Pediatric Neuromuscular Diseases Research Articles

494P Evaluation of transcriptome forward computational strategies to improve molecular diagnosis in rare pediatric neuromuscular disease

494P Evaluation of transcriptome forward computational strategies to improve molecular diagnosis in rare pediatric neuromuscular disease

Effects of a neuropsychosocial teleassistance intervention on social cognition and health-related quality of life of pediatric patients with neuromuscular diseases.

This study aimed to determine the effects of a neuropsychosocial teleassistance group-based intervention on improving social cognitive functioning and health-related quality of life (HRQoL) in pediatric neuromuscular diseases (NMD). Thirty-five pediatric patients with NMD were assigned to the neuropsychosocial intervention program (n = 20) or waiting list control condition (n = 15). The intervention group received an integrative approach that combines training in social cognition with cognitive behavioral therapy. All participants completed a neuropsychological and clinical assessment at baseline and follow-up, which included tests of social cognition, both for emotion recognition and theory of mind, and HRQoL. Repeated-measures multivariate analysis of covariance was used to determine the effects of the teleassistance program. Group × Time interactions revealed significant improvements in the intervention group as compared with the control group for different social cognition's indicators (AR NEPSY-II: p = .003, η2p = .24; TM NEPSY: p < .001, η2p = .35; Verbal task: p < .001, η2p = .35; Happé's Strange Stories: p = .049, η2p = .11) and HRQoL (Psychosocial health: p = .012, η2p = .18; Emotional functioning: p = .037, η2p = 0.13; Social functioning: p = .006, η2p = .21; Total: p = .013, η2p = .17), showing medium to large effects. Patients receiving the neuropsychosocial intervention showed improvements in their social cognition performance and psychosocial HRQoL, providing evidence about the positive effects of the program in pediatric patients with NMD. This should be considered in further research and interventions in this field.

Postural control in pediatric neuromuscular and neurological diseases

Postural control in pediatric neuromuscular and neurological diseases

ATS Core Curriculum 2022. Pediatric Pulmonary Medicine: Updates in pediatric neuromuscular disease.

The American Thoracic Society Core Curriculum updates clinicians annually in pediatric pulmonary disease. This is a concise review of the Pediatric Pulmonary Medicine Core Curriculum presented at the 2022 American Thoracic Society International Conference. Neuromuscular diseases (NMD) comprise a variety of conditions that commonly affect the respiratory system and cause significant morbidity including dysphagia, chronic respiratory failure, and sleep disordered breathing. Respiratory failure is the most common cause of mortality in this population. Substantial progress has been made in diagnosis, monitoring and treatment for NMD over the last decade. Pulmonary function testing (PFT) is utilized to objectively measure respiratory pump function and PFT milestones are utilized in NMD-specific pulmonary care guidelines. New disease modifying therapies are approved for the treatment of patients with Duchenne muscular dystrophy and spinal muscular atrophy (SMA), including the first ever approved systemic gene therapy, in the case of SMA. Despite extraordinary progress in the medical management of NMD, little is known regarding the respiratory implications and long-term outcomes for patients in the era of advanced therapeutics and precision medicine. The combination of technological and biomedical advancements has increased the complexity of the medical decision-making process for patients and families, thus emphasizing the importance of balancing respect for autonomy with the other foundational principles of medical ethics. This review features an overview of PFT, noninvasive ventilation strategies, novel and developing therapies, as well as the ethical considerations specific to the management of patients with pediatric NMD.

A half‐century check‐up for child neurology training

A half‐century check‐up for child neurology training

Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy.

Plastin 3 (PLS3) is an F-actin-bundling protein that has gained attention as a modifier of spinal muscular atrophy (SMA) pathology. SMA is a lethal pediatric neuromuscular disease caused by loss of or mutations in the Survival Motor Neuron 1 (SMN1) gene. Pathophysiological hallmarks are cellular maturation defects of motoneurons prior to degeneration. Despite the observed beneficial modifying effect of PLS3, the mechanism of how it supports F-actin-mediated cellular processes in motoneurons is not yet well understood. Our data reveal disturbed F-actin-dependent translocation of the Tropomyosin receptor kinase B (TrkB) to the cell surface of Smn-deficient motor axon terminals, resulting in reduced TrkB activation by its ligand brain-derived neurotrophic factor (BDNF). Improved actin dynamics by overexpression of hPLS3 restores membrane recruitment and activation of TrkB and enhances spontaneous calcium transients by increasing Cav2.1/2 "cluster-like" formations in SMA axon terminals. Thus, our study provides a novel role for PLS3 in supporting correct alignment of transmembrane proteins, a key mechanism for (moto)-neuronal development.

Hesitancy, reactogenicity and immunogenicity of the mRNA and whole-virus inactivated Covid-19 vaccines in pediatric neuromuscular diseases

ABSTRACT The mRNA-based BNT162b2 and inactivated whole-virus CoronaVac are two widely used COVID-19 vaccines that confer immune protection to healthy individuals. However, hesitancy toward COVID-19 vaccination appeared to be common for patients with neuromuscular diseases (NMDs) due to the paucity of data on the safety and efficacy in this high-risk patient population. Therefore, we examined the underlying factors associated with vaccine hesitancy across time for NMDs and assessed the reactogenicity and immunogenicity of these two vaccines. Patients aged 8–18 years with no cognitive delay were invited to complete surveys in January and April 2022. Patients aged 2–21 years were enrolled for COVID-19 vaccination between June 2021 and April 2022, and they recorded adverse reactions (ARs) for 7 days after vaccination. Peripheral blood was obtained before and within 49 days after vaccination to measure serological antibody responses compared to healthy children and adolescents. Forty-one patients completed vaccine hesitancy surveys for both timepoints, while 22 joined the reactogenicity and immunogenicity arm of the study. Two or more family members vaccinated against COVID-19 was positively associated with intention of vaccination (odds ratio 11.7, 95% CI 1.81–75.1, p = .010). Pain at the injection site, fatigue, and myalgia were the commonest ARs. Most ARs were mild (75.5%, n = 71/94). All 19 patients seroconverted against the wildtype SARS-CoV-2 after two doses of either vaccine, similar to 280 healthy counterparts. There was lower neutralization against the Omicron BA.1 variant. BNT162b2 and CoronaVac were safe and immunogenic for patients with NMDs, even in those on low-dose corticosteroids.

Mental health challenges and digital platform opportunities in patients and families affected by pediatric neuromuscular diseases - experiences from Switzerland.

Receiving the diagnosis of a severe disease may present a traumatic event for patients and their families. To cope with the related challenges, digital interventions can be combined with traditional psychological support to help meet respective needs. We aimed to 1) discuss the most common consequences and challenges for resilience in Neuro Muscular Disease patients and family members and 2) elicit practical needs, concerns, and opportunities for digital platform use. We draw from findings of a transdisciplinary workshop and conference with participants ranging from the fields of clinical practice to patient representatives. Reported consequences of the severe diseases were related to psychosocial challenges, living in the nexus between physical development and disease progression, social exclusion, care-related challenges, structural and financial challenges, and non-inclusive urban design. Practical needs and concerns regarding digital platform use included social and professional support through these platforms, credibility and trust in online information, and concerns about privacy and informed consent. Furthermore, the need for safe, reliable, and expert-guided information on digital platforms and psychosocial and relationship-based digital interventions was expressed. There is a need to focus on a family-centered approach in digital health and social care and a further need in researching the suitability of digital platforms to promote resilience in the affected population. Our results can also inform city councils regarding investments in inclusive urban design allowing for disability affected groups to enjoy a better quality of life.

Congenital or Early Developing Neuromuscular Diseases Affecting Feeding, Swallowing and Speech - A Review of the Literature from January 1998 to August 2021.

Background:The knowledge about the impact of oral motor impairment in neuromuscular diseases (NMDs) is limited but increasing.Objective:The aim of this review was to collect and compile knowledge on how muscle weakness in congenital or early developing NMDs directly or indirectly affects feeding, swallowing, speech and saliva control.Methods:A literature search was performed in PubMed from January 1, 1998, to August 31, 2021. The keywords “feeding”, “dysphagia”, “swallowing”, “dysarthria”, “speech”, “drooling” and “sialorrhea” were used in combination with “paediatric neuromuscular disease” or specific diagnoses.Results:Sixty-five studies were selected for the review, 33 focused on feeding and swallowing, 11 on speech, four on a combination of feeding, swallowing, saliva control or speech and 17 general descriptions. Most of the studies reported on patients with a disorder affecting muscles. These studies show that muscle weakness and impaired motility affecting the muscles innervated by the cranial nerves may influence feeding, swallowing, and speech, and that respiratory function, general health and neurodevelopmental delay also influence these functions. Feeding impairment and breathing difficulties are common in NMDs. Lifesaving interventions such as tube feeding and ventilatory support are common in severe cases.Conclusions:Feeding impairment, dysphagia and dysarthria are prevalent in NMDs with congenital or early age of onset. Feeding and swallowing has been studied more than speech and saliva control. More children with NMD survive thanks to new treatment options and it is therefore urgent to follow up how these therapies may impact the development of feeding, swallowing, and speech.

Does specificity of electrodiagnostic test referrals predict test outcome in children?

Electrodiagnostic testing (EDX) is important in evaluation of pediatric neuromuscular disease. Non-specific referrals have emerged as a leading reason for EDX in recent years. We examine whether referral-specificity is predictive of test outcomes in children. EDX referrals and outcomes were audited over a 7-year period from 2013 to 2020 at CHI-Crumlin. Pre-test details were coded and compared to EDX outcomes using multinomial logistic regression. EDX studies were performed in 702 children (median age 10.2 years). In 36% of patients, EDX-referrals did not specify any pre-test diagnosis. Mononeuropathy (24%) and polyneuropathy (15%) were the leading pre-specified diagnoses as well as the most common test outcomes. Neurology and orthopedics/plastic surgery contributed the majority of referrals. Metabolic medicine and hematology/oncology were most likely to pre-specify a working diagnosis and were the specialties with both the highest proportion of abnormal outcomes and referral accuracy. EDX abnormality was present in 42% of patients and was predicted by specificity of referral and the absence of pain as a leading symptom. The accuracy of specified pre-test diagnoses was highest for suspected anterior horn cell disorders (67%). Accuracy of referrals, as well as abnormal test outcomes, were negatively predicted by the presence of pain as a leading symptom. EDX is informative in children but the likelihood of abnormal test-outcomes is diminished when a pre-specified working diagnosis is lacking or when the primary reason for referral is pain.

Characteristics and feasibility of ambulatory respiratory assessment of paediatric neuromuscular disease: an observational retrospective study

Purpose To investigate the characteristics of respiratory involvement in Chinese paediatric neuromuscular disease (NMD) at early stage and to explore convenient monitoring methods. Materials and methods Children with NMD (age < 18) diagnosed at a multidisciplinary joint NMD clinic at Peking University First Hospital from January 2016 to April 2021 were included. Overnight polysomnography (PSG) and pulmonary function test (PFT) data were analysed, and the characteristics of four groups: congenital muscular dystrophy (CMD), congenital myopathy, spinal muscular atrophy, and Duchenne muscular dystrophy (DMD) were compared. Results A total of 83 children with NMD were referred for respiratory assessment, of who 80 children underwent PSG; 41 performed spirometry and 38, both. The duration of pulse oxygen saturation (SpO2) <90% over apnoea and hypopnoea index (AHI) was lowest in DMD and significantly different from CMD (p = 0.033). AHI was positively correlated with the oxygen desaturation index (ODI) (r = 0.929, p = 0.000). The peak expiratory flow (PEF) were positively correlated with forced vital capacity (FVC), both as actual values and percent pred, respectively (r = 0.820, 0.719, p = 0.000). ROC derived sensitivity and specificity of prediction of AHI > 15/h or duration of SpO2<90% ≥ 60 min from FVC <51% pred was 75.8% and 85.7%, respectively. Conclusions AHI and hypoxia burden were independent factors in children with NMD in PSG and attention needed to be paid in both. FVC might be a daytime predictor for significant sleep-disordered breathing or hypoxia. Nocturnal consecutive oximetry with diurnal peak flow measurement may be convenient and effective for home monitoring at early stage of respiratory involvement.

POSA353 Conceptual Models of the Patient Experience of Duchenne Muscular Dystrophy Constructed from a Qualitative Interview Study with Caregivers

Duchenne muscular dystrophy (DMD) is a rare, progressive, life-threatening pediatric neuromuscular disease. Disruption to daily activities can begin as early as aged 3 years, while loss of ambulation generally occurs in early adolescence. This study aimed to explore the symptoms and impacts of DMD on health-related quality of life (HRQoL), activities of daily living (ADLs), and physical functioning. Fifteen primary caregivers of males with DMD participated in a 60-minute, semi-structured telephone/online interview.

Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences?

Individuals with Duchenne muscular dystrophy (DMD) frequently develop sleep-disordered breathing. Noninvasive ventilation is often prescribed for sleep-disordered breathing treatment based on the American Academy of Sleep Medicine (AASM) criteria. In 2018, DMD disease-specific criteria for sleep-disordered breathing were established. Our study aimed to examine the clinical interpretation differences using these different criteria. We performed a multicenter, retrospective chart review of children with DMD followed at The Hospital for Sick Children, Toronto, Canada, and Rady Children's Hospital, San Diego, California, who underwent polysomnography from August 1, 2012, to February 29, 2020. Baseline characteristics and polysomnography data were summarized using descriptive statistics. Agreement for the diagnosis of sleep-disordered breathing evaluated by kappa statistics and sensitivity/specificity analysis was assessed. One hundred five male children with DMD (mean ± SD age: 12.1 ± 3.8 years; body mass index z score: 0.2 ± 2.3) were included. The proportions of children with DMD that met at least 1 AASM criterion and at least 1 DMD criterion were 45.7% and 67.6%, respectively. We found that 32.4% of children met neither AASM nor DMD criteria. Overall agreement between AASM and DMD criteria was moderate (k = 0.57). There was almost perfect agreement in sleep apnea diagnosis (k = 0.90); however, there was only slight agreement in hypoventilation diagnosis (k = 0.12) between AASM and DMD criteria. There were more children with DMD diagnosed with nocturnal hypoventilation and prescribed noninvasive ventilation using DMD criteria compared with AASM criteria. Future studies should address whether the prescription of noninvasive ventilation for children with DMD based on both criteria is associated with different clinical outcomes. Hurvitz MS, Sunkonkit K, Massicotte C, Li R, Bhattacharjee R, Amin R. Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences? J Clin Sleep Med. 2022;18(2):609-615.

Mental health and psychological adaptation on parents of children with neuromuscular diseases

ABSTRACT The diagnosis of a pediatric neuromuscular disease has a psychological impact on parents. The study aimed to describe mental health and psychological adaptation in parents of children with neuromuscular diseases. The evaluation of parents (n = 35) through the Psychological Adaptation Scale and Adult Self-Report Questionnaire showed that (a) 82.4% of the participants had an adequate level of psychological adaptation; (b) parents presented high levels of mental health problems, (c) significant correlations were found between the mental health problems and psychological adaptation. This study highlights the need for psychological interventions which aim to promote psychological adaptation to NMD diagnoses and protect parental mental health.

Automatic decomposition of pediatric high density surface EMG: A pilot study

This pilot study presents a novel application of high density surface electromyography (EMG) decomposition in pediatric patients, with a view toward promoting its potential clinical application for examination of pediatric neuromuscular diseases. Automatic progressive FastICA peel-off (APFP) framework was used to decompose high density surface EMG signals recorded from the first dorsal interosseous and abductor pollicis brevis muscles of children with spinal muscular atrophy. The performance of the decomposition with reduced EMG recording channels was also investigated. In total 131 motor units were extracted from 15 trials of 64-channel (8 ​× ​8) surface EMG. The decomposition yield reduced to 102 motor units when 36-channel (6 ​× ​6) was used, among which 84 motor units were common ones with an average matching rate of (95.68 ​± ​5.26) %. The decomposition yield further reduced to 65 motor units when only 16-channel (4 ​× ​4) was used, among which 57 were common ones with an average matching rate of (95.99 ​± ​4.56) %. These results indicate that using the APFP framework single motor unit activity can be reliably and automatically extracted from pediatric surface EMG signals recorded by an electrode array, which can facilitate potential clinical application of surface EMG as an alternative or supplement to invasive needle EMG for examination of neuromuscular diseases in children.

Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to chronic respiratory insufficiency and failure. Use of home noninvasive ventilation (NIV) has been linked to improved outcomes including reduced mortality. Despite the importance of NIV, factors promoting optimal NIV usage and determinants of nonadherence have not been rigorously examined. Moreover, given that respiratory issues in DMD span between childhood and adulthood, examination across a broad age group is needed. The objectives of this study were to (1) evaluate NIV usage across a broad spectrum of patients with DMD, including both children and adults, and (2) identify biological and socioeconomic determinants of NIV usage and NIV nonadherence. We performed a retrospective review of all patients with DMD from February 2016 to February 2020 who underwent evaluation at associated pediatric and adult neuromuscular disease clinics. NIV use was determined objectively from device downloads. A priori, we defined nonadherence as < 4 hours use per night, quantified as the percentage of nights below this threshold across a 30-day period within 6 months of a clinic visit. We also assessed the average hours of NIV usage over this time period. Predictors examined included demographics, social determinants, and pulmonary function. 33 patients with DMD were identified, 29 (87%) of whom were using NIV (13 age < 21 years). Mean age was 22.9 ± 6.6 years (range 13-39 years), body mass index was 23.4 ± 10.4 kg/m2, and seated forced vital capacity was 23% ± 18% predicted. Mean nightly NIV usage was 7.4 ± 3.8 hours and mean percentage of nonadherent nights was 13% ± 30%. In univariable analysis, age did not predict use. Those with lower forced vital capacity had higher NIV usage hours (P = .01) and a trend toward less nonadherence (P = .06). Higher estimated household income demonstrated a trend toward increased usage hours and less nonadherence (both P = .08). Multivariable analysis found increased usage hours were predicted best by higher income, higher inspiratory positive airway pressure, and higher bicarbonate. Nonadherence was higher in those with lower income or higher forced vital capacity. In this cohort of adult and pediatric patients with DMD, most individuals were using NIV. While usage hours were higher with lower lung function, substantial variability remains unexplained by examined factors. Nonadherence was observed in some individuals, including those with advanced disease. Further investigations should focus on evaluating patient-oriented outcomes to define optimal NIV usage across the spectrum of disease and determine strategies to counteract issues with nonadherence. Hurvitz MS, Bhattacharjee R, Lesser DJ, Skalsky AJ, Orr JE. Determinants of usage and nonadherence to noninvasive ventilation in children and adults with Duchenne muscular dystrophy. J Clin Sleep Med. 2021;17(10):1973-1980.

Instruments to assess upper‐limb function in children and adolescents with neuromuscular diseases: a systematic review

To synthesize clinical and scientific evidence regarding the instruments available to assess upper-limb function in paediatric patients with neuromuscular disease (NMD). This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines (Prospective Registry of Systematic Reviews no. CRD42020140343). Two independent reviewers searched the PubMed/MEDLINE, LILACS, Embase, and Scopus databases. Inclusion criteria were cross-sectional or longitudinal studies or randomized controlled trials that used scales or questionnaires to assess upper-limb function in paediatric patients with NMDs. The COSMIN Risk of Bias checklist and criteria for good measurement properties were applied to assess the methodological quality of the instruments. In total, 34 articles and 12 instruments were included. The Brooke Upper Extremity (n=16) and Performance of Upper Limb (PUL) (n=12) instruments were the most used tools. The PUL and Duchenne muscular dystrophy (DMD) Upper Limb patient-reported outcome measures (PROMs) tested more measurement properties and provided higher methodological quality scores for patients with DMD. Likewise, the Revised Upper Limb Module (RULM) was the most suitable instrument for patients with spinal muscular atrophy. No instrument has been devised to assess upper-limb function in patients with Charcot-Marie-Tooth disease and no other disease-specific instruments were found. The PUL, DMD Upper Limb PROM, and RULM are the most suitable instruments to assess upper-limb function in the two most prevalent paediatric NMDs. The identified gaps and methodological flaws of the available instruments indicate a need to develop high-quality instruments to assess other types of paediatric NMDs. What this paper adds The most suitable observer-rater instrument to assess upper-limb function in Duchenne muscular dystrophy (DMD) is the Performance of Upper Limb. The most suitable observer-rater instrument to assess upper-limb function in spinal muscular atrophy is the Revised Upper Limb Module. The DMD Upper Limb patient-reported outcome measure is recommended to assess the upper-limb performance of patients with DMD. Literature gaps and methodological flaws indicate the need to develop high-quality instruments to assess other types of paediatric neuromuscular disease.

Diagnostic accuracy of gray scale muscle ultrasound screening for pediatric neuromuscular disease.

Gray scale ultrasound (US) has been demonstrated to be a sensitive and specific tool in the diagnosis of pediatric neuromuscular disease (NMD). With recent advances in genetic testing, the diagnostic work up for NMD has evolved. The purpose of this study was to compare the current diagnostic value of gray scale US to previously defined sensitivities and specificities to determine when this test can add value to a patient's diagnostic workup. Standardized quantitative gray scale US imaging was performed on 148 pediatric patients presenting for electrodiagnostic testing to evaluate for NMD. Patients were categorized as having an NMD, a non-NMD, or as "uncertain." The US results were defined as normal, borderline or abnormal based on echointensity values. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the test were calculated. Forty-five percent of the patients had an NMD, 54% a non-NMD, and in 1% the diagnosis remained uncertain. US was abnormal in 73% of myopathies, 63% of neuromuscular junction disorders, 60% of generalized neuropathies and 58% of focal neuropathies. After excluding patients in whom muscle US was not expected to be abnormal (eg, sensory neuropathy), sensitivity was 83%, specificity 79%, PPV 75%, NPV 86%, and accuracy 81%. Quantitative gray scale muscle US still has good diagnostic value as a screening tool in pediatric NMD. As with any diagnostic test, muscle US is best used in conjunction with history and physical examination to increase specificity and diagnostic yield.

Spinal motor neuron loss occurs through a p53-and-p21-independent mechanism in the Smn2B/− mouse model of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a pediatric neuromuscular disease caused by genetic deficiency of the survival motor neuron (SMN) protein. Pathological hallmarks of SMA are spinal motor neuron loss and skeletal muscle atrophy. The molecular mechanisms that elicit and drive preferential motor neuron degeneration and death in SMA remain unclear. Transcriptomic studies consistently report p53 pathway activation in motor neurons and spinal cord tissue of SMA mice. Recent work has identified p53 as an inducer of spinal motor neuron loss in severe Δ7 SMA mice. Additionally, the cyclin-dependent kinase inhibitor P21 (Cdkn1a), an inducer of cell cycle arrest and mediator of skeletal muscle atrophy, is consistently increased in motor neurons, spinal cords, and other tissues of various SMA models. p21 is a p53 transcriptional target but can be independently induced by cellular stressors. To ascertain whether p53 and p21 signaling pathways mediate spinal motor neuron death in milder SMA mice, and how they affect the overall SMA phenotype, we introduced Trp53 and P21 null alleles onto the Smn2B/− background. We found that p53 and p21 depletion did not modulate the timing or degree of Smn2B/− motor neuron loss as evaluated using electrophysiological and immunohistochemical methods. Moreover, we determined that Trp53 and P21 knockout differentially affected Smn2B/− mouse lifespan: p53 ablation impaired survival while p21 ablation extended survival through Smn-independent mechanisms. These results demonstrate that p53 and p21 are not primary drivers of spinal motor neuron death in Smn2B/− mice, a milder SMA mouse model, as motor neuron loss is not alleviated by their ablation.

Exome sequencing for diagnosing uncommon paediatric neuromuscular disease.

Exome sequencing for diagnosing uncommon paediatric neuromuscular disease.