established according to the severity of diagnosis, urgency of indication, and quality of supporting evidence. Based on inventory, indications in selected tiers were auto-approved. Orders that could not be automatically approved were escalated for task force review. RESULTS: Overall, there were 342 distinct requests for IVIG during the study period (August 1, 2019 to December 31, 2019). All Tier 1 indications were approved. Of all requests, only 2.6% (9) of requests were denied, none of which resulted in adverse effects based on retrospective chart review. Seven patients who regularly receive IVIG had possible adverse effects due to dose reduction or spacing of treatment; however, each complication was multifactorial and not attributed to the shortage or tier system implementation alone. CONCLUSION: Implementation of a multidisciplinary task force and tier system to appropriately triage high-priority indications for limited pharmaceutical agents should be considered in health institutions faced with a drug shortage.

Assessing the feasibility of an intervention for adolescents and parents transitioning out of paediatric eating disorder services: A mixed methods study.

OBJECTIVE: To assess the feasibility of a new intervention designed to support adolescents and parents in the transition from paediatric eating disorder (ED) treatment to adult mental health services. METHOD: Pre-transition adolescents with EDs, and their parents, were invited to complete up to five transition intervention components over 3 months. A mixed methods design was used to assess intervention feasibility, comprised of acceptability and preliminary effectiveness. A single-arm pre-post design was used to collect and analyse quantitative survey and feasibility data. Individual qualitative interviews and written reflections were collected and analysed using content analysis. RESULTS: This study yielded a 33% (10/31) recruitment rate and 68% (13/19) retention rate. On average, participants completed 75% of the expected components in under 3 months, with varied completion of each expected intervention component (40%-100%). Participants found the intervention convenient and helpful. Parents reported a significant decrease in guilt (Z = -2.02, p = 0.04, d = -0.83). By 1-month post-transition, three adolescents transitioned to interim supports and none started specialist adult treatment. CONCLUSIONS: Although this transition intervention did not demonstrate adequate feasibility, its acceptability and effectiveness should be evaluated after an update based on participant feedback. Other solutions to bridge the transition gap for adolescents with EDs should continue to be identified. CLINICAL TRIAL REGISTRATION NUMBER: NCT04888273.

Opportunities and challenges in capturing severe vaping-related injuries among Canadian children and youth.

Although the long-term harms associated with vaping remain largely unknown, there have been numerous accounts of acute vaping-related injuries in the paediatric population. The study of vaping-related injuries is an important yet challenging undertaking, complicated by a lack of appropriate reporting mechanisms and the absence of consensus on definitions and diagnostic codes. We discuss the results of a 12-month national cross-sectional study from the Canadian Paediatric Surveillance Program conducted in 2021-2022 and situate these results within the broader context of other Canadian surveillance and reporting mechanisms. Fewer than five cases of vaping-associated injuries were reported, contrasting with previous surveys which had revealed much higher case numbers. Hypotheses for the low case numbers include decreased exposure to vaping in the context of COVID-19, changes in vaping products, increases in public awareness of vaping-related harms, as well as recent modifications in policies related to vaping product marketing and sales. There is a great need for a multi-pronged surveillance approach leveraging multiple data sources, including self-reported provider and consumer data, as well as administrative data to help inform clinicians and policymakers on how to prevent vaping-associated injuries among youth.

De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities.

The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.

Impending Transition From Pediatric to Adult Health Services: A Qualitative Study of the Experiences of Adolescents With Eating Disorders and Their Caregivers.

Background: There is a dearth of research that identifies pediatric to adult health care transition practices that yield positive outcomes for young people with eating disorders (EDs). Further, adolescent and caregiver perspectives are poorly understood and underrepresented in the literature. The purpose of this study, focused on the impending transition from pediatric to adult health services, was twofold: (a) to identify adolescent and caregiver perspectives of barriers and facilitators of a successful transition for adolescents with EDs; and (b) to understand adolescent and caregiver suggestions of interventions for a successful transition. Design/Method: We recruited five adolescents with EDs who were about to be transferred out of pediatric care as well as their caregivers. We conducted a qualitative study in accordance with the principles of interpretive description. Through conducting semi-structured, in-depth interviews with adolescents and caregivers, we investigated their knowledge about health system transitions and anticipated experiences. We identified participants' perceptions of barriers and facilitators regarding a successful transition, as well as their recommendations to improve the transfer of care. Results: Participants possessed a limited understanding of transition processes despite the fact that they were about to be transferred to adult care. From our analyses, the following themes were identified as barriers during the transition process: re-explaining information to adult healthcare providers, lack of professional support while waiting for uptake into the adult health system, and late timing of transition of care discussions. Both adolescents and caregivers expressed that involvement of parents and the pediatric healthcare team helped to facilitate a successful transfer of care. In addition, participants expressed that the implementation of a Transition Coordinator and Transition Passport would be helpful in facilitating a seamless transfer between systems of care. Discussion: These findings demonstrate a significant gap in the system and highlight the importance of developing interventions that facilitate a successful transition. The themes that emerged from this study can inform the development of interventions to facilitate a coordinated transition from pediatric to adult health services for adolescents with EDs.

Multimodal therapy for rigid, persistent avoidant/restrictive food intake disorder (ARFID) since infancy: A case report.

Avoidant/restrictive food intake disorder (ARFID) is a feeding and eating disorder that results in nutritional inadequacies, weight loss, and/or dependence on enteral feeds, and for which three clinical subtypes have been described. We present a unique case of an 11-year-old boy with rigid ARFID since infancy and features of all three ARFID subtypes. The patient presented with a life-long history of sensory aversion, limited intake and phobia of vomiting resulting in restriction to a single food item (yogurt) for more than 5 years. He presented with severe iron-deficiency anaemia, and deficiencies of vitamins A, C, D, E and zinc. We employed a multimodal therapeutic approach that incorporated elements of cognitive-behavioural therapy (CBT), family-based therapy (FBT) and pharmacological management with an antidepressant medication (sertraline) and an atypical antipsychotic agent (olanzapine). Over the course of a 7-week admission, our approach assisted the patient in successful weight restoration and incorporation of at least three new food items into his daily diet. While there are currently no first-line recommendations for ARFID management, our study lends support to the efficacy of CBT, FBT and pharmacological management for ARFID patients, including complex cases with multiple subtype features. Further research is needed to strengthen ARFID clinical guidelines.

Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations.

Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late-onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC-based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.

ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy.

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N-acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), ClinicalTrials.gov identifier NCT03233841, in combination with an up-to-date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty-five patients representing the known clinical spectrum of Farber disease (living patients aged 1-28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease-causing variants.

Recent Advances in Systems and Network Medicine: Meeting Report from the First International Conference in Systems and Network Medicine.

The First International Conference in Systems and Network Medicine gathered together 200 global thought leaders, scientists, clinicians, academicians, industry and government experts, medical and graduate students, postdoctoral scholars and policymakers. Held at Georgetown University Conference Center in Washington D.C. on September 11-13, 2019, the event featured a day of pre-conference lectures and hands-on bioinformatic computational workshops followed by two days of deep and diverse scientific talks, panel discussions with eminent thought leaders, and scientific poster presentations. Topics ranged from: Systems and Network Medicine in Clinical Practice; the role of -omics technologies in Health Care; the role of Education and Ethics in Clinical Practice, Systems Thinking, and Rare Diseases; and the role of Artificial Intelligence in Medicine. The conference served as a unique nexus for interdisciplinary discovery and dialogue and fostered formation of new insights and possibilities for health care systems advances.

Counselling adolescents and parents about cannabis: A primer for health professionals.

While cannabis use among adolescents is frequent in Canada, youth do recognize the potential harms, and increasingly expect knowledgeable health care providers to discuss substance use in everyday practice. This practice point provides sound, evidence-based tools to help health professionals address nonmedical (recreational) cannabis use and its related risks. After highlighting how to make the clinical setting a safe space for youth to talk about psychoactive substances, specific strategies for approaching cannabis use in effective, developmentally appropriate ways are described. Consistent with current literature, screening questionnaires to help structure discussion and identify adolescents who may benefit from more specialized interventions are recommended. Because one in six adolescents who experiments with cannabis goes on to misuse it, appraising their willingness to change risky behaviours is a key aspect of care, along with supportive goal-setting and helping families. Recommended resources for practitioners and parents are included.

Human GLB1 knockout cerebral organoids: A model system for testing AAV9-mediated GLB1 gene therapy for reducing GM1 ganglioside storage in GM1 gangliosidosis.

GM1 gangliosidosis is an autosomal recessive neurodegenerative disorder caused by the deficiency of lysosomal ß-galactosidase (ß-gal) and resulting in accumulation of GM1 ganglioside. The disease spectrum ranges from infantile to late onset and is uniformly fatal, with no effective therapy currently available. Although animal models have been useful for understanding disease pathogenesis and exploring therapeutic targets, no relevant human central nervous system (CNS) model system has been available to study its early pathogenic events or test therapies. To develop a model of human GM1 gangliosidosis in the CNS, we employed CRISPR/Cas9 genome editing to target GLB1 exons 2 and 6, common sites for mutations in patients, to create isogenic induced pluripotent stem (iPS) cell lines with lysosomal ß-gal deficiency. We screened for clones with <5% of parental cell line ß-gal enzyme activity and confirmed GLB1 knockout clones using DNA sequencing. We then generated GLB1 knockout cerebral organoids from one of these GLB1 knockout iPS cell clones. Analysis of GLB1 knockout organoids in culture revealed progressive accumulation of GM1 ganglioside. GLB1 knockout organoids microinjected with AAV9-GLB1 vector showed a significant increase in ß-gal activity and a significant reduction in GM1 ganglioside content compared with AAV9-GFP-injected organoids, demonstrating the efficacy of an AAV9 gene therapy-based approach in GM1 gangliosidosis. This proof-of-concept in a human cerebral organoid model completes the pre-clinical studies to advance to clinical trials using the AAV9-GLB1 vector.

How can transition to adult care be best orchestrated for adolescents with epilepsy?

Objective evidence is limited for the value of transition programs for youth with chronic illness moving from pediatric to adult care; however, such programs intuitively "make sense". We describe the strengths and weaknesses of a variety of transition programs from around the world for adolescents with epilepsy. Consequences of poorly organized transition beyond suboptimal seizure control may include an increased risk of sudden unexpected death in epilepsy (SUDEP), poor psychological and social outcome, and inadequate management of comorbidities. The content of transition programs for those with normal intelligence differs from those with intellectual disability, but both groups may benefit from an emphasis on sporting activities. Concerns that may interfere with optimal transition include lack of nursing or social work services, limited numbers of adult neurologists/epileptologists confident in the treatment of complex pediatric epilepsy problems, institutional financial support, and time constraints for pediatric and adult physicians who treat epilepsy and the provision of multidisciplinary care. Successful programs eventually need to rely on a several adult physicians, nurses, and other key healthcare providers and use novel approaches to complex care. More research is needed to document the value and effectiveness of transition programs for youth with epilepsy to persuade institutions and healthcare professionals to support these ventures.