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Background: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. Objective: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. Methods: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. Results: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. Conclusions: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

Risdiplam is an oral, survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved for the treatment of spinal muscular atrophy (SMA). SUNFISH (NCT02908685) Part 2, a Phase 3, randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of risdiplam in type 2 and non‑ambulant type 3 SMA. The primary endpoint was met: a significantly greater change from baseline in 32-item Motor Function Measure (MFM32) total score was observed with risdiplam compared with placebo at month 12. After 12 months, all participants received risdiplam while preserving initial treatment blinding. We report 24-month efficacy and safety results in this population. Month 24 exploratory endpoints included change from baseline in MFM32 and safety. MFM‑derived results were compared with an external comparator. At month 24 of risdiplam treatment, 32% of patients demonstrated improvement (a change of ≥ 3) from baseline in MFM32 total score; 58% showed stabilization (a change of ≥ 0). Compared with an external comparator, a treatment difference of 3.12 (95% confidence interval [CI] 1.67-4.57) in favor of risdiplam was observed in MFM-derived scores. Overall, gains in motor function at month 12 were maintained or improved upon at month 24. In patients initially receiving placebo, MFM32 remained stable compared with baseline (0.31 [95% CI - 0.65 to 1.28]) after 12 months of risdiplam; 16% of patients improved their score and 59% exhibited stabilization. The safety profile after 24 months was consistent with that observed after 12 months. Risdiplam over 24 months resulted in further improvement or stabilization in motor function, confirming the benefit of longer-term treatment. ispartof: JOURNAL OF NEUROLOGY vol:270 issue:5 pages:2531-2546 ispartof: location:Germany status: published

Spinal muscular atrophy (SMA) is a rare neuromuscular condition, characterized by loss of motor neurons as a result of a mutation in the survival motor neuron gene. This results in muscle wasting and in the most common and severe type, death before 24 months. Over the recent years there has been a dynamic shift in the therapeutic options for these patients involving both clinical trials in genetic modifying therapies to indirectly improve the survival motor neuron protein level and hence strength, muscle promotor therapies, up/down regulation of modifier genes and more recently gene therapy to replace the mutated survival motor neuron gene. This review addresses the pathogenesis of SMA and the resultant therapeutic approaches as well as the current state in clinical trials and future development.

Objectives: Spinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands.Methods: We developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results.Results: After detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS.Conclusions: NBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug’s approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.

Resumen Introducción. La atrofia muscular espinal es una enfermedad neurodegenerativa huérfana de origen genético que afecta las neuronas motoras del asta anterior de la médula espinal, y produce atrofia y debilidad muscular. En Colombia, son pocos los estudios publicados sobre la enfermedad y no hay ninguno con análisis funcional. Objetivo. Caracterizar clínica y funcionalmente una serie de casos de atrofia muscular espinal del centro-occidente colombiano. Materiales y métodos. Se hizo un estudio descriptivo transversal, entre el 2007 y el 2020, de pacientes con diagnóstico clínico y molecular de atrofia muscular espinal que consultaron en el centro de atención. La evaluación funcional se realizó con las escalas Hammersmith y Chop Intend. En la sistematización de los datos, se empleó el programa Epi-Info, versión 7.0. Resultados. Se analizaron 14 pacientes: 8 mujeres y 6 hombres. La atrofia muscular espinal más prevalente fue la de tipo II, la cual se presentó en 10 casos. Se encontró variabilidad fenotípica en términos de funcionalidad en algunos pacientes con atrofia muscular espinal de tipo II, cinco de los cuales lograron alcanzar la marcha. La estimación de la supervivencia fue de 28,6 años. Conclusiones. Los hallazgos en el grupo de pacientes analizados evidenciaron que los puntajes de la escala de Hammersmith revisada y expandida, concordaron con la gravedad de la enfermedad. Abstract Introduction: Spinal muscular atrophy is a rare genetic neurodegenerative disorder affecting the motor neurons of the anterior horn of the spinal cord, which results in muscle atrophy and weakness. In Colombia, few studies have been published on the pathology and none with functional analysis. Objective: To characterize clinically and functionally some cases of spinal muscular atrophy patients from Central-Western Colombia. Materials and methods: We conducted a cross-sectional descriptive study between 2007 and 2020 with patients clinically and molecularly diagnosed with spinal muscular atrophy who attended a care center. For the functional assessment we used the Hammersmith and Chop-Intend scales and the data were systematized with the Epi-Info, version 7.0 software. Results: We analyzed 14 patients (42.8 % men). The most prevalent spinal muscular atrophy was type II with 71.4 %. We found phenotypic variability in terms of functionality in some patients with type II spinal muscular atrophy, 37.5 % of whom reached gait. Survival was estimated at 28.6 years. Conclusions: The findings in the group of patients analyzed revealed that the scores of the revised and expanded Hammersmith scales correlated with the severity of SMA.

As trials and treatments for Spinal Muscular Atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n=56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.

Spinal muscular atrophy was recently added to the Wisconsin newborn screening panel. Here we report our screening methods, algorithm, and outcomes. Methods: A multiplex real-time PCR assay was used to identify newborns with homozygous SMN1 exon 7 deletion, and those newborns’ specimens further underwent a droplet digital PCR assay for SMN2 copy number assessment. An independent dried blood spot specimen was collected and tested to confirm the initial screening results for SMN1 and SMN2. Results: From October 15, 2019 to October 14, 2020, a total of 60,984 newborns were screened for spinal muscular atrophy. Six newborns screened positive for and were confirmed to have spinal muscular atrophy, making the Wisconsin spinal muscular atrophy birth prevalence 1 in 10,164. Of these six infants, two have two copies of SMN2, two have three copies of SMN2, and two have four copies of SMN2. Five newborns received Zolgensma therapy, and one newborn received Spinraza therapy. Conclusions: Our screening method'spositive predictive value is 100%. This comprehensive approach, providing both timely SMN2 information and SMN1 and SMN2 confirmation as parts of the algorithm for spinal muscular atrophy newborn screening, facilitated timely clinical follow-up, family counseling, and treatment planning.

Background: Spinal Muscular Atrophy (SMA) is the most common neurodegenerative disease in childhood. New therapeutic interventions have been developed to interrupt rapid motor deterioration. The current standard of clinical evaluation for severely weak infants is the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), originally developed for SMA type 1. This test however, remains subjective and requires extensive training to be performed reliably. Objective: Proof of principle of the motion tracking method for capturing complex movement patterns in ten children with SMA. Methods: We have developed a system for tracking full-body motion in infants (KineMAT) using a commercially available, low-cost RGB-depth sensor. Ten patients with SMA (2–46 months of age; CHOP INTEND score 10–50) were recorded for 2 minutes during unperturbed spontaneous whole-body activity. Five predefined motion parameters representing 56 degrees of freedom of upper, lower extremities and trunk joints were correlated with CHOP INTEND scores using Pearson product momentum correlation (r). Test-retest analysis in two patients used descriptive statistics. Results: 4/5 preselected motion parameters highly correlated with CHOP INTEND: 1. Standard deviation of joint angles (r = 0.959, test-retest range 1.3–1.9%), 2. Standard deviation of joint position (r = 0.933, test-retest range 2.9%), 3. Absolute distance of hand/foot travelled (r = 0.937, test-retest range 6–10.5%), 4. Absolute distance of hand/foot travelled against gravity (r = 0.923; test-retest range 4.8–8.5%). Conclusions: Markerless whole-body motion capture using the KineMAT proved to objectively capture motor performance in infants and children with SMA across different severity and ages.

Summary Background Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. Methods We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. Findings 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8–59·0, IQR 9–23) and a mean weight of 9·1 kg (range 4·0–15·0, IQR 7·4–10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p Interpretation This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. Funding None. Translation For the German translation of the abstract see Supplementary Materials section.

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Mastication problems can have a negative impact on the intake of food and quality of life. This cross-sectional study characterizes mastication problems using clinical and instrumental assessments in patients with spinal muscular atrophy (SMA) types 2 and 3 with self-reported bulbar problems. We included 27 patients (aged 13–67 years), 18 with SMA type 2 and 9 patients with SMA type 3 (of whom three were still ambulant) and applied a questionnaire, clinical mastication tests (TOMASS and 6-min mastication test), and muscle ultrasound of the mastication muscles. Non-ambulant patients demonstrated inefficient mastication as reflected by median z scores for masticatory cycles (z = 1.8), number of swallows (z = 4.3) and time needed to finish the cracker (z = 3.4), and limited endurance of continuous mastication as demonstrated by the median z scores of the 6-min mastication test (z = − 1.5). Patients reported increased fatigue directly after the 6-min mastication test as well as 5 min after completing the test (p p = 0.003). Reduced maximal mouth opening was associated with mastication problems (p

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene ( SMN1 ). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.

Обзорная статья посвящена одному из наиболее распространенных наследственных нервно-мышечных заболеваний человека – спинальной мышечной атрофии (СМА). Освещены молекулярный патогенез СМА, клиническая классификация, методы ДНК-диагностики этого клинически полиморфного заболевания. Представлена детальная информация о первом препарате для патогенетической нозомодифицирующей терапии СМА – нусинерсене, его механизме действия, режиме дозирования и интратекального введения, а также приведены краткие результаты клинических исследований его эффективности и безопасности при СМА у детей. Основная часть обзора посвящена сведениям об эффективности и безопасности нусинерсена у взрослых пациентов, страдающих СМА, по данным клинической практики. Представлены как результаты отдельных исследований, посвященных применению нусинерсена у взрослых и позволивших получить достоверную информацию об основных клинических эффектах препарата и его безопасности у взрослых с СМА II и III типов, так и результаты метаанализа применения нусинерсена в данной возрастной группе пациентов., This review is dedicated to one of the most common inherited neuromuscular disorders of humans, i.e. spinal muscular atrophy (SMA). Molecular pathogenesis of SMA, clinical classification, and DNA methods of diagnosis for this clinically polymorphic disease are described. Data on nusinersen, the first disease-modifying drug therapy for SMA, its mechanism of action, dosing regimen, intrathecal administration, and results of clinical trials for efficacy and safety in children with SMA are presented in details. The main part of this review is focused on the evidences of efficacy and safety of nusinersen in adults with SMA, referring to the real clinical practice. The results of individual studies on nusinersen efficacy in adults are discussed, providing reliable information about its major clinical effects and safety of application in adults suffering from SMA types 2 and 3, as well as the results of meta-analysis of nusinersen application in this age group of patients.

Background. The efficacy and safety of onasemnogene abeparvovec have been demonstrated in patients with spinal muscular atrophy (SMA) in several clinical and observational studies. Gene replacement therapy results in Russian patients with SMA is not investigated yet.Objective. The aim of the study is to study the safety and efficacy of onasemnogene abeparvovec in children with SMA in real clinical practice.Methods. The study included patients with proximal 5q SMA administered with onasemnogene abeparvovec. Diagnosis was verified by biallelic deletion in the 7th exon of the SMN1 gene. Gene replacement therapy was administered according to the decision of neurologists consensus in case of the absence of antibodies to the adeno-associated serotype 9 virus. The therapy safety was estimated via clinical and laboratory data from the hospital (at least 7 days) and from outpatient departments (at least 60 days). Efficacy was estimated via CHOP INTEND scale and mastering new motor skills ≥ 6 months after therapy onset.Results. Treatment outcomes were studied in 10 SMA patients aged 19 months (15; 21). All patients developed at least one clinical manifestation (hyperthermia, vomiting, lethargy and/or loose stool) associated with drug administration during the first week of follow-up. Increased hepatic transaminases activity and monocytosis was recorded in all patients, thrombocytopenia — in 9, neutropenia — in 5, increased troponin I concentration — in 3. In three cases it was necessary to increase the oral prednisolone dose of to 2 mg/kg, in one case — the dexamethasone pulse therapy dose. The therapy efficacy was monitored ≥ 6 months after therapy onset via the CHOP INTEND scale in 2 patients (scores increased by 32 and 19 points, respectively), and via mastering new motor skills in 8 patients (positive dynamics was noted in 7 cases).Conclusion. The onasemnogene abeparvovec is relatively safe and quite effective for using in real clinical practice

Background. Spinal muscular atrophy 5q (5q SMA) is the most frequent autosomal recessive hereditary neuromuscular disease. Molecular genetic testing is used for SMA diagnosis, and it can confirm only 5q SMA. The clinical findings and results of paraclinical studies may overlap with hereditary primary-muscular diseases making the diagnosis difficult and delaying the administration of pathogenetic treatment for 5q SMA.Clinical case description. Clinical description of 10 patients with 5q SMA aged from 3 months to 25 years with different severity of proximal tetraparesis, skeletal muscular atrophy and tendon reflexes depression is given. 3 patients under 2 years of age with myogenic pattern at needle electromyography (nEMG) in lateral vastus muscle and 7 patients over 2 years of age with increased levels of creatine phosphokinase (CPK) in blood serum were mistakenly diagnosed for inherited primary-muscular diseases for the period from 1 month to 12 years. After the genetic counselling based on the disease course and clinical findings we suspected and later confirmed 5q SMA.Conclusion. In case of flaccid proximal tetraparesis associated with myogenic pattern at nEMG in young children or with increased CPK levels at late manifestation it is crucial to perform differential diagnosis of 5q SMA since there are options of pathogenetic therapy.

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disorder that develops in infancy and arises from mutation of the immunoglobulin helicase μ-binding protein 2 (IGHMBP2) gene. Whereas IGHMBP2 is ubiquitously expressed, loss or reduction of function leads to alpha motor neuron loss and skeletal muscle atrophy. We previously developed a gene therapy strategy for SMARD1 using a single-stranded AAV9-IGHMBP2 vector and compared two different delivery methods in a validated SMARD1 mouse model. An important question in the field relates to the temporal requirements for this or any potential treatment. To examine the therapeutic window, we utilized our recently developed SMARD1 model, FVB/NJ-Ighmpb2nmd-2J, to deliver AAV9-IGHMBP2 at four different time points starting at post-natal day 2 (P2) through P8. At each time point, significant improvements were observed in survival, weight gain, and motor function. Similarly, treatment improved important hallmarks of disease, including motor unit pathology. Whereas improvements were more pronounced in the early-treatment groups, even the later-treatment groups displayed significant phenotypic improvements. This work suggests that an effective gene therapy strategy could provide benefits to pre-symptomatic and early-symptomatic individuals, thereby expanding the potential therapeutic window for SMARD1.

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder caused by reduction of the ubiquitously expressed protein Survival Motor Neuron (SMN). Low levels of SMN impact on spinal cord motoneurons (MNs) causing their degeneration and progressive muscle weakness and atrophy. To study the molecular mechanisms leading to cell loss in SMN-reduced MNs, we analyzed the NF-κB intracellular pathway in SMA models. NF-κB pathway activation is required for survival and regulates SMN levels in cultured MNs. Here we describe that NF-κB members, inhibitor of kappa B kinase beta (IKKβ), and RelA, were reduced in SMA mouse and human MNs. In addition, we observed that Gemin3 protein level was decreased in SMA MNs, but not in non-neuronal SMA cells. Gemin3 is a core member of the SMN complex responsible for small nuclear ribonucleoprotein biogenesis, and it regulates NF-κB activation through the mitogen-activated protein kinase TAK1. Our experiments showed that Gemin3 knockdown reduced SMN, IKKβ, and RelA protein levels, and caused significant neurite degeneration. Overexpression of SMN increased Gemin3 protein in SMA MNs, but did not prevent neurite degeneration in Gemin3 knockdown cells. These data indicated that Gemin3 reduction may contribute to cell degeneration in SMA MNs. This work was supported by grants from Instituto de Salud Carlos III, PI20/00098 y cofinanciado por la Unión Europea, Fundació La Marató TV3 (202005-30), and CERCA Program/Generalitat de Catalunya. Research fellowships have been awarded to AG by the Generalitat de Catalunya (Serra Hunter Fellowship), to AS and MB by IRBLleida-Diputació de Lleida (Grants for the Promotion of Health Research), and to MPM by the Department of Research and Universities, Generalitat de Catalunya, with funds provided by the European Union (Training grants for predoctoral researchers, FI 2022).

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Background. In many countries, problems of rare orphan diseases have recently been discussed, more specifically, hereditary neuromuscular diseases (HNMDs). As for 2020 data, there were about 400 million people worldwide suffering from different types of rare diseases which comprise over 7,000 nosologies. The data from official statistics in many countries do not provide detailed information on the prevalence of HNMDs; it is possible to obtain precise information on morbidity, mortality, analyses of genetic causes, social impact, etc. only in those countries that have registries of patients with HNMDs. Materials and methods. To evaluate the situation with HNMDs in the Republic of Belarus, the pediatric population was examined. The Republican Center for Hereditary Neuromuscular Diseases (RC HNMD) for children was founded, based on which there were formed a computer database and the registry of patients with hereditary neuromuscular diseases. The age of patients was 0 to 18 years old (including 17 years 11 months 29 days). The study was designed as a retrospective, entire, and comparative (by nosologies). Results. As of December 31, 2020, the HNMDs registry for children (0–17 years) demonstrated that the HNMDs prevalence was 2.34 cases per 10,000 age-matched population. The results showed that in type I spinal muscular atrophy the median time before diagnosis verification decreased almost 3-fold: before 2019 it was 7 months, while in 2019–2020, Me = 2.6 months; p < 0.001. Also, there is a significant reduction of the period for verification of the diagnosis of type II spinal muscular atrophy, i.e. from Me = 16 months (before 2019) to Me = 7.5 months (2019–2020), p < 0.05, which demonstrates the importance of establishing a centralized RC HNMD for children in Belarus and substantiates the necessity of developing its structure and cooperation with other community-based and government organizations. Conclusions. Within the structure of HNMDs nosologies, the top ones were taken by Duchenne-Becker muscular dystrophy — 0.8 per 10.000 age-matched population people spinal muscular atrophy — 0.5 per 10,000 of age-matched population, hereditary polyneuropathies — 0.4 by 10,000 of age-matched population. The study results show that the proportion of children born preterm (before 37 weeks of gestation) from the total amount of all children with registered HNMD accounts for 6.4 %, while the highest rate was found for spinal muscular atrophy, which gives the reason to study children born preterm from the standpoint of alertness due to HNMD. The register data in the Republic of Belarus demonstrate the highest specific weight of dystrophynopathies within the structure of HNMDs, which made 40.8 % (178/436) from the total number of HNMDs cases of Registry with the prevalence of 0.95 per 10,000 age-matched population (0–17 years) along with limb-girdle muscular dystrophies, facioscapulohumeral muscular dystrophies., Актуальність. За даними 2020 року, у світі налічується близько 400 мільйонів осіб із різними типами рідкісних захворювань, що включають понад 7000 нозологій. Дані офіційної статистики в багатьох країнах не дають докладної інформації про захворюваність на спадкові нервово-м’язові захворювання (СНМЗ); лише в країнах, що мають регістри пацієнтів із СНМЗ, можливо отримати детальну інформацію про захворюваність, смертність, аналіз генетичних причин, соціальні наслідки та ін. Матеріали та методи. Для оцінки ситуації з СНМЗ у Республіці Білорусь досліджували дитяче населення. Створено Республіканський центр спадкових нервово-м’язових захворювань (РЦ СНМЗ) для дітей, на базі якого сформовані комп’ютерна база даних і регістр СНМЗ. До популяції увійшли пацієнти віком від 0 до 18 років (включно 17 років 11 місяців 29 днів). Виконано ретроспективне суцільне порівняльне (за нозологіями) дослідження. Результати. На підставі даних регістру СНМЗ для дітей (0–17 років) встановлена поширеність СНМЗ у педіатричній популяції на 31.12.2020 року — 2,34 випадку на 10 000 населення відповідного віку. Результати показали, що при спінальній м’язовій атрофії (СМА) I типу медіана часу до встановлення діагнозу скоротилася майже втричі: так, якщо в період до 2019 р. Me = 7 місяців, то в 2019–2020 роках Me = 2,6 місяця, p ˂ 0,001. Також суттєво скоротилися терміни верифікації діагнозу СМА II типу: від Мe = 16 місяців (у період до 2019 р.) до Me = 7,5 місяця (2019–2020 рр.), p ˂ 0,05, що вказує на важливість створення централізованого РЦ СНМЗ для дітей у Республіці Білорусь і підтверджує необхідність роботи з розвитку його структури та взаємодії з іншими громадськими та державними організаціями. Висновки. У структурі нозологій СНМЗ лідирували міодистрофії Дюшенна — Беккера — 0,8 на 10 000 населення (0–17 років), СМА — 0,5 на 10 000 населення (0–17 років), спадкові полінейропатії — 0,4 на 10 000 населення (0–17 років). Частка народжених недоношеними (до 37 тижнів терміну гестації) із числа всіх дітей, зареєстрованих із СНМЗ, становила 6,4 %, при цьому найбільш висока відзначена у випадках СМА, що дає підставу розглядати недоношених новонароджених із позицій настороженості щодо СНМЗ. Висока питома вага в структурі СНМЗ, за даними регістру, в Республіці Білорусь належить дистрофінопатіям, які разом із попереково-кінцівковими міодистрофіями, фаціоскапулохумеральними м’язовими дистрофіями становили 40,8 % (178/436) від загальної кількості випадків СНМЗ у регістрі, досягаючи поширеності 0,95 на 10 000 населення (0–17 років).

Spinal muscular atrophy (SMA) is characterized by the loss of alpha motor neurons in the spinal cord and a progressive muscle weakness and atrophy. SMA is caused by loss-of-function mutations and/or deletions in the survival of motor neuron (SMN) gene. The role of SMN in motor neurons has been extensively studied, but its function and the consequences of its loss in muscle have also emerged as a key aspect of SMA pathology. In this study, we explore the molecular mechanisms involved in muscle defects in SMA. First, we show in C2C12 myoblasts, that arginine methylation by CARM1 controls myogenic differentiation. More specifically, the methylation of HuR on K217 regulates HuR levels and subcellular localization during myogenic differentiation, and the formation of myotubes. Furthermore, we demonstrate that SMN and HuR interact in C2C12 myoblasts. Interestingly, the SMA-causing E134K point mutation within the SMN Tudor domain, and CARM1 depletion, modulate the SMN–HuR interaction. In addition, using the Smn2B/− mouse model, we report that CARM1 levels are markedly increased in SMA muscles and that HuR fails to properly respond to muscle denervation, thereby affecting the regulation of its mRNA targets. Altogether, our results show a novel CARM1–HuR axis in the regulation of muscle differentiation and plasticity as well as in the aberrant regulation of this axis caused by the absence of SMN in SMA muscle. With the recent developments of therapeutics targeting motor neurons, this study further indicates the need for more global therapeutic approaches for SMA.

The article presents up-to-date data on the peculiarities of the diagnosis of spinal muscular atrophy (SMA) in childhood. It has been shown that the progressive motor neurons degeneration in the spinal cord and brainstem resulting in system damage, such as progressive muscle weakness, hypotonia, muscles atrophy, developmental delay, bulbar syndrome, paradoxical breathing, heart, respiratory failure, damage to the bones and internal organs, is caused by survival of motor neuron 1 gene mutation, which codes for a full-length survival motor neuron protein necessary for motor neurons. Consequently, genetic testing is important to confirm SMA diagnosis as early as possible to prescribe treatment for the patients in time. Moreover, prescribed SMA treatment according to contemporary standards using the new disease-modifying medicines have created a turning point in SMA management and it appeared to slow disease progression and prolong motor development and ability to walk compared to the known natural history., В статье представлены современные данные об особенностях диагностики спинальных мышечных атрофий (СМА) у детей. Показано, что мутации гена выживаемости мотонейронов обусловливают недостаточный синтез соответствующего белка, что оказывается критичным для выживания мотонейронов и приводит к их дегенерации с развитием системных поражений в виде прогрессирующей мышечной слабости, мышечной гипотонии, атрофии мышц, проксимальных симметричных вялых парезов, потерей пациентом двигательных функций, развитием бульбарного синдрома, парадоксального брюшного дыхания, поражений сердечно-сосудистой, дыхательной системы, костной ткани и внутренних органов. Таким образом, своевременно проведенное генетическое обследование подтверждает клинический диагноз СМА и обеспечивает раннюю диагностику и назначение адекватной терапии таким больным. Более того, лечение СМА согласно современным стандартам, в том числе с применением новых препаратов болезньмодифицирующей терапии, способно замедлить прогрессирование и стабилизировать течение заболевания., У статті наведені сучасні дані про особливості діагностики спінальних м’язових атрофій (СМА) в дитячому віці. Показано, що мутації гена виживання мотонейронів обумовлюють недостатній синтез відповідного білка, що виявляється критичним для виживання мотонейронів і призводить до їх дегенерації з розвитком системних уражень у вигляді прогресуючої м’язової слабкості, м’язової гіпотонії, атрофії м’язів, проксимальних симетричних млявих парезів, втратою пацієнтом моторних функцій, розвитком бульбарного синдрому, парадоксального черевного дихання, ураження серцево-судинної, дихальної системи, кісткової тканини і внутрішніх органів. Отже, своєчасно проведене генетичне обстеження підтверджує клінічний діагноз СМА і забезпечує ранню діагностику й призначення адекватної терапії таким хворим. Більше того, лікування СМА згідно із сучасними стандартами, у тому числі із залученням нових препаратів хворобомодифікуючої терапії, здатне уповільнити прогресування й стабілізувати перебіг захворювання.

Objective: To identify factors parents considered in treatment decision making for children diagnosed with spinal muscular atrophy on newborn screening. Methods: Participants were recruited through the University of Rochester or through flyers and Cure SMA social media outreach and asked to complete a telephone or online survey. Data were analyzed through mixed methods using descriptive statistics and theme identification in narrative responses. Results: Eighteen parents with children diagnosed with spinal muscular atrophy on newborn screening participated. Thirteen of 18 chose onasemnogene abeparvovec, 2 of 18 chose risdiplam, 1 of 18 chose nusinersen, and 2 of 18 did not receive treatment. The most commonly reported factors impacting treatment choice included treatment frequency and administration method. Seventeen (94.4%) parents felt that inclusion of spinal muscular atrophy on newborn screening was positive because it could allow for better outcomes with earlier treatment. Conclusion: Treatment frequency and administration method were the most important factors for parents in determining spinal muscular atrophy treatment. Parents felt positively about newborn screening due to opportunity for earlier treatment.

BACKGROUND: Cerebral Palsy (CP) and Spinal Muscular Atrophy (SMA) are common causes of motor disability in childhood. Gait exoskeletons are currently being used as part of rehabilitation for children with walking difficulties. OBJECTIVE: To assess the safety and efficacy and describe the main characteristics of the clinical articles using robot-assisted gait training (RAGT) with exoskeleton for children with CP or SMA. METHODS: A computer search was conducted in five bibliographic databases regarding clinical studies published in the last ten years. In order to be included in this review for further analysis, the studies had to meet the following criteria: (1) assess efficacy or safety of interventions; (2) population had to be children with CP or SMA aged between 3 and 14; (3) exoskeleton must be bilateral and assist lower limbs during walking. RESULTS: Twenty-one articles were selected, of which only five were clinical trials. 108 participants met the inclusion criteria for this study, all with a diagnosis of CP. The evidence level of the selected papers was commonly low. CONCLUSIONS: RAGT therapy seems to be safe for children with CP. However, further investigation is needed to confirm the results related to efficacy. There is no evidence of RAGT therapy for SMA children.

Spinal muscular atrophy with respiratory distress type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot-Marie Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype, including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively, this model provides important biological insight into SMARD1 disease development.

Motor neuron diseases involve degeneration of motor neurons in the brain (upper motor neurons), brain stem, and spinal cord (lower motor neurons). Symptoms vary depending on the degree of upper and lower neuron involvement, but progressive painless weakness is the predominant complaint. Motor neuron disease includes numerous specific disorders, including amyotrophic lateral sclerosis, spinal muscular atrophy, spinal bulbar muscular atrophy, and other inherited and acquired conditions. Abnormalities on nerve conduction studies, repetitive nerve stimulation, needle electromyography, and other electrodiagnostic techniques help to distinguish these disorders from each other, and from other disorders with progressive weakness.

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, typically caused by survival motor neuron 1 (SMN1) gene deletion in chromosome 5q resulting in loss of SMN protein. SMA type 1 progresses rapidly leading to increased mortality usually before the age of 2 years. Nusinersen, the first approved disease-modifying treatment for all 5q-SMA types and ages, is an antisense oligonucleotide administered intrathecally via repeated lumbar punctures. However, adult SMA patients typically present with severe scoliosis and spinal deformity. We present a 28-year-old patient with SMA type 1 and severe spinal deformity, who received nusinersen via a subcutaneously implanted Ommaya reservoir connected with an intrathecal catheter at the thoracic level. The repetitive administrations were completed uneventfully, obviating the need for repeated laborious lumbar punctures and eliminating radiation exposure. In adult SMA patients, performing recurrent lumbar punctures can be technically challenging raising the need for an alternative route of administration. The use of Ommaya reservoirs is a viable, practical for repeated infusions, and safe option for the intrathecal delivery of nusinersen for select cases such as an adult SMA type 1 survivor with severe spinal deformity.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington's disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells' substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

Spinal muscular atrophy (SMA), a degenerative motor neuron disease and a leading cause of infant mortality, is caused by loss of functional survival motor neuron (SMN) protein due to SMN1 gene mutation. Here, using mouse and cell models for behavioral and histological studies, we found that SENP2 (SUMO/sentrin-specific protease 2)-deficient mice developed a notable SMA-like pathology phenotype with significantly decreased muscle fibers and motor neurons. At the molecular level, SENP2 deficiency in mice did not affect transcription but decreased SMN protein levels by promoting the SUMOylation of SMN. SMN was modified by SUMO2 with the E3 PIAS2α and deconjugated by SENP2. SUMOylation of SMN accelerated its degradation by the ubiquitin-proteasome degradation pathway with the ubiquitin E1 UBA1 (ubiquitin-like modifier activating enzyme 1) and E3 ITCH. SUMOylation of SMN increased its acetylation to inhibit the formation of Cajal bodies (CBs). These results showed that SENP2 deficiency induced hyper-SUMOylation of the SMN protein, which further affected the stability and functions of the SMN protein, eventually leading to the SMA-like phenotype. Thus, we uncovered the important roles for hyper-SUMOylation of SMN induced by SENP2 deficiency in motor neurons and provided a novel targeted therapeutic strategy for SMA. KEY MESSAGES: SENP2 deficiency enhanced the hyper-SUMOylation of SMN and promoted the degradation of SMN by the ubiquitin-proteasome pathway. SUMOylation increased the acetylation of SMN to inhibit CB formation. SENP2 deficiency caused hyper-SUMOylation of SMN protein, which further affected the stability and functions of SMN protein and eventually led to the occurrence of SMA-like pathology.

Background. Spinal muscular atrophies (SMA) are clinically and genetically heterogenous inherited orphan diseases leading to progressive spinal motoneurons degeneration and loss of function. Risdiplam and nusinersen are both authorized in Russia for pathogenic SMA treatment and included in the list of vital and essential drugs.Objective: health economic evaluation of risdiplam (Evrysdi®) in patients with spinal muscular atrophy.Material and methods. The health economic analysis was done in accordance with local Russian regulation. Cost-minimization analysis was used. We accounted for direct medical costs of pathogenic treatment of SMA, adverse events correction, and supportive care. Decision tree analysis was used. In budget impact analysis the rise of risdiplam share from 0% to 8.5% during 3 years was modelled. Time horizon was 3 years. Probabilistic sensitivity analysis was done.Results. Total direct medical costs for risdiplam (53,372,153 rubles for one patient in 3 years) were by 21.1% (14,968,427.82 rubles) lower comparing to nusinersen. The most pronounced difference in favor of risdiplam (41,9%) was during first treatment year. The rise of risdiplam share from 0% to 8.5% during 3 years is associated with lower budget costs by 13.9% in 3 years.Conclusion. Risdiplam is economically more effective comparing to nusinersen, because having equal effectiveness, it’s use is associated with lower direct medical costs.

In this article we review the commonest cause of neurogenic arthrogryposis, termed Spinal Muscular Atrophy Lower Extremity Dominant (SMALED), due to variants in DYNC1H1 and BICD2. We discuss the characteristic clinical and radiological phenotype of this disorder and how this has facilitated the identification of the genetic cause of SMALED2. We also review the similarities and differences between the human SMALED phenotype and mouse models and how this has informed our understanding of the potential mechanisms governing motor neuron loss in these disorders.

Closing the gap in knowledge on the cause of neurodegenerative disorders is paving the way toward innovative treatment strategies, among which gene therapy has emerged as a top candidate. Both conventional gene therapy and genome editing approaches are being developed, and a great number of human clinical trials are ongoing. Already 2 years ago, the first gene therapy for a neurodegenerative disease, spinal muscular atrophy type 1 (SMA1), obtained market approval. To realize such innovative strategies, gene therapy delivery tools are key assets. Here, we focus on recombinant adeno-associated virus (AAV) vectors and report on strategies to improve first-generation vectors. Current efforts focus on the viral capsid to modify the host-vector interaction aiming at increasing the efficacy of target cell transduction, at simplifying vector administration, and at reducing the risk of vector dose-related side effects.

Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.

Neuromuscular diseases represent an heterogenous group of more than 400 diseases, with a very broad phenotypic spectrum. Given their rarity and complexity, neuromuscular diseases are often diagnosed with a very significant delay after which irreversible muscle damage may limit the efficacy of treatments when available. In this context, neonatal screening could constitute a solution for early detection and treatment. A systematic review of the literature in PubMed up to May 1, 2021, was conducted according to PRISMA guidelines, including classical neuromuscular diseases and diseases with a clear peripheral nervous system involvement (including central nervous system disease with severe neuropathy). We found seven diseases for which newborn screening data were reported: spinal muscular atrophy (9), Duchenne muscular dystrophy (9), Pompe disease (8), X-linked adrenoleukodystrophy (5), Krabbe disease (4), Myotonic dystrophy type 1 (1), metachromatic leukodystrophy (1). The future of newborn screening for neuromuscular disorders pass through a global technological switch, from a biochemical to a genetic-based approach. The rapid development of therapy also requires the possibility to quickly adapt the list of treated conditions, to allow innovative therapies to achieve their best efficacy.

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300–1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans. Biodistribution analysis of two patients with spinal muscular atrophy shows widespread onasemnogene abeparvovec DNA, mRNA and SMN protein throughout the central nervous system and peripheral organs following intravenous gene therapy administration.

Objective. To analyze the natural course of type 1 spinal muscular atrophy in children with the onset of the disease up to 6 months in the Russian population.Material and methods. The retrospective multicenter study included data of 54 children with an established diagnosis of type 1 spinal muscular atrophy who did not receive therapy with nusinersen, risdiplam, branaplam, onasemogen abeparvovec-xioi, or other anti-sense oligonucleotides / selective SMN2 splicing modifiers or genetherapy drugs for SMN1 genetransduction. Basedon medical records, the scientists have collected all available information on the health status of children, the need for respiratory support and death or start of long-term mechanical ventilation.Results. The median time from birth to the onset of the combined event (death or initiation of long-term respiratory support), determined using the Kaplan-Meier method, was 365 [269; 409] days (12 months). The date of death was known in 22 out of 54 children. The median age of death was 301,5 [181; 375] days (9,9 months). The initiation date of long-term respiratory support was known in 15 of 54 patients, the median was 180 [91; 276] days (5,9 months). Both the start date of long-term respiratory support and the date of death were known in 5 of 54 children; whileit was found that the median time from the initiation of long-term respiratory support to death in these children was 361 [135; 619] day (11,87 months).In a subgroup of 32 children with available date of initiation of long-term respiratory support and / or the date of death, the median time from birth to the combined event was 245,5 [173; 331] days (8,07 months).Conclusion. In the course of a retrospective study, the authors obtained the information on the date of the onset of constant respiratory support and the date of death from the date of birth in the absence of pathogenetic treatment in children with type 1 spinal muscular atrophy. The data obtained in the Russian population are comparable with the published international data. This information can be useful for additional assessment of the health status of patients who received drugs affecting the level of SMN protein in the body, as well as reference data for the development of new approaches to therapy.

Miracles, like London buses, just seem to come along. The truth is, there are no miracles, just lots of hard work behind the scenes, minds open to opportunity, serendipity, and possibly a little luck. In my time as a pediatric respiratory physician, I have borne witness to remarkable advances in treatment that have changed patients' fortunes overnight. Examples of these include artificial surfactant replacement for premature newborns, conjugate Haemophilus influenzae type b vaccination, propranolol for infants with subglottic haemangiomas, mandibular distraction for babies with micrognathia, cystic fibrosis transmembrane conductance regulator modulators therapy for patients with cystic fibrosis, and antisense oligonucleotide therapy for infants with spinal muscular atrophy. There are lessons to be learned from reflection upon these life-transforming treatments, and perhaps it is a good time just to pause and wonder.

Few studies have characterised the relationship between disease and gait function in children and young people with rare neuromuscular disorders (NMDs). This study aimed to describe the relationship between disease and gait in a large paediatric cohort from a neuromuscular outpatient clinic. A prospective, cross-sectional study of gait in independently ambulant children and young people aged 4–21 years with a clinical or genetically confirmed NMD. Participants traversed an electronic walkway barefoot and in footwear at self-selected and fast pace. Analysis of disease included a typically developing (TD) reference group. A sample of 113 participants with NMD, mean age 9.5 years (SD 3.1), 28% female, grouped into nine diagnostic subgroups. Eighty percent reported limitations to functional mobility. Children with NMD walked slower, with a shorter and wider step compared to a TD reference group, with moderate to large effect sizes for each of these gait parameters indicative of the clinical significance of these gait deviations. Children with Duchenne muscular dystrophy (DMD) walked slowest with a markedly wide gait pattern. Footwear had little overall effect on gait in children with NMDs. All children could accelerate over short distances. Gait, notably speed, step length, and width are clinically significant biomarkers of disease in paediatric NMDs, affording objective functional measures in clinical settings and research.Implications for rehabilitationGait should be considered a functional biomarker of disease in children and young people with neuromuscular disorders (NMDs).Comparison of gait in a paediatric neuromuscular cohort indicates that children with Duchenne muscular dystrophy (DMD) walk slowest with a shorter step length and a wider step width which increases with age and disease progression.Measurement of gait speed is a simple, pragmatic tool to monitor disease progression in the outpatient clinical environment and relates to everyday function.In clinical research, gait can be measured as a functional outcome to demonstrate change from disease-modifying interventions and treatments in NMDs. Gait should be considered a functional biomarker of disease in children and young people with neuromuscular disorders (NMDs). Comparison of gait in a paediatric neuromuscular cohort indicates that children with Duchenne muscular dystrophy (DMD) walk slowest with a shorter step length and a wider step width which increases with age and disease progression. Measurement of gait speed is a simple, pragmatic tool to monitor disease progression in the outpatient clinical environment and relates to everyday function. In clinical research, gait can be measured as a functional outcome to demonstrate change from disease-modifying interventions and treatments in NMDs.

Background. Analysis of Pompe disease (PD) clinical features in children in order to determine its main clinical and laboratory characteristics based on the results of laboratory and instrumental studies that allow to select such patients into the screening group for enzymatic diagnosis in dried blood spots was the objective of this study. Materials and methods. In a period from 2002 to 2016, 522 children with PD suspicion were examined in the Center of Orphan Diseases of National Children’s Specialized Hospital “Ohmatdyt”. There were 282 boys and 240 girls aged from 4 months to 13 years. Results. According to electroneuromyography results and mutations in SMN gene revealing, spinal muscular atrophy was diagnosed in 98 (19 %) patients, Duchenne primary muscular dystrophy — in 70 (13 %). 71 (13.6 %) patients had different forms of hereditary neuropathy. In 38 (7.2 %) cases, the dominant type of disease inheritance was revealed, later we did not provide laboratory tests in those patients in order to confirm the PD diagnosis. Thus, 245 (47 %) patients were included into the selective (screening) group for enzymatic diagnosis using dried blood spot. In these patients, a heterogeneous clinical picture of the disease was noted: muscle weakness due to myopathic syndrome in combination with cardiomyopathy, delay in physical development, hyperCKemia. Twenty five patients aged 2 to 8 months besides myopathic syndrome had elevated levels of alanine aminotransferase and aspartate aminotransferase, creatine phosphokinase (more than 220 U/l), lactate dehydrogenase (more than 250 U/l), left ventricular hypertrophic cardiomyopathy; also in 10 patients, hepatomegaly and cardiopulmonary failure were revealed. Based on enzymatic tests, PD diagnosis (infantile form) was established in 5 patients (in 3 cases — classical form, in 2 cases — atypical). The clinical picture was heterogeneous, however, in all cases, slow increase in body weight, delay of static and kinetic skills forming were noted. Three patients receive enzyme replacement therapy. This allowed to prevent early death, and in one case, it was almost possible to restore independent walking. Conclusions. PD in children is characterized by different system failure and various clinical forms, in specific treatment absence, PD leads to patients’ early death. The PD main manifestations in children are hypertrophic cardiomyopathy, myopathic syndrome in combination with a specific biochemical phenotype. Enzymatic diagnosis in dried blood spots in the group of selective screening will increase the effectiveness of PD early diagnosis and treatment in children.

During the last decade a number of innovative treatments including gene therapies have been approved for the treatment of monogenic inherited diseases. For some neuromuscular diseases these approaches have dramatically changed the course of the disease. For others relevant challenges still remain and require disease specific approaches to overcome difficulties related to the immune response and the efficient transduction of target cells. This review provides an overview of the current development status of mutation specific treatments for neuromuscular diseases and concludes with on outlook on future developments and perspectives.

Introduction/aims Spinal muscular atrophy (SMA) type III is a relatively mild form of SMA. Few studies have investigated the changes in both respiratory and upper limb function within this population after loss of ambulation. The aim of this study was to assess change in percentage of predicted forced vital capacity (FVC% predicted) and change in the Revised Upper Limb Module (RULM) score in these patients throughout a 24-month period after loss of ambulation. Effect of scoliosis and its surgical correction, disease duration since loss of ambulation, weight, and height were also investigated. Methods Retrospective analyses were performed on 24 nonambulant SMA III patients from data collected at two centers in the United Kingdom. Results The FVC% predicted score showed a significant progressive deterioration of 17% over the 24-month period. Respiratory deterioration correlated significantly with age, weight, disease duration since loss of ambulation, and spinal correctional surgery. Longitudinal RULM data were available for 16 patients; a significant deterioration was observed with a mean decrease in score of 3 over 24 months. Age correlated negatively with RULM score, as did height and time since loss of ambulation. A significant positive correlation between FVC% predicted and RULM was demonstrated. Discussion This study highlights how SMA type III patients have progressive deterioration of respiratory and upper limb function after loss of ambulation. Combining data from these assessments could provide insight into clinical progression, inform clinical trials, and provide assistance in managing disease progression expectations for patients.

Spinal muscular atrophy is a heterogeneous disease that results in loss of motor function. In an evolving treatment landscape, establishing the suitability and limitations of existing motor function scales and patient-reported outcomes used to monitor patients with this disease is important. A systematic review was conducted to examine utility of motor function scales and patient-reported outcomes in evaluating patients with spinal muscular atrophy. Published literature was reviewed up to June 2021 with no start date restriction. Of the reports screened, 122 were deemed appropriate for inclusion and are discussed in this review (including 24 validation studies for motor function scales or patient-reported outcomes). Fifteen motor function scales and patient-reported outcomes were identified to be commonly used (≥5 studies), of which 11 had available validation assessments. Each instrument has its strengths and limitations. It is imperative that the patient population (e.g., age, mobility), goals of treatment, and outcomes or endpoints of interest be considered when selecting the appropriate motor function scales and patient-reported outcomes for clinical studies.

Background The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot–Marie–Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria. Case reports Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic–clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2. Conclusions DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.

Introduction: Communicating the diagnosis of a genetic and neurodegenerative disease, such as spinal muscular atrophy (SMA), requires a transmission centered on the patient and/or the family caregiver, ensuring autonomy to those involved and strengthening the doctor–patient relationship. Objective: Analyzing the communication of the SMA diagnosis from the perspective of patients and family members. Methods: This qualitative study was developed through semi-structured interviews, via teleconsultation. The analysis was developed by systematically condensing the answers and synthesizing them into four thematic axes (clarification of the diagnosis, communication of the prognosis, affective memory related to the event, and advice to physicians). Results and discussion: Twenty-nine patients with SMA and 28 family caregivers of people with this condition, from all regions of Brazil, reported that individualized, clear, honest, and welcoming communication, emphasizing positive aspects, in the presence of family members and with the possibility of continuous monitoring, was important to meeting their communication needs. A lack of empathy, monitoring and guidance, and estimating life expectancy resulted in negative experiences. Conclusions: The communication needs of patients and family members described during the clarification of the diagnosis and prognosis of SMA predominantly involve empathic factors related to the attitude of the attending physician throughout the evolution of the disease. Future research evaluating other neurodegenerative diseases and the development of research protocols are important to improving communication between physicians, patients, and family members.

Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives. This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured. A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items. This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA.

BackgroundThe aim of this study was to evaluate the prevalence of anxiety, depression, sleep, and associated factors in caregivers of children with spinal muscular atrophy (SMA). Materials and MethodsBeck Depression Inventory (BDI), the State-Trait Anxiety Inventory-State (STAI-S), the State-Trait Anxiety Inventory-Trait (STAI-T), and Pittsburgh Sleep Quality Index (PSQI) were used to assess the anxiety, depression, and sleep quality of the caregivers of children with SMA. Higher scores indicated worse outcome for all three questionnaires. ResultsFifty-six caregivers of children with SMA were included in the study. Median age of children was 6 (3.2-10) years and mean age of the caregivers was 37.0 +/- 6.5 years. Median scores of the BDI, STAI-S, STAI-T, and PSQI were 12 (7.2-17), 35.5 (31-44), 40.5 (35-48), and 7.0 (5.0-10.0), respectively. There was a positive correlation between BDI and PSQI scores (p < 0.05). There was a negative correlation between the age of the caregivers and PSQI, BDI, STAI-T scores (p = 0.01, r = -0.341; p = 0.006, r = -0.364; p = 0.003, r = -0.395, respectively). There was a negative correlation between the age of the patients and the PSQI scores of the caregivers (p = 0.01, r = -0.33). There was a negative correlation between BDI scores and household income (p = 0.01, r = -0.34). ConclusionCaregivers of children with SMA had elevated depression and anxiety levels and they also had decreased sleep quality. Economic and social support resources are needed to help caregivers of those children.

AIM This study explored hypoglycaemia and metabolic crises, including hyperketosis, in patients with spinal muscular atrophy (SMA). METHODS The study comprised four adolescents aged 15-17 and six adults aged 19-37 with SMA type II and eight adult controls aged 21-41, who were recruited by the Rigshospitalet, Denmark, from May 1st to October 30th 2017. We used stable isotope technique and indirect calorimetry to investigate fat and glucose metabolism during a 24-h fast or until hypoglycaemia occurred. RESULTS All patients with SMA II developed moderate to severe hyperketosis and 60% had symptoms of hypoglycaemia or blood glucose levels below 3 mmol/L. None of the controls developed hyperketosis or hypoglycaemia. Plasma bicarbonate decreased, in line with increased ketone bodies, indicating the start of metabolic acidosis in patients with SMA II. Increased fat production and utilisation were seen in healthy controls during the fasting period, but were absent in patients with SMA II, indicating blunted fat oxidation. CONCLUSION Low skeletal muscle mass was the best explanation for why patients with SMA II had an increased risk of hypoglycaemia, hyperketosis, metabolic acidosis and disturbed fat and glucose metabolism during fasting. These risks have implications for children facing surgery and those with severe illnesses.