Real-Life Outcome After Gene Replacement Therapy for Spinal Muscular Atrophy: A Multicenter Experience.

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.

Evaluation of sputum cultures in children with spinal Muscular atrophy.

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.

Pulmonary function tests for evaluating the severity of Duchenne muscular dystrophy disease.

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.

Targeted transcript analysis in muscles from patients with genetically diverse congenital myopathies.

Congenital myopathies are a group of early onset muscle diseases of variable severity often with characteristic muscle biopsy findings and involvement of specific muscle types. The clinical diagnosis of patients typically relies on histopathological findings and is confirmed by genetic analysis. The most commonly mutated genes encode proteins involved in skeletal muscle excitation-contraction coupling, calcium regulation, sarcomeric proteins and thin-thick filament interaction.

Clinical improvement of a toddler with COVID-19 focal cerebral arteriopathy possibly due to intra-arterial nimodipine.

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.

Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients.

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.

Adeno-associated virus serotype 9 antibody titers in patients with SMA pre-screened for treatment with onasemnogene abeparvovec -routine care evidence.

Spinal muscular atrophy (SMA) is characterized by progressive weakness of skeletal and respiratory muscles. This study aimed to evaluate the prevalence of pre-existing anti adeno-associated virus serotype 9 antibody (AAV9-Ab) titers among infantile-onset SMA diagnosed infants pre-screened for treatment with AAV9-based onasemnogene abeparvovec, and to explore whether clinical and/or demographic characteristics are correlated with AAV9 Ab test results. This is a retrospective multicenter study of children diagnosed with 5q SMA younger than two years of age.

Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness.

Background: Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network.

Biallelic truncating variants in the muscular A-type lamin-interacting protein (MLIP) gene cause myopathy with hyperCKemia.

Background And Purpose: Muscular A-type lamin-interacting protein (MLIP) is most abundantly expressed in cardiac and skeletal muscle. In vitro and animal studies have shown its regulatory role in myoblast differentiation and in organization of myonuclear positioning in skeletal muscle, as well as in cardiomyocyte adaptation and cardiomyopathy. We report the association of biallelic truncating variation in the MLIP gene with human disease in five individuals from two unrelated pedigrees.

External lumbar drainage in progressive pediatric idiopathic intracranial hypertension.

Objective: Pediatric idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure despite normal cerebrospinal fluid and neuroimaging findings. Initial management is typically medical; however, nearly 10% of children will eventually require surgery for persistent headache and/or vision loss. External lumbar drainage, which is a considerably safer treatment option, has not been adequately analyzed in children with medically refractory IIH.

COVID-19 in advanced Duchenne/Becker muscular dystrophy patients.

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy. As a result of progressive muscle weakness, pulmonary function decreases during the second decade of life and lung disease contributes significantly to morbidity and mortality in these patients. Corticosteroids are the current standard of care for patients with DMD, despite known adverse effects such as obesity and immunosuppression.

Liposomal Bupivacaine (Bupigel) Demonstrates Minimal Local Nerve Toxicity in a Rabbit Functional Model.

We previously reported the development of a novel formulation of an ultra-long-acting local anesthetic based on bupivacaine encapsulated in large multivesicular liposomes (Bupisomes) embedded in hydrogel. This formulation (Bupigel) prolonged bupivacaine release from the formulation in dissolution-like studies in vitro and analgesia in vivo in mouse, rat, and pig models. In this study we assessed Bupigel neurotoxicity on rabbit sciatic nerve using histopathology and electrophysiologic testing.

Impact of a national population-based carrier-screening program on spinal muscular atrophy births.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease. Population carrier screening for SMA was introduced in Israel in 2008 through health-care services' insurance plans and expanded to the entire Israeli population in 2013 by a national health program. The aim of the study was to evaluate the impact of carrier screening on reducing the rate of birth of infants with SMA.

Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy.

Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300-<400 or <400 m).

Prognostic Parameters of Acute Transverse Myelitis in Children.

Acute transverse myelitis is a rare and disabling disorder. Data on the imaging features in children are sparse. The aim of this study was to describe the clinical and magnetic resonance imaging findings characteristic of pediatric idiopathic acute transverse myelitis and to identify those with prognostic value.

Single Exon Skipping Can Address a Multi-Exon Duplication in the Dystrophin Gene.

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease typically caused by protein-truncating mutations that preclude synthesis of a functional dystrophin. Exonic deletions are the most common type of lesion, however, whole exon duplications account for between 10-15% of all reported mutations. Here, we describe in vitro evaluation of antisense oligonucleotide-induced splice switching strategies to re-frame the transcript disrupted by a multi-exon duplication within the gene.

Impaired Regeneration in Dystrophic Muscle-New Target for Therapy.

Muscle stem cells (MuSCs), known as satellite cells (SCs) have an incredible ability to regenerate, which enables the maintenance and growth of muscle tissue. In response to damaging stimuli, SCs are activated, proliferate, differentiate, and fuse to repair or generate a new muscle fiber. However, dystrophic muscles are characterized by poor muscle regeneration along with chronic inflammation and fibrosis.

Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents.

Introduction: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology.

Methods: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center.

Improvement of motor conduction velocity in hereditary neuropathy of LAMA2-CMD dy/dy mouse model by glatiramer acetate.

Objective: Glatiramer acetate (GA), an agent modulating the immune system, has been shown to cause significantly improved mobility and hind limb muscle strength in the dy/dy mouse model for LAMA2-congenital muscular dystrophy (LAMA2-CMD). In view of these findings and the prominent peripheral nervous system involvement in this laminin-α2 disorder we evaluated GA's effect on dy/dy motor nerve conduction electrophysiologically.

Methods: Left sciatic-tibial motor nerve conduction studies were performed on wild type (WT) mice (n = 10), control dy/dy mice (n = 11), and GA treated dy/dy mice (n = 10) at 18 weeks of age.