Clinical features, functional consequences, and rescue pharmacology of missense GRID1 and GRID2 human variants.

GRID1 and GRID2 encode the enigmatic GluD1 and GluD2 proteins, which form tetrameric receptors that play important roles in synapse organization and development of the central nervous system. Variation in these genes has been implicated in neurodevelopmental phenotypes. We evaluated GRID1 and GRID2 human variants from the literature, ClinVar, and clinical laboratories and found that many of these variants reside in intolerant domains, including the amino terminal domain of both GRID1 and GRID2. Other conserved regions, such as the M3 transmembrane domain, show different intolerance between GRID1 and GRID2. We introduced these variants into GluD1 and GluD2 cDNA and performed electrophysiological and biochemical assays to investigate the mechanisms of dysfunction of GRID1/2 variants. One variant in the GRID1 distal amino terminal domain resides at a position predicted to interact with Cbln2/Cbln4, and the variant disrupts complex formation between GluD1 and Cbln2, which could perturb its role in synapse organization. We also discovered that, like the lurcher mutation (GluD2-A654T), other rare variants in the GRID2 M3 domain create constitutively active receptors that share similar pathogenic phenotypes. We also found that the SCHEMA schizophrenia M3 variant GluD1-A650T produced constitutively active receptors. We tested a variety of compounds for their ability to inhibit constitutive currents of GluD receptor variants and found that pentamidine potently inhibited GluD2-T649A constitutive channels (IC50 50 nM). These results identify regions of intolerance to variation in the GRID genes, illustrate the functional consequences of GRID1 and GRID2 variants, and suggest how these receptors function normally and in disease.

Evaluation of early treatment with intravenous idursulfase and intrathecal idursulfase-IT on cognitive function in siblings with neuronopathic mucopolysaccharidosis II.

Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, heterogeneous lysosomal storage disease. Approximately two-thirds of patients develop cognitive impairment, which is difficult to assess in clinical trials, partly owing to the variable nature of cognitive impairment. Analyzing data from siblings can help to minimize this heterogeneity. We report analyses of cognitive function from siblings with MPS II enrolled in clinical trials: a natural history study (NCT01822184), a randomized, open-label, phase 2/3 study of intravenous (IV) idursulfase with or without intrathecal idursulfase (idursulfase-IT; NCT02055118), and its extension (NCT2412787). Cognitive function was assessed using Differential Abilities Scales, Second Edition General Conceptual Ability (DAS-II GCA) scores; Bayley Scales of Infant and Toddler Development, Third Edition; and Vineland Adaptive Behavior Scales, Second Edition Adaptive Behavior Composite (VABS-II ABC). Seven sets of siblings (six pairs and one set of three) were included. All patients received IV idursulfase and 10 received subsequent idursulfase-IT. Younger siblings initiated IV idursulfase at an earlier age than their older sibling(s) in six of the sets; the younger sibling started treatment before 1 year of age in three sets. Monthly idursulfase-IT was generally associated with a stabilization of cognitive function: DAS-II GCA and VABS-II ABC scores were higher at age-matched assessments in the majority of those who either received idursulfase-IT earlier than their sibling or who received idursulfase-IT versus no idursulfase-IT. These data suggest that early initiation of intrathecal enzyme replacement therapy may stabilize or slow cognitive decline in some patients with neuronopathic MPS II.

Genetic and metabolic investigations for neurodevelopmental disorders: position statement of the Canadian College of Medical Geneticists (CCMG).

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist. METHODS OF STATEMENT DEVELOPMENT: A multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022. RESULTS AND CONCLUSIONS: Chromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.

Family-centred care interventions for children with chronic conditions: A scoping review.

INTRODUCTION: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions. METHODS: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care. RESULTS: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). CONCLUSION: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population. PATIENT OR PUBLIC CONTRIBUTION: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination.

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Ethical and practical considerations related to data sharing when collecting patient-reported outcomes in care-based child health research.

PURPOSE: The collection and use of patient reported outcomes (PROs) in care-based child health research raises challenging ethical and logistical questions. This paper offers an analysis of two questions related to PROs in child health research: (1) Is it ethically obligatory, desirable or preferable to share PRO data collected for research with children, families, and health care providers? And if so, (2) What are the characteristics of a model best suited to guide the collection, monitoring, and sharing of these data? METHODS: A multidisciplinary team of researchers, providers, patient and family partners, and ethicists examined the literature and identified a need for focus on PRO sharing in pediatric care-based research. We constructed and analyzed three models for managing pediatric PRO data in care-based research, drawing on ethical principles, logistics, and opportunities to engage with children and families. RESULTS: We argue that it is preferable to share pediatric PRO data with providers, but to manage expectations and balance the risks and benefits of research, this requires a justifiable data sharing model. We argue that a successful PRO data sharing model will allow children and families to have access to and control over their own PRO data and be engaged in decision-making around how PROs collected for research may be integrated into care, but require support from providers. CONCLUSION: We propose a PRO data sharing model that can be used across diverse research settings and contributes to improved transparency, communication, and patient-centered care and research.

Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Ultrasound findings of finger, wrist and knee joints in Mucopolysaccharidosis Type I.

INTRODUCTION: Musculoskeletal findings in MPS can progress after enzyme replacement. Our aim was to examine synovial recesses, tendons, retinacula and pulleys using ultrasonography for structural and inflammatory changes. MATERIAL AND METHODS: The wrist, metacarpophalangeal (MCP), proximal and distal interphalangeal (PIP and DIP) joints, the finger flexor tendons and the knee including entheses of quadriceps and patella tendons were assessed clinically. Ultrasonography of the various synovial recesses of the wrist as well as the extensor retinaculum, carpal tunnel, MCP, PIP and DIP joints of the second finger, extensor and flexor tendons, A1-5 pulleys and the knee joint including relevant entheses followed. Significance of differences between patient values and available normative data were assessed using t-tests. RESULTS: Ultrasonography showed significant abnormal intraarticular material in the wrist without a clear distribution to synovial recesses and without effusions. Doppler signals were found in a perisynovial distribution and not intrasynovial as expected in in inflammatory arthritis. Findings were similar in the knee but not the fingers. Flexor and extensor tendons were also mostly normal in their structure but significant thickening of retinaculae and the flexor tendon pulleys was seen (p<0.0001 compared to normal). CONCLUSION: MPS I patients showed intraarticular deposition of abnormal material in the wrist and knee but not in the finger joints where significant thickening of retinaculae/pulleys controlling tendon position was dominant. No ultrasound findings of inflammatory pathology were demonstrated but rather a secondary reaction to abnormal deposition and direct damage of GAG.

Glycerol phenylbutyrate efficacy and safety from an open label study in pediatric patients under 2 months of age with urea cycle disorders.

BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.