Malnutrition in Spinal Muscular Atrophy Type I: Case Report of a Novel Nutritional Intervention With Improved Growth and Function While Receiving Parallel Gene Splicing Therapies.

Children with spinal muscular atrophy (SMA) frequently experience feeding intolerance and diminished growth. Although splicing modulators to prevent symptoms are available worldwide, adequate nutrition to support growth, development, and improved quality of life remains essential. We present a case study of a one-year-old malnourished male with SMA type I who achieved improved growth and feeding tolerance with a human milk (HM)-derived nutrition intervention. Despite feeding with appropriately balanced semielemental formula, he remained severely malnourished after two months of hospitalization. Feeds were partially replaced with HM-based diet plus a HM-based fat modular. Feeding tolerance, fecal calprotectin levels, and z scores for weight and length improved while receiving the HM-based intervention. We hypothesize that the HM-based feeding reduced intestinal inflammation by diminishing pathogenic elements of his microbiome. Owing to their aberrant fatty acid metabolism, patients with SMA are uniquely positioned to benefit from HM-based nutrient acquisition even while receiving splicing modulators to stabilize the disease process.

Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1.

The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades, the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life and creating new challenges and goals. Many nutritional problems, gastrointestinal disorders and metabolic and endocrine alterations are commonly identified in patients affected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidisciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Nutritional Therapy in Children With Spinal Muscular Atrophy in the Era of Nusinersen.

OBJECTIVES: Spinal muscular atrophy (SMA) is a genetic motor neuron disorder characterized by progressive muscle atrophy. Our aims were to evaluate the impact of nutritional intervention and nusinersen therapy on the nutritional status of SMA patients. STUDY DESIGN: This prospective study included all children and young adults (<24 years of age) with SMA who attended our multidisciplinary SMA clinic, during January 2017-July 2019. We documented demographic, clinical, anthropometric, and nutritional data at baseline and follow-up. A nutritional intervention was implemented according to standards of the 2018 Consensus Statement of SMA Management. RESULTS: The cohort included 51 SMA patients with a median age of 7.2 (interquartile range 2.1-15.3) years. Among them, 24 (47%) were SMA type 1, 16 (31.4%) SMA type 2, and 11 (21.6%) SMA type 3 patients. At baseline, 28 (54.9%) patients presented with malnutrition, 20 (71.4%) of whom with severe malnutrition. A decline in the frequency of severe malnutrition of SMA type 1 patients was observed at follow-up. The body mass index of patients who started nusinersen therapy after the nutritional intervention increased significantly compared with patients that started nusinersen therapy before the nutritional intervention (P = 0.042). There was also a significant increase in total energy and protein consumption in the former group (P = 0.043). CONCLUSIONS: Malnutrition is frequent among children with SMA, and the nutritional status of patients that started nusinersen therapy after implementation of a nutritional intervention underwent a more significant improvement. The importance of combining adequate nutritional management with disease-modifying treatment is highlighted.

Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy.

The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed. Twenty patients were included, eight with early onset most severe phenotype, eight with the more typical type 1 phenotype and 4, who achieved some head control, with a milder phenotype. Both baseline values and trajectories of progression were different in the three subgroups (p = 0.0001). Infants with the most severe phenotype had the lowest scores (below 20) on their first assessment and had the most rapid decline. Those with the typical phenotype had scores generally between 20 and 40 and also had a fast decline. The infants with the milder phenotype had the highest scores, generally above 35, and a much slower deterioration. Infants with three SMN2 copies had an overall milder phenotype and milder progression while two SMN2 copies were found in all three subgroups.

Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.

Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.

Strategies for treating scoliosis in children with spinal muscular atrophy.

Progressive pulmonary dysfunction is a major complication of spinal muscular atrophy (SMA). Growing constructs are a well-established alternative to spinal arthrodesis to maximize pulmonary growth. We describe patients who demonstrated sustained pulmonary function and improved quality of life following hybrid growing construct implantation. The purpose of this article is to demonstrate a range of approaches for managing scoliosis in children with SMA by utilizing vertical expandable prosthetic titanium rib implantation or growing rods with lateral rib fixation to improve clinical and patient-reported outcomes. Pulmonary compromise and quality of life decline are leading concerns in the SMA population. This case series highlights important surgical strategies that can be utilized to treat scoliosis in patients with SMA.

[Audiovisual stimulation in children with severely limited motor function: does it improve their quality of life?]. / Estimulacion audiovisual en niños con limitacion grave de la motricidad: mejora su calidad de vida?

INTRODUCTION: Children with neurological diseases that impose severe limitations on their mobility have a deficient quality of life (QL). AIMS: To study whether the QL of such patients improves with the application of a programme of audiovisual stimulation. PATIENTS AND METHODS: A prospective study was conducted on nine children, six of whom were males (mean age: 42.6 ± 28.6 months), with severely limited mobility and who had been hospitalised for long periods. Two audiovisual stimulation programmes were produced and applied, together with videos, by means of a specially designed structure. The stimulus was applied twice a day for 10 minutes over 20 days. The first ten days the stimulus was carried out in a passive manner and the second block of ten days it was performed with the guidance of the observer. Biological, behavioural and cognitive variables were recorded and an adapted QL survey was applied. RESULTS: Three cases of spinal muscular atrophy, two of congenital muscular dystrophy, two of myopathy and two with other conditions were diagnosed. Eight patients completed the follow-up. From the baseline point of view, they presented a regular QL (7.2 ± 1.7 points; median: 7.0; range: 6-10), which improved to good on finishing the therapy (9.4 ± 1.2 points; median: 9.0; range: 8-11), with an intra-individual difference of 2.1 ± 1.6 (median: 2.5; range: -1 to 4; CI 95% = 0.83-3.42; p = 0.006). Improved cognition and a favourable perception in the caregivers were detected. No changes took place in the biological or behavioural variables. CONCLUSIONS: Audiovisual stimulation can be used to enhance the quality of life of children with severely limited mobility.

TITLE: Estimulacion audiovisual en niños con limitacion grave de la motricidad: mejora su calidad de vida?Introduccion. Los niños con enfermedades neurologicas que condicionan una limitacion grave de la movilidad tienen una calidad de vida (CV) deficiente. Objetivo. Estudiar si la CV de dichos pacientes mejora con la aplicacion de un programa de estimulacion audiovisual. Pacientes y metodos. Estudio prospectivo en nueve niños, seis de ellos varones (edad media: 42,6 ± 28,6 meses), con limitacion grave de la movilidad, hospitalizados de manera prolongada. Se elaboraron dos programas de estimulo audiovisual que, junto con videos, se aplicaron mediante una estructura especialmente diseñada. La frecuencia fue de dos veces al dia, por 10 minutos, durante 20 dias. Los primeros diez dias se llevo a cabo de manera pasiva y los segundos diez con guia del observador. Se registraron variables biologicas, conductuales, cognitivas y se aplico una encuesta de CV adaptada. Resultados. Se diagnosticaron tres casos de atrofia muscular espinal, dos de distrofia muscular congenita, dos de miopatia y dos con otros diagnosticos. Ocho pacientes completaron el seguimiento. Desde el punto de vista basal, presentaron CV regular (7,2 ± 1,7 puntos; mediana: 7,0; rango: 6-10), que mejoraba a buena al finalizar (9,4 ± 1,2 puntos; mediana: 9,0; rango: 8-11), con diferencia intraindividual de 2,1 ± 1,6 (mediana: 2,5; rango: ­1 a 4; IC 95% = 0,83-3,42; p = 0,006). Se detecto mejoria en cognicion y percepcion favorable de los cuidadores. No hubo cambio en las variables biologicas ni conductuales. Conclusion. Mediante la estimulacion audiovisual es posible mejorar la calidad de vida de niños con limitacion grave de la movilidad.

Spinal muscular atrophy type 1: are proactive respiratory interventions associated with longer survival?

CONTEXT: Spinal muscular atrophy type 1, an autosomal recessive motor neuron disease, is a leading genetic cause of death in infancy and early childhood. OBJECTIVE: To determine whether the early initiation of noninvasive respiratory interventions is associated with longer survival. DESIGN: Single-institution retrospective cohort study identified children with spinal muscular atrophy type 1 from January 1, 2002 to May 1, 2009 who were followed for 2.3 mean yrs. SETTING: Tertiary care children's hospital and outpatient clinics in a vertically integrated healthcare system. PATIENTS OR OTHER PARTICIPANTS: Forty-nine children with spinal muscular atrophy type 1 were grouped according to the level of respiratory support their caregivers chose within the first 3 months after diagnosis: proactive respiratory care (n = 26) and supportive care (n = 23). INTERVENTIONS: Proactive respiratory care included bilevel noninvasive ventilation during sleep and twice a day cough assist while supportive respiratory care included suctioning, with or without supplemental oxygen. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier survival curves were assessed based on intention to treat. Children treated with early proactive respiratory support had statistically longer survival compared to supportive care (log rank 0.047); however, the adjusted hazard ratio for survival was not statistically different (2.44 [95% confidence interval 0.84-7.1]). Children in the proactive group were more likely to be hospitalized for respiratory insufficiency (83% vs. 46%) and had shortened time after diagnosis until first hospital admission for respiratory insufficiency (median 118 vs. 979 days). CONCLUSION: Longer survival time with spinal muscular atrophy type 1 is associated with early, noninvasive respiratory care interventions after diagnosis.

Aquatic therapy for a child with type III spinal muscular atrophy: a case report.

Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by degeneration of alpha motor neurons. This case report describes an aquatic therapy program and the outcomes for a 3-year-old girl with type III SMA. Motor skills were examined using the 88-item Gross Motor Function Measure (GMFM), the Peabody Developmental Motor Scales (PDMS-2), and the GAITRite system. The child received aquatic therapy twice per week for 45-min sessions, for 14 weeks. The intervention included aquatic activities designed to improve gross motor skills and age-appropriate functional mobility. The GMFM total score improved by 11% following the intervention. The Standing Dimension score improved by 28% and the Walking, Running, and Jumping Dimension score improved by 18%. The gross motor quotient for the PDMS-2 improved from 66 to 74. The child's gait showed improvement in walking velocity, stride length, and single-limb support time as a percentage of the gait cycle. The outcomes of this case report demonstrate the successful improvement of gross motor function and gait in a 3-year-old child with SMA. This study provides clinical information for therapists utilizing aquatic therapy as a modality for children with neuromuscular disorders.

Glossopharyngeal pistoning for lung insufflation in children with spinal muscular atrophy type II.

AIM: To evaluate whether children with spinal muscular atrophy (SMA) type II were able to learn glossopharyngeal pistoning for lung insufflation (GI), and to evaluate the effects of GI on pulmonary function and chest expansion. METHODS: Eleven children with SMA type II were recruited. They performed 10 cycles of GI, four times per week, for 8 weeks. Lung function and chest expansion were measured before and after the 8-week period. RESULTS: Five of the 11 children learned the technique. The median GI volume was 0.28 (range 0.15-0.98) L. Four of the children who completed the study showed a mean increase in inspiratory vital capacity (IVC) of 0.13 L (95% confidence interval (CI) 0.03-0.23) and peak expiratory flow (PEF) of 116 L/min (95% CI 60-173). They also had an increased chest expansion with GI at the level of the xiphoid process of 1.50 cm (95% CI 0.16-2.84) and at the level of the fourth costa of 1.79 cm (95% CI 0.85-2.73). The children reported temporary symptoms of dizziness and tension in the chest. CONCLUSION: Five of the 11 children were able to learn the technique of GI and for the four who fulfilled the training, it had positive effects on IVC, PEF and chest expansion. GI did not cause major discomfort.

Identification of a battery of tests for drug candidate evaluation in the SMNDelta7 neonate model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is characterized by selective loss of alpha-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNDelta7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2(+/+);SMNDelta7(+/+);Smn(-/-) mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.

A preliminary report on spinal muscular atrophy lymphoblastoid cell lines: are they an appropriate tool for drug screening?

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease of the motor neurons that results in progressive muscle weakness. It is also the leading hereditary cause of infant mortality. Homozygous loss of the survival motor neuron (SMN1) gene causes SMA, and the number of copies of the SMN2 gene modulates the severity of the disease. Increasing the expression of the SMN2 gene by pharmacological agents is one of the therapeutic approaches currently being implemented. METHODS: In this preliminary study, we investigated the effect of phenylbutyrate, a histone deacetylase (HDAC) inhibitor, on SMN2 expression in two SMA type III Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines to understand the suitability of lymphoblastoid cell lines in drug screening. These cell lines are regarded as a good source as they can easily be established from the peripheral leucocytes of patients. Quantitative analysis of SMN2 mRNA was performed on established cell lines treated with various concentrations of phenylbutyrate and for a range of incubation periods using real-time polymerase chain reaction. Western blot analysis was used to determine SMN protein levels. RESULTS: Real-time polymerase chain reaction and Western blot analysis demonstrated that the levels of SMN2 full-length (fl-SMN2) transcripts and protein were not increased in phenylbutyrate-treated cell lines compared to non-treated controls. CONCLUSION: These results suggest that EBV-transformed lymphoblastoid cell lines are not suitable for studying the effect of certain HDAC inhibitors on SMN2 gene expression.

Perspectives on clinical trials in spinal muscular atrophy.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.

Cambio intraoperatorio de plan anestésico en una paciente con Enfermedad de Werdnig Hoffmann tipo II / Intraoperative change of anesthetic technique in a patient with intermediate Werdning Hoffman (type II) disease

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Thalamic lesions in a long-surviving child with spinal muscular atrophy type I: MRI and EEG findings.

Brain magnetic resonance imaging was conducted in a girl with genetically confirmed spinal muscular atrophy (SMA) type I. This patient has survived 6 years, to date, under mechanical ventilation. T2-weighted and fluid-attenuated inversion recovery images revealed high signal intensity lesions in the anterolateral portions of the bilateral thalami. Electroencephalography disclosed diffuse beta activity upon awakening and during light sleep. In addition, fast and prolonged spindles were observed. Although mild neuronal changes in the lateral nucleus of the thalamus have been described in several autopsied cases, this is the first study to demonstrate neuroradiologically and neurophysiologically the thalamic lesions in genetically confirmed SMA type I.