Nitrous oxide (N2O) is a common recreational drug. Chronic use inactivates vitamin B12 resulting in neurological damage. Most studies have focused on adults. This study aims to describe unique features of N2O-related myeloneuropathy in adolescents. Adolescents aged 14–18 years admitted with N2O-related myeloneuropathy to three tertiary medical centers in 2024 were enrolled. Their medical records were reviewed retrospectively. A systematic review was conducted for N2O-related neurologic complications in adolescents, using Embase, MEDLINE, Scopus and PubMed databases. Clinical data from the case series and systematic review were extracted and analyzed together. Five new and 54 reported patients (2011–2026) were included. All presented with neurological complaints, predominantly sensory. Vitamin B12 deficiency was detected in 45

Background: Variants in the ryanodine receptor 1 (RYR1) gene have been linked to a range of disorders, from congenital myopathy to adult-onset manifestations, with phenotypes varying from mild to severe. Methods: A retrospective review was conducted on an Israeli cohort of 36 individuals with RYR1 variants, identified through genetic testing as part of a national collaboration among multiple pediatric and adult neuromuscular clinics. Clinical features, molecular data, laboratory results, electromyographic findings, and muscle histology were analyzed. Each variant was classified according to its respective domain within the RYR1 gene. Results: Thirty-six cases were included in the analysis; 31 were from 11 unrelated families, and 5 were sporadic. Nine individuals were asymptomatic with normal CK levels. Most of the 27 affected patients presented with variable degrees of perinatal weakness, often accompanied by respiratory impairment or arthrogryposis. Weakness was predominantly proximal, with clinical courses that included deterioration, improvement, or stabilization. Three cases of King-Denborough syndrome were identified. Additional presentations included malignant hyperthermia and, in isolated cases, periodic paralysis. Muscle biopsies demonstrated considerable histologic heterogeneity, including fiber-size variation, internal nuclei, multiminicores, and fibrosis or dystrophic features. The pathogenic RYR1 variants included five compound-heterozygous genotypes, two homozygous variants, and two heterozygous variants. There was a positive correlation between variants located in the Bsol domain and disease severity. Conclusions: This cohort confirms and expands the clinical and histological diversity associated with RYR1 variants in Israel. Variants in the Bsol domain appear to be indicative of disease severity.

The introduction of nusinersen revolutionized the treatment of spinal muscular atrophy (SMA). However, nusinersen is administered by interlaminar intrathecal injection which is challenging in patients with severe scoliosis, a common comorbidity of advanced SMA. This study evaluated the technical benefits of fluoroscopic guidance of intrathecal nusinersen administration in complex SMA patients with or without a fixation device. The cohort included 12 patients aged 10-20 years (total 124 injections). The total success rate was 99 %, with failure to complete only one out of 124 procedures. Demographic characteristics were diverse. Mean age at first injection was 14.2 years. Mean duration of radiation exposure was 77 s; mean dose area product was 2.32 Gycm2; and mean cumulative air kerma was 20.91mGy. Adverse events included post-dural-puncture headache (4.8 % of procedures), mostly mild and self-limited, and one allergic reaction. Treatment was discontinued in 2 patients because of difficult intrathecal access, and in 2 for reasons unrelated to the injection technique. Fluoroscopy-guided nusinersen administration is a feasible option for patients with SMA and complex access. Success depends on proper patient positioning and expertise of the interventional radiologist. Radiation exposure is lower than with other techniques. Larger prospective studies are needed to confirm these findings.

Background/Objectives: Spinal Muscular Atrophy (SMA) is a genetic neurodegenerative disease characterized by severe muscle weakness and atrophy. Advances in disease-modifying therapies have dramatically changed the natural history of SMA and the outcome measures that are used to assess the clinical response to therapy. Standard assessment methods for SMA are limited in their ability to detect minor changes in fine motor abilities and in patients’ daily functions. The aim of this pilot study was to evaluate the feasibility and preliminary use of the Touchscreen-Assessment Tool (TATOO) alongside standardized tools to detect changes in upper extremity motor function among individuals with SMA receiving nusinersen therapy. Methods: Thirteen individuals with genetically-confirmed SMA, aged 6–23 years, eight with SMA type 2, and five with SMA type 3, participated. The patients continued the maintenance dosing of nusinersen during the study period. They were evaluated at the onset of the study, then twice more at intervals at least six months apart. Upper extremity functional assessments were performed via the TATOO and standardized tools: the Hand Grip Dynamometer (HGD), Pinch Dynamometer (PD), Revised Upper Limb Module (RULM), and Nine-Hole Peg Test (NHPT). Results: Significant changes in fine motor function were detected using the TATOO together with other standardized tools. Participants demonstrated notable improvements in hand grip strength and fine motor performance, as measured by the NHPT. The RULM results were not statistically significant for the total study group, particularly in ambulatory patients with SMA type 3. TATOO provided detailed metrics, and revealed enhancements in accuracy and speed across various tasks. However, given the small sample size, the lack of a control group, and the lack of baseline assessment before receiving therapy, these findings should be considered preliminary and exploratory. Conclusions: The findings suggest that the TATOO, alongside traditional assessment tools, offers a sensitive measure of fine motor function changes in patients with SMA. This study highlights the potential of touchscreen-based assessments to address gaps in current outcome measures and emphasizes the need for larger, multicenter studies that will include pre-treatment, baseline, and control data.

Excitation-contraction (EC) coupling is an essential process for skeletal muscle function. Pathogenic variants in different EC coupling components have previously been associated with various neuromuscular disorders. In this study we aimed to identify the genetic etiology of a muscular condition characterized by early-onset muscle weakness, elevated CK, ptosis and low body weight, which was observed in three individuals from two unrelated consanguineous families. Exome sequencing (ES) performed in multiple individuals of one family, and ES in combination with SNP array-based homozygosity mapping in the proband of the other family, revealed different homozygous loss-of-function variants in the second exon of CACNB1 in the affected individuals from each family. CACNB1 encodes the β1 subunit of the skeletal muscle dihydropyridine receptor (DHPR), a voltage-gated Ca2+ channel with a major role in EC coupling. Molecular impact of the identified variants was assessed in LHCN-M2 human myoblasts. Long-read RNA sequencing in LHCN-M2 wild-type myotubes showed that in differentiated skeletal muscle cells virtually all CACNB1 transcript isoforms contain exon 2 and will therefore be affected by genetic variants in this exon. Pathogenicity of the identified CACNB1 variants was further validated by replicating one of them (c.85-1G>A) in LHCN-M2 cells using CRISPR-Cas9-mediated base-editing. Analysis of LHCN-M2 edited myotubes demonstrated that in addition to the loss of β1 subunits, these cells displayed severely reduced protein levels of α1S, the pore-forming subunit of DHPR. We conclude that pathogenic variants in CACNB1 cause a new congenital muscular disorder.

IntroductionThe COVID-19 pandemic has significantly affected global mental health, with children being particularly vulnerable. This study examines the psychological repercussions of the pandemic by comparing the prevalence of anxiety in healthy children and in those with Neurofibromatosis Type 1 (NF1), a hereditary disorder characterized by diverse clinical manifestations, including cognitive and behavioral challenges. The uncertainties of the pandemic may have influenced anxiety levels differently in these two populations.ResultsA cross-sectional survey of 52 parents revealed that, although not statistically significant, more children with NF1 reported generalized anxiety and social phobia compared with their healthy peers. Conversely, healthy children tended to report more symptoms of somatization disorder, although this difference was not significant. Parent-reported scores showed a significant association between NF1 and separation anxiety disorder.DiscussionThe findings suggest that the pandemic may have exacerbated pre-existing emotional challenges in children with NF1, potentially due to disruptions in healthcare access and increased social isolation. In contrast, typically developing children may have experienced stressors related to remote learning and social distancing. These results underscore the importance of tailored interventions and support for children with NF1 to address their specific emotional needs during crises.ConclusionThis study highlights the distinct psychological impact of the COVID-19 pandemic on typically developing children and those with NF1. While further research is needed to clarify the long-term effects, the findings emphasize the necessity of early screening and targeted interventions to mitigate emotional distress in children with NF1 during times of crisis.

OBJECTIVE:We describe outcomes following onasemnogene abeparvovec monotherapy for patients with ≥four survival motor neuron 2 (SMN2) gene copies in RESTORE, a noninterventional spinal muscular atrophy patient registry. METHODS:We evaluated baseline characteristics, motor milestone achievement, post-treatment motor function, use of ventilatory/nutritional support, and adverse events as of December 22, 2022. RESULTS:At data cutoff, 19 patients in RESTORE had ≥four SMN2 copies and were treated with onasemnogene abeparvovec monotherapy (n=12 [63.2%] four copies; n=7 [36.8%] >four copies). All patients were identified by newborn screening and were reported as asymptomatic at diagnosis. Median age at onasemnogene abeparvovec administration was 3.0 months. Median time from treatment to last recorded visit was 15.4 months, with a range of post-treatment follow-up of 0.03-39.4 months. All 12 children who were assessed for motor development achieved new milestones, including standing alone (n=2) and walking alone (n=5). Five children reported one or more treatment-emergent adverse events (one Grade 3 or greater). No deaths or use of ventilatory/nutritional support were reported. CONCLUSIONS:Real-world findings from the RESTORE registry indicate that patients with ≥four SMN2 gene copies treated with onasemnogene abeparvovec monotherapy demonstrated improvements in motor function. Adverse events experienced by these patients were consistent with previously reported findings.

BackgroundThe prevalence of obesity among children and adolescents is rising and poses a major health concern. Bariatric surgery is well established in adults and has become an option for adolescents. Thiamine (B1) deficiency is common following bariatric surgery in adults. It may present as Beri-Beri, Wernicke encephalopathy, or Korsakoff psychosis.ObjectiveOur aim was to describe the clinical features, diagnosis, and treatment of adolescents who presented with B1 deficiency after bariatric surgery at one center, and to summarize the data from the literature.PatientsThree adolescents with morbid obesity (two boys and one girl, aged 15.5 to- 17-years-old), presented at Schneider Children's Medical Center of Israel with progressive lower limb pain and weakness 2-3 month following a bariatric procedure (sleeve gastrectomy or narrowing of a bariatric band). The girl also had upper limb involvement and cerebellar signs. All three were non-compliant with micronutrient supplementation. After admission, they received intravenous B1 and oral multivitamin supplementation, and their symptoms improved considerably.ConclusionsMicronutrient supplementation following bariatric surgery is crucial to prevent deficiencies. In adolescents, compliance with micronutrient supplementation should be assessed before and after such surgery. Thiamine deficiency may cause polyneuropathy, among other symptoms. Treatment reduces the severity of neurological complications.

Onasemnogene abeparvovec (OA) is a novel gene replacement therapy for patients with spinal muscular atrophy (SMA). This study provides real-world respiratory data for pediatric SMA patients receiving OA who were assessed before and one year after treatment in a multicenter cohort study conducted from 2019 to 2021. Twenty-five OA-treated SMA patients (23 with type 1 and 2 with type 2; median age at treatment 6.1 months, with a range of 0.36–23 months) were included. Sixteen were treatment-naïve, and nine had received various prior treatments. Two patients died due to respiratory failure during the study period. Of the remaining 23 patients, four were put on non-invasive ventilation (NIV), bringing ventilated patients to a total of ten during the post-treatment year. Three patients required permanent NIV support, while 13 did not require any respiratory support. Ventilation time decreased from 14.3 to 11.1 hours per day, and respiratory hospitalizations decreased by 26

CAPN3 encodes calpain-3, a calcium-activated skeletal muscle-specific protease. Pathogenic variants in CAPN3 are associated with autosomal recessive and autosomal dominant limb-girdle muscular dystrophy (LGMDR1/LGMD2A and LGMDD4, respectively). Patients present with weakness of the pelvic and shoulder girdle and elevated creatine kinase levels. Here, we report in detail on three children and one adult from four unrelated Israeli families of Iraqi Jewish descent with features of LGMDR1, who were found to harbor the same homozygous missense variant in CAPN3, p.Gln123Lys. All subjects manifested lower limb weakness with onset in the first or second decades of life; the three children presented with toe walking and significantly elevated creatine kinase levels (6,000-21,000U/L). The variant affects an evolutionarily conserved amino acid in a conserved domain of the protein common to the calpain super family. We conclude that the p.Gln123Lys variant in CAPN3 is associated with autosomal recessive limb-girdle muscular dystrophy with a recognizable clinical phenotype. Furthermore, this variant likely represents a founder mutation in individuals of Iraqi Jewish ancestry. These findings can help guide workup for individuals presenting with suggestive features and should be considered in relevant population screening.

CAPN3 encodes a calcium-activated skeletal muscle-specific protease. Pathogenic variants in CAPN3 are associated with autosomal recessive and dominant limb-girdle muscular dystrophy. We report on three children and one adult from four unrelated Iraqi Jewish families, who harbor the same homozygous variant in CAPN3, p.Gln123Lys. Patients shared recognizable features of toe-walking and elevated creatine phosphokinase since childhood. The variant affects a conserved protein domain common to the calpain super family and likely represents a founder mutation in individuals of Iraqi Jewish ancestry. Our findings have potential implications on screening in relevant populations, allowing for more prompt diagnoses and future therapies.

In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity. This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment. Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age ( r  = 0.55, p  = 0.02). Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Background: Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder. Despite increased survival due to novel therapies, morbidity from respiratory complications still persists. We aim to describe these patients' sputum cultures as an expression of chronic infectious airway disease. Methods: Retrospective review of medical records of all children with SMA followed at the multidisciplinary respiratory neuromuscular clinic at Schneider Childrens' Medical Center of Israel over a 16-year period. Sputum cultures were obtained during routine visits or pulmonary exacerbations. Results: Sixty-one SMA patients, aged 1 month to 21 years, were included in this cohort. Of these, sputum cultures were collected from 41 patients. Overall, 288 sputum cultures were obtained, and 98 (34%) were negative for bacterial growth. For the first culture taken from each patient, 12 out of 41 (29%) were sterile. The most common bacteria were pseudomonas aeruginosa (PSA) (38%) and staphylococcus aureus (19.6%). PSA was found in SMA type I patients more frequently than in type II patients (15/26=58% vs 4/13=31%, p<0.001). PSA infection was positively associated with noninvasive ventilation, recurrent atelectasis, recurrent pneumonias, swallowing difficulties, but no significant association was found with cough assist machine usage. The incidence of positive cultures did not differ between those treated with Onasemnogene abeparvovec or Nusinersen compared to those without treatment, but the age of first PSA isolation was slightly older with Nusinersen treatment (p=0.01). Conclusions: Airway bacterial colonization is common in SMA type I patients and is not decreased by Onasemnogene abeparvovec or Nusinersen treatment.

Background: Onasemnogene abeparvovec-xioi (OA) has been available since 2019 as a gene replacement therapy for individuals with spinal muscular atrophy (SMA) under age two years. We aim to expand upon the sparse knowledge about its safety and clinical efficacy. Methods: The clinical outcome data of all the individuals with SMA who were treated with gene therapy in four tertiary hospitals in Israel were retrieved and analyzed. Results: The study participants included 25 individuals who received the gene therapy between age 11 days and 23 months and whose median follow-up duration was 18.0 (interquartile range [IQR], 12.4 to 18.3) months. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by a median (IQR) of 13 (8 to 20) points at the last follow-up compared with baseline. None of the patients experienced regression in motor abilities after gene therapy, which was generally well tolerated. There was gradual improvement in motor function, especially among presymptomatic patients (P <= 0.001) whose disease duration was shorter (<= 8 months) before receiving gene therapy (P <= 0.001) and who did not experience recurrent infections and illnesses in the months following treatment (P <= 0.001). Conclusions: OA was well tolerated and led to favorable functional motor outcomes at six to 24 months after treatment initiation. Better progress in motor function was observed in individuals who received OA earlier and who were presymptomatic, irrespective of the SMN2 copy number or type. Our results further strengthen the clinical efficacy of OA and reinforce the importance of early recognition of SMA via newborn screening programs. (c) 2023 Elsevier Inc. All rights reserved.

Aim: In Duchenne muscular dystrophy (DMD), lung disease contributes significantly to morbidity and mortality. This study aimed to assess the usefulness of various pulmonary function tests in evaluating DMD severity.Methods: This retrospective study analysed lung function tests of patients with DMD-treated in the multidisciplinary respiratory neuromuscular clinic at Schneiders' Children Medical Center of Israel. Data were analysed according to age, ambulatory status and glucocorticoid treatment.Results: Among 90 patients with DMD, 40/63 (63.5%) ambulatory patients and 22/27 (81.5%) nonambulatory patients successfully performed spirometry. Significant annual declines were demonstrated among nonambulatory patients, in percentile predicted forced vital capacity (3.8%) and in total lung capacity (5.5%) per year. The decline correlated with age and loss of ambulation but not with steroid treatment. Peak cough flow values were randomly distributed and did not correlate with age, ambulation or treatment. In nonambulatory patients, transcutaneous carbon dioxide measurement correlated significantly with age (r = 0.55, p = 0.02).Conclusion: Forced vital capacity, total lung capacity and transcutaneous carbon dioxide correlated with the clinical severity of disease in children with DMD. These measures may be useful in follow-up and clinical trials. A comparable correlation was not found for peak cough flow.

Pediatric stroke is considered an infrequent complication of COVID-19. Focal cerebral arteriopathy (FCA) is one of the most common causes of arterial ischemic stroke in a previously healthy child. The present report describes a toddler with FCA most likely induced by SARS-CoV-2 infection who showed significant clinical improvement that may be related to injection of intra-arterial nimodipine. To our knowledge, this is the first reported use of nimodipine in this setting.

BACKGROUND AND PURPOSE:The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. METHODS:Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. RESULTS:Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. CONCLUSIONS:Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease characterized by severe muscle weakness and atrophy. Advances in novel drug therapies has changed dramatically the natural history of the disease and outcome measures are used to assess the clinical response to therapy. Recent research has given rise to a central issue regarding the low sensitivity and limited ability of standard SMA assessment tools in detecting the subtle changes in fine motor abilities, which occur following the use of those therapies. Furthermore, there is lack of standardized and ecological tools for assessment of fine motor abilities and changes in SMA patients' daily functions. The purpose of this study was to evaluate the use touchscreen app. as an assessment tool for detecting changes in the upper extremity (UE) motor functions among SMA patients as a response to the use of the genetic therapies. 14 patients aged 6- 23 years were recruited. Nine patients were diagnosed with SMA type 2 and five were diagnosed with SMA type 3. The patients were evaluated every six months. The study included assessment of fine motor functions, using the touchscreen app which included temporal (e.g. reaction times, duration) and accuracy (touch all corners, double tapping, drag items and pinch ability) tasks. Our preliminary tests results show that the App. is able to detect fine changes in the performance, mainly in the parameters of reaction time and duration in most of the tasks. The participants were highly motivated to use the App. comparing to standard tools and it was easy to use among all ages and types of SMA. The results of this pilot study may contribute to the new developing knowledge about the influence of the genetic therapies on motor functions of the UE in the SMA population. In addition, the results may help to establish assessments for SMA that are ecological and more sensitive in detecting changes in motor abilities and function in daily activities. Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease characterized by severe muscle weakness and atrophy. Advances in novel drug therapies has changed dramatically the natural history of the disease and outcome measures are used to assess the clinical response to therapy. Recent research has given rise to a central issue regarding the low sensitivity and limited ability of standard SMA assessment tools in detecting the subtle changes in fine motor abilities, which occur following the use of those therapies. Furthermore, there is lack of standardized and ecological tools for assessment of fine motor abilities and changes in SMA patients' daily functions. The purpose of this study was to evaluate the use touchscreen app. as an assessment tool for detecting changes in the upper extremity (UE) motor functions among SMA patients as a response to the use of the genetic therapies. 14 patients aged 6- 23 years were recruited. Nine patients were diagnosed with SMA type 2 and five were diagnosed with SMA type 3. The patients were evaluated every six months. The study included assessment of fine motor functions, using the touchscreen app which included temporal (e.g. reaction times, duration) and accuracy (touch all corners, double tapping, drag items and pinch ability) tasks. Our preliminary tests results show that the App. is able to detect fine changes in the performance, mainly in the parameters of reaction time and duration in most of the tasks. The participants were highly motivated to use the App. comparing to standard tools and it was easy to use among all ages and types of SMA. The results of this pilot study may contribute to the new developing knowledge about the influence of the genetic therapies on motor functions of the UE in the SMA population. In addition, the results may help to establish assessments for SMA that are ecological and more sensitive in detecting changes in motor abilities and function in daily activities.