Early motor, cognitive, language, behavioural and social emotional development in infants and young boys with Duchenne Muscular Dystrophy- A systematic review.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene. Deficiency of the dystrophin protein causes not only motor, but also cognitive, language, behavioural and social emotional problems. This is the first systematic review investigating five early developmental domains in boys with DMD between 0 and 6 years old. Interactions between different domains and links with mutation types and sites were explored. A systematic search was performed in PubMed, Web of Science and Scopus. An adapted version of the Scottish Intercollegiate Guidelines Network (SIGN) Checklists for case-control and cohort studies was used to evaluate quality. Fifty-five studies of high or acceptable quality were included. One was an RCT of level 1b; 50 were cohort studies of level 2b; and four were an aggregation of case-control and cohort studies receiving levels 2b and 3b. We found that young boys with DMD experienced problems in all five developmental domains, with significant interactions between these. Several studies also showed relationships between mutation sites and outcomes. We conclude that DMD is not only characterised by motor problems but by a more global developmental delay with a large variability between boys. Our results emphasise the need for harmonisation in evaluation and follow-up of young boys with DMD. More high-quality research is needed on the different early developmental domains in young DMD to facilitate early detection of difficulties and identification of associated early intervention strategies.

Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022. METHODS: Data were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis. RESULTS: We identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype. CONCLUSIONS: This is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.

Patients' Perceptions of Nusinersen Effects According to Their Responder Status.

Background and Objective: Patients with spinal muscular atrophy (SMA) treated with a disease-modifying therapy (DMT) are often classified as responders or non-responders based on the attainment of a specific improvement threshold on validated functional scales. This categorization may significantly impact treatment reimbursement in some countries. The aim of this research is to evaluate the perception of treatments and their benefit by patients considered as responders or non-responders. Methods: In this non-commercial multicenter study, 99 post-symptomatically treated SMA type I-III patients with a median age of 11.2 (0.39-57.4) years at treatment initiation were stratified into three groups based on their treatment outcomes, i.e., those exhibiting clinically significant improvement (N = 41), those with non-clinically significant improvement (N = 18), or those showing no improvement (N = 40). Fifteen months after treatment, the initiation patients or patients' caregivers were assessed using a patient-rated scoring system based on the Patient Global Impression of Change (PGIC) scale, comprising 22 questions targeting important aspects and tasks in the daily life of patients with SMA. Results: We found no statistical difference in the patient perception of treatment benefits in 17 out of 22 domains across patient groups. Conclusions: Our results suggest that functional motor scales do not recapitulate patients' and patients' caregivers' experience of the effect of nusinersen treatment in SMA.

2024 update: European consensus statement on gene therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.

Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties: Insights from Clinical Practice.

Background: Emerging evidence underscores the high prevalence of neurobehavioral difficulties like ADHD, ASD and OCD, in patients with Duchenne muscular dystrophy (DMD). The substantial impact of these complex behavioral challenges in addition to motor function decline on the well-being of affected individuals and their families is increasingly evident. However, a uniform approach for effective screening, assessment and management of the neurobehavioral symptoms remains elusive. Objective: We explored strategies used by healthcare professionals with clinical expertise in DMD to address neurobehavioral symptoms, in order to uncover diverse practices and to identify potential directions for clinical approaches in managing DMD neurobehavioral symptoms. Methods and results: Twenty-eight respondents from 16 different countries completed an online survey. Only 35% of the centers systematically screened for neurobehavioral difficulties in their DMD population. Predominant screening methods included history taking and clinical observation. Common neurobehavioral difficulties encompassed learning challenges, dependency from adults, anxiety, concentration difficulties, and social deficits. The participating centers frequently employed parental counseling and liaison with psychosocial healthcare professionals for psychosocial intervention. Conclusion: This study underscores the complex behavioral landscape in DMD, highlighting the need for validated screening, assessment and management strategies and collaborative efforts in implementing these. We advocate for international consensus recommendations for screening, assessment and management of neurobehavioral difficulties in DMD to enhance patient care and communication across healthcare settings.

Development and Pilot Validation of the DuMAND Checklist to Screen for Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND).

Background: Patients with Duchenne muscular dystrophy (DMD) face a higher risk of neurobehavioral problems, yet an international consensus on screening, assessing, and managing these difficulties is lacking. Objective: This report introduces the term Duchenne Muscular Dystrophy-Associated Neurobehavioral Difficulties (DuMAND) to comprehensively cover the spectrum of neurobehavioral issues in DMD patients, including behavior, psychiatric disorders, and various cognitive, academic, and psychosocial deficits. To facilitate screening, the DuMAND Checklist, a 43-item tool with five subscales, was developed. Methods and results: DuMAND categories were derived through literature review, parent (48 mothers and 37 fathers), and expert (n = 28) input and feedback. The DuMAND Checklist subscales were developed iteratively, incorporating item selection, expert panel (n = 10) assessment for face validity, comprehensiveness, and a pilot validation study in a DMD sample (n = 20). DuMAND encompasses five categories: cognition and learning, social responsiveness, emotion regulation, externalizing behavior, and eating and sleeping. Preliminary validation of the DuMAND Checklist indicates acceptable-to-excellent internal consistency and construct validity. Conclusion: By introducing the DuMAND concept, this study seeks to inspire a consensus approach for screening, assessing, and managing neurobehavioral issues in DMD. Incorporating screening, using the DuMAND Checklist, in addition to medical follow-up will facilitate early intervention, addressing a critical gap in identification of neurobehavioral disorders in DMD. Future research is needed to further evaluate psychometric properties of the DuMAND Checklist and investigate the natural course of DuMAND.

Gait classification for growing children with Duchenne muscular dystrophy.

Classifying gait patterns into homogeneous groups could enhance communication among healthcare providers, clinical decision making and clinical trial designs in boys with Duchenne muscular dystrophy (DMD). Sutherland's classification has been developed 40 years ago. Ever since, the state-of-the-art medical care has improved and boys with DMD are now longer ambulatory. Therefore, the gait classification requires an update. The overall aim was to develop an up-to-date, valid DMD gait classification. A total of 137 three-dimensional gait analysis sessions were collected in 30 boys with DMD, aged 4.6-17 years. Three classes were distinguished, which only partly aligned with increasing severity of gait deviations. Apart from the mildly affected pattern, two more severely affected gait patterns were found, namely the tiptoeing pattern and the flexion pattern with distinct anterior pelvic tilt and posterior trunk leaning, which showed most severe deviations at the ankle or at the proximal segments/joints, respectively. The agreement between Sutherland's and the current classification was low, suggesting that gait pathology with the current state-of-the-art medical care has changed. However, overlap between classes, especially between the two more affected classes, highlights the complexity of the continuous gait changes. Therefore, caution is required when classifying individual boys with DMD into classes.

Lessons for future clinical trials in adults with Becker muscular dystrophy: Disease progression detected by muscle magnetic resonance imaging, clinical and patient-reported outcome measures.

BACKGROUND AND PURPOSE: Because Becker muscular dystrophy (BMD) is a heterogeneous disease and only few studies have evaluated adult patients, it is currently still unclear which outcome measures should be used in future clinical trials. METHODS: Muscle magnetic resonance imaging, patient-reported outcome measures and a wide range of clinical outcome measures, including motor function, muscle strength and timed-function tests, were evaluated in 21 adults with BMD at baseline and at 9 and 18 months of follow-up. RESULTS: Proton density fat fraction increased significantly in 10/17 thigh muscles after 9 months, and in all thigh and lower leg muscles after 18 months. The 32-item Motor Function Measurement (MFM-32) scale (-1.3%, p = 0.017), North Star Ambulatory Assessment (-1.3 points, p = 0.010) and patient-reported activity limitations scale (-0.3 logits, p = 0.018) deteriorated significantly after 9 months. The 6-min walk distance (-28.7 m, p = 0.042), 10-m walking test (-0.1 m/s, p = 0.032), time to climb four stairs test (-0.03 m/s, p = 0.028) and Biodex peak torque measurements of quadriceps (-4.6 N m, p = 0.014) and hamstrings (-5.0 N m, p = 0.019) additionally deteriorated significantly after 18 months. At this timepoint, domain 1 of the MFM-32 was the only clinical outcome measure with a large sensitivity to change (standardized response mean 1.15). DISCUSSION: It is concluded that proton density fat fraction imaging of entire thigh muscles is a sensitive outcome measure to track progressive muscle fat replacement in patients with BMD, already after 9 months of follow-up. Finally, significant changes are reported in a wide range of clinical and patient-reported outcome measures, of which the MFM-32 appeared to be the most sensitive to change in adults with BMD.

Respiratory morbidity in patients with spinal muscular atrophy-a changing world in the light of disease-modifying therapies.

Respiratory complications are common in spinal muscular atrophy (SMA) and significantly contribute to morbidity and mortality in these patients. Generalized respiratory and bulbar muscle weakness translates into diverse and complex clinical consequences necessitating strict follow-up and specialized care. The natural history of SMA has evolved drastically in recent years as a result of the introduction of novel, disease-modifying therapies. While the impact of these therapies on motor function is well described in literature, its consequence for respiratory management has not been extensively studied. In this review we aim to provide a comprehensive overview of the respiratory morbidities, their follow-up, management, and the impact of novel therapies in SMA.

Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

The impact of clinical trial participation on quality of life and psychosocial well-being in children with Duchenne muscular dystrophy and their parents.

Clinical trials provide Duchenne muscular dystrophy (DMD) patients access to medication. Nevertheless, such involvement can impose certain burdens, as the protocol may entail strict adherence and additional demands. This study assessed the psychosocial functioning and quality of life in boys with DMD and their parents who participate in clinical trials. DMD families participating in clinical trials (n = 25) and families with DMD patients not involved in clinical trials (N = 18) were included. Questionnaires assessing psychosocial well-being and quality of life were completed by the participants and their parents. MANOVAs were employed to compare outcomes between groups. The results showed that mothers in the clinical trial group experienced significantly higher scores of somatic complaints. Fathers in the clinical trial group reported significantly fewer psychological issues compared to fathers from the other group. DMD patients participating in clinical trials reported a better overall and emotional quality of life compared to them not involved in clinical trials. This study suggests that clinical trial participation may have positive effects on quality of life and psychosocial outcomes. It highlights the importance of providing support and counseling throughout the clinical trial decision making process to minimize potential burden for both eligible and ineligible patients.

Comparison of two corticosteroid regimens on brain volumetrics in patients with Duchenne muscular dystrophy.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is a neuromuscular disorder in which many patients also have neurobehavioral problems. Corticosteroids, the primary pharmacological treatment for DMD, have been shown to affect brain morphology in other conditions, but data in DMD are lacking. This study aimed to investigate the impact of two corticosteroid regimens on brain volumetrics in DMD using magnetic resonance imaging (MRI). METHODS: In a cross-sectional, two-center study, T1-weighted MRI scans were obtained from three age-matched groups (9-18 years): DMD patients treated daily with deflazacort (DMDd, n = 20, scan site: Leuven), DMD patients treated intermittently with prednisone (DMDi, n = 20, scan site: Leiden), and healthy controls (n = 40, both scan sites). FSL was used to perform voxel-based morphometry analyses and to calculate intracranial, total brain, gray matter, white matter, and cerebrospinal fluid volumes. A MANCOVA was employed to compare global volumetrics between groups, with site as covariate. RESULTS: Both patient groups displayed regional differences in gray matter volumes compared to the control group. The DMDd group showed a wider extent of brain regions affected and a greater difference overall. This was substantiated by the global volume quantification: the DMDd group, but not the DMDi group, showed significant differences in gray matter, white matter, and cerebrospinal fluid volumes compared to the control group, after correction for intracranial volume. INTERPRETATION: Volumetric differences in the brain are considered part of the DMD phenotype. This study suggests an additional impact of corticosteroid treatment showing a contrast between pronounced alterations seen in patients receiving daily corticosteroid treatment and more subtle differences in those treated intermittently.

International consensus recommendations for the identification and treatment of tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).

BACKGROUND: Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and under-treated yet associated with a profound burden of disease. The contemporary evidence base for the identification and treatment of TAND is much more limited and, to date, consensus recommendations for the diagnosis and management of TAND have also been limited and non-specific. METHODS: The TANDem project was launched with an international, interdisciplinary, and participatory consortium of 24 individuals, including TSC family representatives, from all World Health Organization (WHO) regions but one. One of the aims of the TANDem project was to generate consensus recommendations for the identification and treatment of TAND. At the time of this project, no internationally adopted standard methodology and methodological checklists existed for the generation of clinical practice recommendations. We therefore developed our own systematic procedure for evidence review and consensus-building to generate evidence-informed consensus recommendations of relevance to the global TSC community. RESULTS: At the heart of the consensus recommendations are ten core principles surrounded by cluster-specific recommendations for each of the seven natural TAND clusters identified in the literature (autism-like, dysregulated behavior, eat/sleep, mood/anxiety, neuropsychological, overactive/impulsive, and scholastic) and a set of wraparound psychosocial cluster recommendations. The overarching recommendation is to "screen" for TAND at least annually, to "act" using appropriate next steps for evaluation and treatment, and to "repeat" the process to ensure early identification and early intervention with the most appropriate biological, psychological, and social evidence-informed approaches to support individuals with TSC and their families. CONCLUSIONS: The consensus recommendations should provide a systematic framework to approach the identification and treatment of TAND for health, educational, social care teams and families who live with TSC. To ensure global dissemination and implementation of these recommendations, partnerships with the international TSC community will be important. One of these steps will include the generation of a "TAND toolkit" of "what to seek" and "what to do" when difficulties are identified in TAND clusters.

Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ).

BACKGROUND: Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are often present but underidentified and undertreated in individuals with tuberous sclerosis complex (TSC). The clinician-completed TAND-Lifetime Checklist (TAND-L) was developed to address this identification and treatment gap. Stakeholder engagement identified the need for a TAND Checklist that can (1) be completed by caregivers or individuals with TSC and (2) quantify TAND difficulties. The aim of this study was to develop a self-report quantified TAND Checklist (TAND-SQ) and conduct feasibility and acceptability testing. METHODS: This aim was addressed in three phases: (1) development of the TAND-SQ Checklist, (2) feasibility and acceptability testing of the "near-final" TAND-SQ Checklist, and (3) preparation of the final TAND-SQ Checklist. Participants included 23 technical experts from the TAND consortium in all phases and 58 lived experts (caregivers and individuals with TSC) in phase 2. All participants completed a TAND-SQ Checklist and a checklist feedback form. RESULTS: Phase 1 additions to the TAND-SQ, when compared with the TAND-L, included four new items and a quantification rating. Phase 2 showed high ratings for the "near-final" TAND-SQ Checklist on comprehensiveness, clarity, ease of use, and overall acceptability. In phase 3, questions on strengths, strategies, and a TAND Cluster Profile were added. CONCLUSION: The TAND-SQ Checklist is presented here for use by individuals with TSC and their caregivers. The next steps as part of the TANDem project include internal and external validation of the checklist and linking of TAND Cluster Profiles generated from the checklist to evidence-informed consensus recommendations within a smartphone application.

Psychopharmaceutical treatment for neurobehavioral problems in Duchenne muscular dystrophy: a descriptive study using real-world data.

Patients with Duchenne muscular dystrophy (DMD) are at risk to develop neurobehavioral problems. Evidence on how to treat these difficulties is scarce. This descriptive study reports the clinical experience with psychopharmaceutical treatment in 52 patients with DMD. Electronic patient files were searched for patients with DMD that had been treated with psychopharmaceuticals between 2008 and 2022. Information about neurobehavioral symptoms, type of medication, side effects, and behavioral changes were collected. Two independent clinicians used the clinical global impression scale (CGI) to assess severity of the neurobehavioral problems before and the change in symptoms after treatment. Descriptive statistics were used. Our results include 52 males with DMD (mean age 11 years) treated with psychopharmaceuticals of which 55.8% had four or more comorbid neurobehavioral symptoms. The clinical condition was much improved on the GCI in 54.2% treated with methylphenidate, in 38.9% of the patients treated with fluoxetine, and in 22.2% treated with risperidone. Minimal effects and side effects were also reported. In conclusion, patients with DMD may experience severe neurobehavioral symptoms interfering with learning and/or development. Treatment with psychopharmaceuticals can improve these neurobehavioral symptoms, but further research is needed to gain better insights in psychopharmaceutical treatment in patients with DMD.

The Dilemma of Choice for Duchenne Patients Eligible for Exon 51 Skipping The European Experience.

Antisense oligonucleotide (ASO) mediated exon skipping aims to reframe dystrophin transcripts for patients with Duchenne muscular dystrophy (DMD). Currently 4 ASOs have been approved by the Food and Drug Administration targeting exon 45, 51 and 53 based on low level dystrophin restoration. Additional studies to confirm functional effects are ongoing. Furthermore, efforts are ongoing to increase muscle specific delivery of ASOs. Consequently, there are 5 clinical trials ongoing or planned for exon 51 skipping ASOs in Europe. While exon 51 skipping applies to the largest group of patients, DMD expert centers do not have sufficient numbers of patients or capacity to run all these trials in parallel. Even at a national level numbers may be too scarce. At the same time, some families now face the choice between participation in different clinical trials of exon 51 skipping, sometimes in addition to the choice of participating in a micro-dystrophin gene therapy trial. In this opinion paper, we outline the challenges, compare the different exon 51 skipping trials, and outline how different European centers and countries try to cope with running multiple trials in parallel for a small group of eligible patients.

Risdiplam in types 2 and 3 spinal muscular atrophy: A randomised, placebo-controlled, dose-finding trial followed by 24 months of treatment.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is caused by reduced levels of survival of motor neuron (SMN) protein due to deletions and/or mutations in the SMN1 gene. Risdiplam is an orally administered molecule that modifies SMN2 pre-mRNA splicing to increase functional SMN protein. METHODS: SUNFISH Part 1 was a dose-finding study conducted in 51 individuals with types 2 and 3 SMA aged 2-25 years. A dose-escalation method was used to identify the appropriate dose for the subsequent pivotal Part 2. Individuals were randomized (2:1) to risdiplam or placebo at escalating dose levels for a minimum 12-week, double-blind, placebo-controlled period, followed by treatment for 24 months. The dose selection for Part 2 was based on safety, tolerability, pharmacokinetic, and pharmacodynamic data. Exploratory efficacy was also measured. RESULTS: There was no difference in safety findings for all assessed dose levels. A dose-dependent increase in blood SMN protein was observed; a median twofold increase was obtained within 4 weeks of treatment initiation at the highest dose level. The increase in SMN protein was sustained over 24 months of treatment. Exploratory efficacy showed improvement or stabilization in motor function. The pivotal dose selected for Part 2 was 5 mg for patients with a body weight ≥20 kg or 0.25 mg/kg for patients with a body weight <20 kg. CONCLUSIONS: SUNFISH Part 1 demonstrated a twofold increase in SMN protein after treatment with risdiplam. The observed safety profile supported the initiation of the pivotal Part 2 study. The long-term efficacy and safety of risdiplam are being assessed with ongoing treatment.

Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects.

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca2+) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), a homo- or heterotetramer of the IP3R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP3R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP3R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca2+ signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca2+ signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP3R3 in IP3R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype-phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca2+ channels and immunodeficiency and identify IP3Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca2+-associated immunodeficiency from store-operated entry to impaired Ca2+ mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca2+ signaling.

Illness Perceptions and Illness Identity in Adolescents and Emerging Adults With Neuromuscular Disorders.

BACKGROUND: Neuromuscular disorders (NMD) are intrusive medical conditions with implications for psychosocial development. OBJECTIVES: This paper explores illness perceptions and illness identity dimensions of youth with NMD. First, we compare illness identity outcomes and illness perceptions of NMD patients with a comparison group of adolescents with type 1 diabetes mellitus (DM). Second, we report about the relationships between NMD-related variables and illness perceptions and illness identity. METHODS: Scores on the Brief Illness Perception Questionnaire and the Illness Identity Questionnaire were compared between a group of NMD patients (N = 59; 12-22 years) and an age- and gender-matched group of DM patients (N = 118). NMD-related variables included time since diagnosis, prognosis, wheelchair use, and physical limitations. RESULTS: Youth with NMD scored significantly higher on two of the four illness identity dimensions than youth with DM. NMD patients reported significantly less positive illness perceptions, experienced more physical symptoms, and had a lower score on understanding of their illness. Within the NMD group, wheelchair-users have a better understanding of their disease than those who are not wheelchair-bound. CONCLUSIONS: The present study is the first to investigate illness identity and illness perceptions in NMD. More research is needed to provide insight in the identity formation process of the growing group of adolescents with NMDs.