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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. Studies of the economic impact of disease on society or the social and economic burden, known as developmental disease cost analysis, are equivalent to public health epidemiological studies. Spinal muscular atrophy (SMA) has significant social and economic burden according to various studies.Objective. The aim of the study is to compare Russian and international methodological approaches and results of health technology assessment (HTA) of SMA from the perspective of social and economic burden. Materials and methods. Literature searches were conducted using the Medline, PubMed, ClinicalTrials.gov, and Cochrane Library databases. Keywords and criteria for inclusion and exclusion have been used. The following parameters were used: costs, year of calculation, assessment method, primary and secondary results, type of economic assessment, perspective, time horizon, intervention, analysis of the sensitivity of the results. Both direct medical and non-medical costs were taken into account, as well as indirect costs.Results. The analysis of SMA burden the USA, Germany, Spain, Australia, France, Great Britain, and the Russian Federation was carried out based on 8 international studies and one Russian study that described the costs of SMA. All costs, including indirect ones, were estimated only in 4 international studies and in Russian one. The main source of information was either patient registers or cross-sectional retrospective studies of patients diagnosed with SMA. The costs were higher for type I SMA in all countries. The highest total SMA costs were in the United States, and the lowest in Russian Federation and Spain. Costs excluded new disease-modifying drugs such as nusinersen, risdiplam, and onasemogen abeparvovec in all conducted studies.Conclusions. The social and economic burden of SMA in Russian Federation in 2020 before the introduction of pathogenetic therapy into practice was 2.38 billion RUR/year. The costs of inpatient treatment and rehabilitation were 30.8 and 32.3% of total costs, respectively. These costs, before the introduction of pathogenetic therapy into practice, are lower than in Western Europe and United States, which is most likely since domestic studies used the standards of primary health care for children with SMA implemented in 2012, as well as low indirect costs for SMA in Russian Federation. Unified methodology for assessing the socio-economic significance of orphan diseases is required to carry out HTA of orphan diseases in Russian Federation. It should be based on domestic registries, otherwise on valid data, including those based on data from real clinical practice (RWD /RWE).

This longitudinal cohort study aimed to determine whether circulating neurofilaments (NFs) can monitor response to molecular therapies in newborns with spinal muscular atrophy (SMA; NCT02831296). We applied a mixed-effect model to examine differences in serum NF levels among healthy control infants (n = 13), untreated SMA infants (n = 68), and SMA infants who received the genetic therapies nusinersen and/or onasemnogene abeparvovec (n = 22). Increased NF levels were inversely associated with SMN2 copy number. SMA infants treated with either nusinersen or onasemnogene abeparvovec achieved important motor milestones not observed in the untreated cohort. NF levels declined more rapidly in the nusinersen cohort as compared with the untreated cohort. Unexpectedly, those receiving onasemnogene abeparvovec monotherapy showed a significant rise in NF levels regardless of SMN2 copy number. In contrast, symptomatic SMA infants who received nusinersen, followed by onasemnogene abeparvovec within a short interval after, did not show an elevation in NF levels. While NF cannot be used as the single marker to predict outcomes, the elevated NF levels observed with onasemnogene abeparvovec and its absence in infants treated first with nusinersen may indicate a protective effect of co-therapy during a critical period of vulnerability to acute denervation., Graphical abstract, These findings show serum neurofilaments as biomarkers to monitor spinal muscular atrophy disease onset, progression, and treatment response early in life. The absence of elevated neurofilament levels in infants treated first with nusinersen may indicate a protective effect of co-therapy with nusinersen and gene therapy during a critical period.

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).

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.

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.

Introduction Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited. Methods We conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1–3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs. Results We identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types. Conclusion Our analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01938-w.

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.

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.

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 Spinal muscular atrophy (SMA) is a rare neurogenetic disease which involves multisystem dysfunctions such as respiratory, digestive, and motor disorders. Anxiety, depression and other psychological disorders often accompany severe chronic physical diseases. The aim of this study was to investigate the prevalence of anxiety and depression along with their influencing factors among school-age patients with SMA. Methods We conducted a cross-sectional study on school-age SMA patients in China. Patients aged 8–18 years with a genetic diagnosis of 5qSMA were invited to answer a questionnaire composed of sociodemographic and clinical questions, then to complete the Screen for Child Anxiety-Related Emotional Disorders and Depression Self-Rating Scale for depression and anxiety level evaluation. At the end of the questionnaire, further questions assessed the subjective anxiety and subjective depression of patients’ caregivers and their expectations for their child’s future. Results Complete data were available for 155 patients. The sample included 45.8% boys and 54.2% girls; 65.2% were type II, 27.1% were type III, and the remainder were type I SMA. Rates of anxiety and depression in these school-age SMA patients were 40.0% and 25.2%, respectively. Gender, age, and disease type were not associated with anxiety or depression, but respiratory system dysfunction, digestive system dysfunction, skeletal deformity, rehabilitation exercise, academic delay, specialized support from school, household income level, caregivers’ subjective anxiety, and caregivers’ expectations were significantly related to both anxiety and depression. Conclusions There was a high prevalence of anxiety and depression in school-age SMA patients in China. Professional psychological care maybe included in the standard of care. These results also call for possible targets for intervention such as reducing complications, improving drug accessibility, retaining normal schooling, strengthening school support, and enhancing the ability of the caregivers of SMA patients to assist in the diagnosis and treatment of the disease, so improving the mental health of SMA patients.

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.

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.

Most childhood neuromuscular disorders are caused by mutations causing abnormal expression or regulation of single genes or genetic pathways. The potential for gene therapy, gene editing and genetic therapies to ameliorate the course of these conditions is extraordinarily exciting, but there are significant challenges associated with their use, particularly with respect to safety, efficacy, cost and equity. Engagement with these novel technologies mandates careful assessment of the benefits and burdens of treatment for the patient, their family and their society. The examples provided by spinal muscular atrophy and Duchenne muscular dystrophy illustrate the potential value and challenges of gene and genetic therapies for paediatric neurological conditions. The cost and complexity of administration of these agents is a challenge for all countries. Jurisdictional variations in availability of newborn screening, genetic diagnostics, drug approval and reimbursement pathways, treatment and rehabilitation will affect equity of access, nationally and internationally. These challenges will best be addressed by collaboration by governments, pharma, clinicians and patient groups to establish frameworks for safe and cost-effective use of these exciting new therapies.

Introduction/aims Intrathecal nusinersen administration can be challenging in certain adult spinal muscular atrophy (SMA) patients with difficult spinal anatomy who require imaging techniques (fluoroscopy or computed tomography scans) or invasive approaches (catheter placement, laminotomy) to identify the intrathecal space. We used ultrasound (US) assistance to access the lumbar intrathecal space in patients with SMA who experienced previous difficulties or failures with intrathecal dosing. Methods Eighteen adult patients with difficult spines were enrolled. We used ultrasound assistance and we recorded the successful administrations, number of attempts, procedure times and "patient satisfaction". Results There were 57 consecutive successful nusinersen spinal administrations in all patients enrolled. In 50% of patients 2 or fewer attempts were needed to obtain a successful administration, with 4 or fewer attempts in 83.3%; only 3 patients reported more than 4 attempts because of both severe scoliosis and severe spine rotation (2 patients) and obesity (1 patient). The mean procedure time was 11.8 minutes (range 1.7-28.9). Patient satisfaction was 4.97/5 (range 4-5, median 5) on Likert scale at 5 minutes and at 72 hours. No major adverse events were reported, and 2 post-dural puncture headaches were managed with medical therapy and with complete resolution within 72 hours. Discussion US assistance seems to be a valid option among treatment choices for intrathecal nusinersen administration in patients with difficult spine. The absence of radiation exposure and the lack of need for intravenous sedation or general anesthesia are additional potential advantages to US assisted administration. This article is protected by copyright. All rights reserved.

Spinal musküler atrofi (SMA), survival motor neuron (SMN1) genindeki delesyonlar veya mutasyonların neden olduğu otozomal resesif bir nöromusküler bir hastalıktır. Çocuk ölümlerinin en yaygın kalıtsal nedenidir. SMN1, tüm ökaryotik organizmaların genomunda tek kopya olarak bulunur. Genomik duplikasyon ile ikinci bir gen SMN2 insanlarda ortaya çıkmıştır. Hastaların yaklaşık %95’i SMN1 geninin ekzon 7’sinde homozigot delesyonlara sahiptir. Bundan dolayı SMN proteini yeterli miktarda üretilemez. SMN2, ekzon 7’deki sübstitüsyondan (C-T) dolayı küçük miktarda fonksiyonel SMN proteini üretir. SMA; başlangıç yaşı, motor gerilemenin şiddeti ve beklenen yaşam süresine göre beş tip (0-IV) olarak sınıflandırılmaktadır. Tip I (Werding-Hoffmann) en ciddi formudur ve özellikle yenidoğanları etkilemektedir. SMA hastalarındaki fenotipik değişkenlik, SMN2 geninin kopya sayısı ile ilişkilidir. SMN2’nin kopya sayısı hastalığın şiddeti ile korelasyon göstermektedir. SMN proteini, nöronal hücrelerde mRNA transportu, RNA metabolizması gibi anahtar düzenleyici rollere sahiptir. Günümüzde SMA tedavisi için ana hedef; küçük moleküller, oligonükleotidler ve gen replasmanı ile motor nöronlarda SMN seviyesini artırmaktır. SMA tedavisi için kök hücre çalışmaları da yapılmaktadır. FDA, 2016 yılından beri SMA tedavisi için üç yeni ilaç onayladı. Bu ilaçlar; nusinersen (oligonükleotit), onasemnogene abeparvovec xioi (gen replasmanı) ve risdiplam (SMN2 gen modülatörü)’dır. İlaçların etkililiğinde erken tanı önemli bir role sahiptir. SMN bağımlı terapötik yaklaşımlar presemptomatik olarak uygulandığında motor nöron disfonksiyonları reversible olabilir. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease lead to by deletions or mutations in the survival motor neuron (SMN1) gene. SMA is the most common inherited cause of childhood mortality. SMN1 exists as a single copy in the genome of all eukaryotic organisms. Genomic duplication causes a second gene, SMN2 in humans. Approximately 95% of SMA patient has homozygous deletions in exon 7 of SMN1. Thus, SMN protein can’t be produced sufficiently. SMN2 produces a small amount functional SMN protein due to substitution (C-T) in exon 7. SMA is classfied into five types (0-IV) based on age of onset, severity of motor decline and life expectancy. Type I (Werding-Hoffmann) is the most severe and primarily affects infants. Phenotypic variability in SMA patients is also associated with the copy number of the SMN2 gene. The copy number of SMN2 correlates with the severity of the disease. The SMN protein has a key regulator roles such as mRNA transport, RNA metabolism in neuronal cells. Currently, the main target for SMA treatment is to increase SMN protein level in motor neuron cells with small molecules, oligonucleotides, and gene replacement. Stem cell studies are performed as well for SMA treatment. FDA has approved three drugs in the SMA treatment since 2016. These drugs are nusinersen (oligonucleotide), onasemnogene abeparvovec-xioi (gene therapy), and risdiplam (SMN2 gene modifier). Early diagnosis has important role in drugs efficacy. Motor neuron dysfunctions may be reversible when SMN-dependent therapeutic approaches can be applied presymptomatically.

Introduction: Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by biallelic deletion of the SMN1 gene. Nusinersen, an antisense oligonucleotide delivered intrathecally, binds to the pre-mRNA of SMN1’s pseudogene, SMN2, to prevent exon skipping and produce functional SMN protein to compensate for the deficiency caused by SMN1 deletion. Case Presentation: We reviewed 15 cerebrospinal fluid (CSF) cytology specimens from 8 patients receiving nusinersen for SMA. Macrophages with peculiar inclusions (“nusinophages”) were seen in 8 specimens from 4 of the patients: 1 infant and 3 children with SMA type 1. This finding has only previously been reported in adults with SMA types 2 and 3 and in 2 infants with SMA type 1. Discussion/Conclusion: Specimens containing nusinophages had a significantly higher proportion of macrophages and lower proportion of lymphocytes than those in which nusinophages were not detected. The macrophage inclusions do not represent iron or microorganisms and instead are composed, at least in part, of glycosaminoglycans. Because CSF is a common specimen type, cytotechnologists and cytopathologists need to be aware of these inclusions, so they do not interpret them erroneously as evidence of infection or hemorrhage, especially in light of the fact that oligonucleotide therapy has been approved for a variety of conditions and is currently under investigation for intrathecal delivery in several other neurodegenerative disorders.

Spinal muscular atrophy (SMA) is caused by the loss of the survival motor neuron 1 (SMN1) gene function. The related SMN2 gene partially compensates but produces insufficient levels of SMN protein due to alternative splicing of exon 7. Evrysdi™ (risdiplam), recently approved for the treatment of SMA, and related compounds promote exon 7 inclusion to generate full-length SMN2 mRNA and increase SMN protein levels. SMNΔ7 type I SMA mice survive without treatment for ~17 days. SMN2 mRNA splicing modulators increase survival of SMN∆7 mice with treatment initiated at postnatal day 3 (PND3). To define SMN requirements for adult mice, SMNΔ7 mice were dosed with an SMN2 mRNA splicing modifier from PND3 to PND40, then dosing was stopped. Mice not treated after PND40 showed progressive weight loss, necrosis, and muscle atrophy after ~20 days. Male mice presented a more severe phenotype than female mice. Mice dosed continuously did not show disease symptoms. The estimated half-life of SMN protein is 2 days indicating that the SMA phenotype reappeared after SMN protein levels returned to baseline. Although SMN protein levels decreased with age in mice and SMN protein levels were higher in brain than in muscle, our studies suggest that SMN protein is required throughout the life of the mouse and is especially essential in adult peripheral tissues including muscle. These studies indicate that drugs such as risdiplam will be optimally therapeutic when given as early as possible after diagnosis and potentially will be required for the life of an SMA patient.

Objective: To describe the healthcare resource utilization (HCRU) related to patients with spinal muscular atrophy (SMA) treated at the Brazilian Unified Health System (SUS) since 2015 according to age-groups. Methods: This study analyzed outpatient and inpatient data for SMA patients from the Brazilian Unified Health System database (DATASUS) from January 2015 to September 2020. Data were collected from patients with ICD-10 codes G12.0 (Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]) or G12.1 (Other inherited spinal muscular atrophy), plus with at least one claim of nusinersen OR at least one claim of any SMA-related procedure groups codes since 2010. SMA-related procedures were defined based on collaborative work involving authors from medical boarding composed by physicians from SUS. Results: In total, 3,775 patients with SMA fulfilled the eligibility criteria. Physiotherapy changed from 11.34 (2.49 – 24.40) procedures PPPY in the 0 - 6-month old group to 3.30 (0.84 – 11.76) procedures PPPY in the > 36-month old group. The median of orthosis was 1.64 (0.66 – 3.41) procedures PPPY in the 0 – 6-month old group and 0.63 (0.34 – 1.33) PPPY in the > 36-month-old group. Exams were primarily performed for younger groups (0 – 6 months and > 6 – 18 months). The percentage of patients that needed some ventilatory care seems greater, and the speech therapy and the use of nusinersen seem lower along with age. Conclusion: This study has demonstrated important HCRU at the SUS setting with SMA patients. In addition, our results highlight the need to implement evidence-based strategies to manage SMA patients and drive cost savings for the health care system

Introduction/aims There are currently three medications approved for spinal muscular atrophy (SMA), but the use of these medications in combination has not been well described. Methods This is a retrospective report of four cases of SMA treated with dual onasemnogene and risdiplam therapy at our institution. Results Following onasemnogene therapy, all four patients experienced a perceived plateau of therapeutic benefit, at which time daily risdiplam was started. Transient fatigue and weakness was seen in two patients following risdiplam initiation, but this resolved within 1 mo. One patient was hospitalized with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and post-viral pneumonia, weeks following risdiplam initiation. No other adverse effects related to onasemnogene and risdiplam combination therapy were identified and all patients experienced objective and subjective improvement. Discussion Combination therapy with onasemnogene and risdiplam in patients with SMA appears to be well-tolerated. Further large prospective trials are needed to determine whether dual therapy is more efficacious than monotherapy, and to identify rare adverse events that may occur with the use of combination therapy.

Background: Spinal muscular atrophy (SMA) is a rare neurodegenerative disease characterized by progressive muscular weakness, which occurs in one in 6,000 to 10,000 live births. The burden of SMA on Canadian patients and caregivers is not known. Objective: To characterize the burden of SMA in Canada as reported by patients and caregivers, including disease and treatment impacts, indirect costs, and caregiver burden. Methods: Surveys were distributed by Cure SMA Canada and Muscular Dystrophy Canada to individuals with SMA and their caregivers. The online surveys were anonymous and completed between January 28 and February 21, 2020. Results: 965 patient and 962 caregiver responses met the eligibility criteria. Patients reported SMA subtypes as: type I (25.0%), type II (41.3%), type III (29.3%). Using the EQ-5D, patients were shown to have impaired quality of life with an average health utility index of 0.49 (SD: 0.26). The median expenditure was $4,500 CAD (IQR: $1,587 – $11,000) for assistive devices; $6,800 CAD (IQR: $3,900–$13,000) on health professional services; and $1,200 CAD (IQR: $600 –$3,100) on SMA-related travel and accommodation in the past 12 months. Caregivers reported needing respite care (45.7%), physiotherapy for an injury from a lift/transfer (45.7%), or other health impacts (63.3%). Caregivers reported changes to personal plans, sleep disturbances, and work adjustments, with a mean Caregiver Strain Index score of 7.5 [SD: 3.3]. Conclusion: SMA in Canada is associated with a significant burden for patients and their caregivers.

Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics. Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA. Methods: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada. Results: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently. Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

ObjectiveTo assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening.MethodsInformed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses.ResultsBy treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment.ConclusionNBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease‐modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno‐associated virus–based gene replacement therapy, delivers functional human SMN through a one‐time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient‐centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient‐centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti–adeno‐associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day‐to‐day care at time of treatment and patient‐ and family‐centered discussions on realistic expectations are also recommended. We detail the importance of following standard‐of‐care guidance and long‐term monitoring of all children with SMA who have received one or more disease‐modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder.

Less than a decade ago, patients diagnosed with Spinal Muscular Atrophy (SMA) had no treatments other than pulmonary, gastrointestinal, and orthopedic care. These palliative treatments were focused on managing symptoms and did not address the cause of the disease itself. Now, there are several FDA (U.S. Food and Drug Administration) approved drugs to treat SMA, which can stop or slow disease progression. In order to discuss the development of treatments for patients with SMA, the disease must first be explained in detail.

Spinal administration of medications is challenging in patients with complete posterior spinal fusion. We describe percutaneous image-guided intrathecal port placement for administration of the antisense oligonucleotide nusinersen for children and young adults with spinal muscular atrophy. To describe and present our initial experience with a new technique for administering nusinersen in patients with spinal muscular atrophy and posterior spinal fusion. We reviewed medical records of 13 patients who received intrathecal ports using DynaCT, biplane fluoroscopy and iGuide from April 2018 through June 2019, and we describe the clinical course over 1 year. Image-guided catheter and port implantation was successful in all cases. Two ports were subsequently removed, one for persistent cerebrospinal fluid leak and one for superficial infection. The other 11 have functioned successfully for a minimum of 23 months. We report our experience with image-guided intrathecal port placement in children with complete posterior spine fusion. The implanted port permits dosing in an outpatient setting and avoids the need for multiple future radiologic procedures, and it reduces discomfort, procedural costs and potential risks and sequelae of multiple anesthetics and radiation exposures. Further studies are needed to define the relative risks and benefits of intrathecal ports compared to other approaches such as repeated transforaminal lumbar punctures.

Bei der 5q-spinalen Muskelatrophie (5q-SMA) handelt es sich um eine autosomal-rezessive neuromuskulare Erkrankung, welche durch eine biallele Mutation des Survival of motor neuron 1 SMN1-Gens verursacht wird. Der hierdurch entstehende SMN-Mangel verursacht eine progressive Degeneration anteriorer Motorneurone, die zu einer muskularen Atrophie und in zwei Drittel der Falle zu einer Skoliose fuhrt. In Abhangigkeit von den beschriebenen Subtypen kommt es bei der SMA zu einer zunehmenden Ateminsuffizienz und einem fruhen Versterben der PatientInnen. Herausragende Fortschritte in der Grundlagenforschung haben in den letzten Jahren zur Zulassung neuer Therapien gefuhrt, die das Krankheitsbild und dessen Therapie verandern werden. Wir stellen diese innovativen Therapieansatze als auch die operativen Strategien bei Skoliosen vor, und geben einen Ausblick auf zukunftige Herausforderungen.

Introduction: Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disease causing degeneration of nerves at anterior horn of spinal cord. The most common and severe form is SMA type 1 which starts before 6 months of age. Patients do not survive more than 2 years and usually die of respiratory failure. Although there was no specific cure for the disease until the last 3 years, new treatment modalities, with the improving gene-technology have given good results in progression of the disease and early diagnosis and treatment gained importance. Case: A male 28-days-old baby visited our clinic for routine physical examination and was found to be slightly hypotonic. He had decreased strength in sucking and crying and had slowing in motion in the last 4-5 days. C-reactive protein level was slightly elevated. Since he had a sepsis-like presentation, he was referred to neonatal intensive care unit (ICU). He was given antibiotics and monitored. However, in follow-up he became more hypotonic and deep tendon reflexes were lost. He was diagnosed as SMA type I and was referred for nusinersen (antisense-oligonucleotide) treatment. After treatment, he showed a good progress in motor functions and still does not need any respiratory support. Conclusions: We presented this case to draw attention to SMA in differential diagnosis of hypotonic newborns with sepsis-like presentation and emphasize the importance of early diagnosis and treatment.

Aim: This study aims to reveal the problems faced by families of children with spinal muscular atrophy (SMA), by evaluating their care burden, needs, and expectations. Materials and Methods: The participants were the primary caregivers of 34 children between the ages of 0 and 18 years diagnosed with SMA. Thirteen children were diagnosed with type 1, 13 children with type 2 and 8 children with type 3 SMA. Data on the medical history, functional levels of the participants, and the characteristics of families were collected. The childrens’ parents completed the Family Needs Survey and the Zarit Caregiver Burden Scale. Results: According to the results of the Family Needs Survey, it was found that information was the most common requirement, and this was independent of the level of education. According to the Caregiver Burden Scale, it was recorded that 64.7% of the caregivers were under mild/moderate burden. While there was a moderate correlation (r = 0.574; P < .001) between the Caregiver Burden Scale and the Family Needs Survey, it was observed that the functional level of the child was not associated with family needs and caregiver burden. Conclusions: Our study suggests that the needs of families of SMA patients, especially related to income level, have changed. The caregivers’ burden is not directly related to the income level or the functional level of the child. Families’ need for information should also be prioritized within the rehabilitation program.

Spinal muscular atrophy (EBF) is an autosomal recessive neuromuscular disease with genetic inheritance. EBF is classified into: type I - patients have symptoms up to 6 months of age; type II - after 6 months of age, symptoms begin; type III - it starts after 18 months of age. The objective of this study was to clinically characterize two brothers diagnosed with EBF. It is a clinical case study of two individuals, male gender, attended at Clínica Escola de Fisioterapia, at Universidade Estadual do Centro Oeste do Paraná- UNICENTRO, Campus CEDETEG. Selected by eligibility both were diagnosed with spinal muscular atrophy. The physiotherapy stages evaluation was carried out, which consist of anamnesis, functional examination, physical examination and respiratory evaluation. Patient 1, was diagnosed with EBF type IIIb at 16 years old, with reports of falls and weakness mainly in lower limbs, in the evaluation positive Gowers sign, anserine gait, hypotonic, MMSS areflexia and lower limb hyporeflexia, breathing pattern apical were found. Patient 2 was diagnosed with EBF type IIIa at 1 year of age, currently using a wheelchair for locomotion, on physical examination he had scoliosis with right convexity, deformities in the costal grid, decreased muscle strength in the upper limbs and lower limbs, mixed respiratory pattern. From the physical therapy evaluation performed on these patients, it could be noted that the weakness of the respiratory muscles is directly related to the clinical sign presented by both. Keywords: Physiotherapy Specialty. Neuromuscular Diseases. Spinal Muscular Atrophy. ResumoA atrofia muscular espinhal (AME) é uma doença neuromuscular autossômica recessiva com herança genética. A AME é classificada em: tipo I – pacientes apresentam sintomas até 6 meses de idade; tipo II – após os 6 meses de idade inicia-se os sintomas; tipo III – inicia-se após 18 meses de idade. O objetivo desse trabalho foi caracterizar clinicamente dois irmãos com diagnóstico de AME. É um estudo de casos clínicos de dois indivíduos, do gênero masculino, atendidos na Clínica Escola de Fisioterapia, da Universidade Estadual do Centro Oeste do Paraná – UNICENTRO, Campus CEDETEG. Selecionados por elegibilidade ambos diagnosticados com atrofia muscular espinhal. Foram realizadas as etapas da avaliação fisioterapêutica que consistem em anamnese, exame funcional, exame físico e avaliação respiratória. O paciente 1, foi diagnosticado com AME tipo IIIb aos 16 anos, com relatos de quedas e fraqueza principalmente em MMII, na avaliação constatou-se, sinal de Gowers positivo, marcha anserina, hipotônico, arreflexia de MMSS e hiporeflexia de MMII, padrão respiratório apical. O paciente 2 recebeu o diagnóstico de AME tipo IIIa com 01 ano de idade, atualmente utiliza cadeira de rodas para locomoção, no exame físico apresenta escoliose com convexidade a direita, deformidades no gradil costal, força muscular diminuída em MMSS e MMII, padrão respiratório misto. A partir da avaliação fisioterapêutica realizada nesses pacientes, pode-se notar que a fraqueza dos músculos respiratórios está diretamente relacionada com o quadro clinico apresentado por ambos. Palavras-chave: Fisioterapia. Doenças Neuromusculares. Atrofia Muscular Espinhal.

Background and purpose This was an investigation of treatment expectations and of the perception of therapy in adult patients with 5q-associated spinal muscular atrophy (5q-SMA) receiving nusinersen. Methods A prospective, non-interventional observational study of nusinersen treatment in adult 5q-SMA patients was conducted at nine SMA centers in Germany. The functional status, treatment expectations and perceived outcomes were assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale—extended (ALS-FRS-ex), the Measure Yourself Medical Outcome Profile (MYMOP2), the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and the Net Promoter Score (NPS). Results In all, 151 patients were included with a median age of 36 years (15–69 years). SMA type 3 (n = 90, 59.6%) prevailed, followed by type 2 (33.8%) and type 1 (6.6%). In SMA types 1–3, median ALS-FRS-ex scores were 25, 33 and 46 (of 60 scale points), respectively. MYMOP2 identified distinct treatment expectations: head verticalization (n = 13), bulbar function (n = 16), arm function (n = 65), respiration (n = 15), trunk function (n = 34), leg function (n = 76) and generalized symptoms (n = 77). Median symptom severity decreased during nusinersen treatment (median observational period 6.1 months, 0.5–16 months) from 3.7 to 3.3 MYMOP2 score points (p < 0.001). The convenience of drug administration was critical (49.7 of 100 TSQM-9 points, SD 22); however, the overall treatment satisfaction was high (74.3, SD 18) and the recommendation rating very positive (NPS +66). Conclusions Nusinersen was administered across a broad range of ages, disease durations and motor function deficits. Treatment expectations were highly differentiated and related to SMA type and functional status. Patient-reported outcomes demonstrated a positive perception of nusinersen therapy in adult patients with 5q-SMA., publishedVersion

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.

BackgroundThis observational study describes our experience delivering nusinersen through lumbar puncture with real-time ultrasound guidance in spinal muscular atrophy (SMA) patients with severe scoliosis.ResultsIntrathecal nusinersen via real-time ultrasound-guided lumbar puncture was given to three patients who had severe thoracic and lumbar scoliosis: a 34-year-old female with type 3a SMA, a 28-year-old male with type 2a SMA, and a 14-year-old girl with type 3a SMA. Lumbar puncture was performed without sedation under ultrasound guidance using a 22G echogenic needle in the interlaminar aspect of the L4–L5 or L5–S1 interspace and a full dose of nusinersen (12 mg/5 mL) was injected after visualizing free cerebrospinal fluid flow. Patients completed their four loading doses and one maintenance dose of nusinersen. All 15 procedures were successful and well tolerated.ConclusionsReal-time ultrasound-guided lumbar puncture is an effective and radiation-free technique to administer intrathecal nusinersen in SMA patients with severe scoliosis when done by practitioners with expertise in this procedure.