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Two siblings presented similarly with congenital hypotonia, lactic acidosis, and failure to thrive. Later in childhood, the brother developed cystinuria and nephrolithiasis whereas the older sister suffered from cystinuria and chronic neurobehavioral disturbances. Biopsied muscle studies demonstrated deficient cytochrome c oxidase activities consistent with a mitochondrial disease. Whole exome sequencing (WES), however, revealed a homozygous 2p21 deletion involving two contiquous genes, SLC3A1 (deletion of exons 2‐10) and PREPL (deletion of exons 2‐14). The molecular findings were consistent with the hypotonia–cystinuria 2p21 deletion syndrome, presenting similarly in infancy with mitochondrial dysfunction but diverging later in childhood and displaying intrafamilial phenotypic variability.

Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

Objective To estimate muscle oxygen uptake and quantify fatigue during exercise in ambulatory individuals with spinal muscular atrophy (SMA) and healthy controls. Methods Peak aerobic capacity (VO2peak) and workload (Wpeak) were measured by cardiopulmonary exercise test (CPET) in 19 ambulatory SMA patients and 16 healthy controls. Submaximal exercise (SME) at 40% Wpeak was performed for 10 minutes. Change in vastus lateralis deoxygenated hemoglobin, measured by near‐infrared spectroscopy, determined muscle oxygen uptake (ΔHHb) at rest and during CPET and SME. Dual energy X‐ray absorptiometry assessed fat‐free mass (FFM%). Fatigue was determined by percent change in workload or distance in the first compared to the last minute of SME (FatigueSME) and six‐minute walk test (Fatigue6MWT), respectively. Results ΔHHb‐PEAK, ΔHHb‐SME, VO2peak, Wpeak, FFM%, and 6MWT distance were lower (P

ObjectiveTo describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).MethodsThis was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.ResultsThere were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8–16.6) and 15.1 (13.8–16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.ConclusionsIn SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Background: Individuals with spinal muscular atrophy (SMA) III walk independently, but experience muscle weakness, gait impairments, and fatigue. Although SMA affects proximal more than distal muscles, the characteristic pattern of selective muscle weakness has not been explained. Two theories have been proposed: 1) location of spinal motor neurons; and 2) differences in segmental innervation. Objective: To identify neuroanatomical models that explain the selective muscle weakness in individuals with SMA and assess the relationship of these models to ambulatory function. Methods: Data from 23 ambulatory SMA participants (78.2% male), ages 10–56 years, enrolled in two clinical studies (NCT01166022, NCT02895789) were included. Strength was assessed using the Medical Research Council (MRC) score; ambulatory function was measured by distance walked on the 6-minute walk test (6 MWT). Three models were identified, and relationships assessed using Pearson correlation coefficients and linear regression. Results: All models demonstrated a positive association between strength and function, (p

Background The advent of new therapies in spinal muscular atrophy (SMA) has highlighted the need to have natural history data for comparison. Natural history studies using structured assessments in type I however are very limited. We identified and reviewed all the existing longitudinal history data in infants with type I SMA first assessed before the age of 7 months with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Main text Three longitudinal natural history studies, two performed in the United States and one in Italy, were identified. The different study design of these three studies made it possible for the cumulative dataset to include the full spectrum of severity; from infants with neonatal onset to those with a milder phenotype that were not always included in the individual natural history studies. The cumulative analysis confirmed that, even in a larger cohort, there was never an improvement on the CHOP INTEND over time. This was true for all the infants, irrespective of their age or baseline CHOP INTEND scores. Infants with neonatal onset had low CHOP INTEND scores and a fast decline. The relatively large number of patients allowed us to calculate the rate of progression in subgroups identified according to SMN2 copy number and baseline CHOP INTEND scores. Conclusion A detailed understanding of the existing data is important, as it will be difficult to acquire new systematic longitudinal history data because of the availability of disease modifying therapies. The cumulative findings in this review help to better understand the variability of natural history data in untreated patients and will be of use for comparison to the real world patients treated with the recently approved therapies that have shown encouraging results in clinical trials.

Gait tasks are commonly administered during motor assessments of children with neurodevelopmental disorders (NDDs). Gait analyses are often conducted in laboratory settings using costly and cumbersome experiments. In this paper, we propose a computational pipeline using computer vision techniques as an ecological and precise method to quantify gait in children with NDDs with challenging behaviors. We analyzed videos of 15 probands (PB) and 12 typically developing (TD) siblings, engaged in a preferred-pace walking task, using pose estimation software to track points of interest on their bodies over time. Analyzing the extracted information revealed that PB children had significantly less whole-body gait synchrony and poorer balance compared to their TD siblings. Our work offers a cost-effective method while preserving the validity of its results. This remote approach increases access to more diverse and distant cohorts and thus lowers barriers to research participation, further enriching our understanding of motor outcomes in NDDs.

Introduction Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments, and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen, but its impact on fatigue has not been studied. Methods Post hoc analyses were used to examine changes in 6‐minute walk test (6MWT) distance and fatigue in children and adolescents with SMA type II and III who received their first dose of nusinersen in the phase Ib/IIa, open‐label CS2 study and were ambulatory during CS2 or the extension study, CS12. Results Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, whereas median fatigue changed by −3.8% (−19.7%, 1.4%). Discussion These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later‐onset SMA.

ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.ResultsTwenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.ConclusionsNusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.Clinicaltrials.gov identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

Introduction The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. Methods Longitudinal 12 month data was collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. Results The 12 month changes ranged between -7 and 9 (mean: -0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (-0.45 in type 2, -0.23 in non-ambulant type 3 and -0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. Discussion Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non-ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426-430, 2019.

Ref: Different trajectories in upper limb and gross motor function in spinal muscular atrophy INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 months. METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-month changes also included the analysis of concordance between scales with changes grouped as stable (+2 points), improved (>+2) or declined (>-2). RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2 the point of slope change was 4.1 years for the HFMSE and 5.8 for the RULM, while for type 3 it was 6 years for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least 2 assessments at 12-month. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups. DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

INTRODUCTION: The 6-minute walk test (6MWT) is a well-established clinical assessment of functional endurance, validated as a measure of walking ability in spinal muscular atrophy (SMA). The current availability of disease-modifying therapies for SMA indicates a growing need for normative reference data to compare SMA patients with healthy controls. METHODS: The literature was searched in two scientific databases. Studies were evaluated and selected based on adherence to American Thoracic Society guidelines for administering the 6MWT. Reference equations from the selected studies were applied to 6MWT data collected from SMA patients to calculate and compare % predicted values. RESULTS: Three pediatric and six adult studies were selected for comparison. The % predicted values using the pediatric and adult equations ranged from 47.7 ± 18.2% to 67.6 ± 26.2% and 43.0 ± 17.9% to 59.5 ± 26.2%, respectively, and were significantly different (P < 0.001). DISCUSSION: Results suggest significant variability between % predicted values derived from published reference equations in children and adults, despite adherence to 6MWT standardization.

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA.

Background Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes. Methods Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability. Results Inter and intra-rater reliability were both excellent. Intraclass correlation coefficients (ICC) ranged between 0.906-0.994 across initial training meetings and 0.824-0.996 across annual retraining meetings. This was similar for CHOP INTEND (ICC = 0.824-0.951), HFMSE (ICC = 0.981-0.996), and RULM (ICC = 0.966-0.990). Intra-rater reliability for the CHOP INTEND, HFMSE, and RULM were ICC = 0.895 (95% CI: 0.852-0.926; n = 116), ICC = 0.959 (95% CI: 0.942-0.971; n = 125), and ICC = 0.948 (95% CI: 0.927-0.963; n = 126) respectively. Conclusions Rigorous evaluator training ensures reliability of assessment of subjects with spinal muscular atrophy (SMA) in multicenter international trials.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2.

Background Physical exercise training might improve muscle and cardiorespiratory function in spinal muscular atrophy (SMA). Optimization of aerobic capacity or other resources in residual muscle tissue through exercise may counteract the muscle deterioration that occurs secondary to motor neuron loss and inactivity in SMA. There is currently no evidence synthesis available on physical exercise training in people with SMA type 3. Objectives To assess the effects of physical exercise training on functional performance in people with SMA type 3, and to identify any adverse effects. Search methods On 8 May 2018, we searched the Cochrane Neuromuscular Specialised Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, AMED, and LILACS. On 25 April 2018 we searched NHSEED, DARE, and ClinicalTrials.gov and WHO ICTRP for ongoing trials. Selection criteria We included randomized controlled trials (RCTs) or quasi-RCTs lasting at least 12 weeks that compared physical exercise training (strength training, aerobic exercise training, or both) to placebo, standard or usual care, or another type of non-physical intervention for SMA type 3. Participants were adults and children from the age of five years with a diagnosis of SMA type 3 (Kugelberg-Welander syndrome), confirmed by genetic analysis. Data collection and analysis We used standard Cochrane methodological procedures. Main results We included one RCT that studied the effects of a six-month, home-based, combined muscle strength and recumbent cycle ergometry training program versus usual care in 14 ambulatory people with SMA. The age range of the participants was between 10 years and 48 years. The study was evaluator-blinded, but personnel and participants could not be blinded to the intervention, which placed the results at a high risk of bias. Participants performed strength training as prescribed, but 50% of the participants did not achieve the intended aerobic exercise training regimen. The trial used change in walking distance on the six-minute walk test as a measure of function; a minimal detectable change is 24.0 m. The change from baseline to six months' follow-up in the training group (9.4 m) was not detectably different from the change in the usual care group (-0.14 m) (mean difference (MD) 9.54 m, 95% confidence interval (CI) -83.04 to 102.12; N = 12). Cardiopulmonary exercise capacity, assessed by the change from baseline to six months' follow-up in peak oxygen uptake (VO2max) was similar in the training group (-0.12 mL/kg/min) and the usual care group (-1.34 mL/kg/min) (MD 1.22 mL/kg/min, 95% CI -2.16 to 4.6; N = 12). A clinically meaningful increase in VO2max is 3.5 mL/kg/min.The trial assessed function on the Hammersmith Functional Motor Scale - Expanded (HFMSE), which has a range of possible scores from 0 to 66, with an increase of 3 or more points indicating clinically meaningful improvement. The HFMSE score in the training group increased by 2 points from baseline to six months' follow-up, with no change in the usual care group (MD 2.00, 95% CI -2.06 to 6.06; N = 12). The training group showed a slight improvement in muscle strength, expressed as the manual muscle testing (MMT) total score, which ranges from 28 (weakest) to 280 (strongest). The change from baseline in MMT total score was 6.8 in the training group compared to -5.14 in the usual care group (MD 11.94, 95% CI -3.44 to 27.32; N = 12).The trial stated that training had no statistically significant effects on fatigue and quality of life. The certainty of evidence for all outcomes was very low because of study limitations and imprecision. The study did not assess the effects of physical exercise training on physical activity levels. No study-related serious adverse events or adverse events leading to withdrawal occurred, but we cannot draw wider conclusions from this very low-certainty evidence. Authors' conclusions It is uncertain whether combined strength and aerobic exercise training is beneficial or harmful in people with SMA type 3, as the quality of evidence is very low. We need well-designed and adequately powered studies using protocols that meet international standards for the development of training interventions, in order to improve our understanding of the exercise response in people with SMA type 3 and eventually develop exercise guidelines for this condition.

Highlights • This paper reports patterns of natural progression in type I SMA. • The HINE is used to capture motor developmental milestones in SMA. • Motor developmental milestones are rarely acquired in type I SMA infants., The aim of this retrospective multicentric study was to assess developmental milestones longitudinally in type I SMA infants using the Hammersmith Infant Neurological Examination. Thirty-three type I SMA infants, who classically do not achieve the ability to sit unsupported, were included in the study. Our results confirmed that all patients had a score of 0 out of a scale of 4 on items assessing sitting, rolling, crawling, standing or walking. A score of more than 0 was only achieved in three items: head control (n = 13), kicking (n = 15) and hand grasp (n = 18). In these items, the maximal score achieved was 1 out of a scale of 4, indicating only partial achievement of the milestone. Infants with symptom onset after 6 months of age had longer preservation of a score of 1 when compared to those with onset before 6 months of age. Our results suggest that even when current standards of care are applied, developmental milestones are rarely even partially achieved as part of natural history in type I SMA infants. No infants in this study achieved a major milestone such as rolling over, or sitting independently, which would therefore represent robust outcomes in future interventional trials.

Objectives:To examine academic performance in dystrophinopathy as a function of dystrophin gene mutation position as well as intellectual function, executive skills, socioeconomic status (SES), behavior, and physical ability.Methods:In a cross-sectional study, boys with dystrophinopathy (ages 5–17;n=50) completed tests of academics (Woodcock-Johnson-III: spelling, reading, calculation and total scores), executive functioning (selective attention/inhibitory control, set shifting, working memory, and processing speed), single word comprehension and nonverbal reasoning. Motor skills were assessed and parents provided demographic information and child behavioral assessments. Dystrophin gene mutation positions were dichotomized into groups (upstream versus downstream of exon 43, location of isoforms previously linked to intellectual impairment). Genetic mutation groups were compared on measures of academic achievement, and multiple regression analyses examined unique and joint contributions of executive skills, intelligence quotient (IQ), SES, motor abilities, behavior, and mutation positions to academic outcomes.Results:Academic performance was slightly, yet significantly, lower than IQ and varied as a function of dystrophin gene position, wherein boys possessing the downstream mutation exhibited greater impairment than boys with the upstream mutation. Digit span forward (indexing verbal span), but no other measure of executive function, contributed significant variance to total academic achievement, spelling and calculation.Conclusions:Weak academic performance is associated with dystrophinopathy and is more common in downstream mutations. A specific deficit in verbal span may underlie inefficiencies observed in children with dystrophinopathy and may drive deficits impacting academic abilities. (JINS, 2018,24, 928–938)

Purpose To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures. Methods Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded. Results A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive. Conclusions Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

Background The benefits of exercise on long-term health and well-being are well established. The possible benefits of exercise in Spinal Muscular Atrophy (SMA) have not been explored in a controlled clinical trial format. Objective To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients. Methods Fourteen participants, ages 10-48 years, were randomized to control and exercise cohorts after a 1 month lead-in period. The exercise group received 6 months of intervention. Thereafter, both groups received the intervention for the remaining 12 months. Participants were monitored for a total of 19 months. Exercise included individualized home-based cycling and strengthening. The primary outcome measure was distance walked during the six-minute walk test (6MWT). Secondary outcomes included strength, function, exercise capacity, quality of life and fatigue. Results Twelve participants completed the first 7 months of the study, and 9 completed all 19 months. At baseline, the groups were similar on all clinical variables. There were no group changes at any time point in the 6MWT, fatigue, or function. Percent-predicted VO2 max improved 4.9% in all participants in 6 months (p = 0.036) (n = 10). Conclusion Daily exercise is safe in ambulatory SMA and should be encouraged. We did not uncover any deleterious effects on strength, function, or fatigue. Our study documented a reduction in oxidative capacity and a blunted conditioning response to exercise possibly representing an important insight into underlying pathophysiological mechanisms. These findings also may be linked causally to mitochondrial depletion in SMA and warrant further study.

This is the second half of a two-part document updating the standard of care recommendations for spinal muscular atrophy published in 2007. This part includes updated recommendations on pulmonary management and acute care issues, and topics that have emerged in the last few years such as other organ involvement in the severe forms of spinal muscular atrophy and the role of medications. Ethical issues and the choice of palliative versus supportive care are also addressed. These recommendations are becoming increasingly relevant given recent clinical trials and the prospect that commercially available therapies will likely change the survival and natural history of this disease.

Background Reports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients’ and caregivers’ views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE). Methods First, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE. Results Part 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion. The caregivers provided a comparison to activities of daily living for each of the HFMSE items. Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement. Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2. Conclusions Our findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers. Electronic supplementary material The online version of this article (doi:10.1186/s12883-017-0790-9) contains supplementary material, which is available to authorized users.

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

Background Spinal Muscular Atrophy (SMA) is a recessively-inherited neuromuscular disease characterized by weakness and muscle atrophy. Although anecdotal benefits from exercise have been noted, and despite promising pre-clinical and pilot reports, the effect of exercise has not been addressed in a controlled trial in SMA. Objective To assess the effects of exercise on measures of function, strength, and exercise capacity in ambulatory SMA patients. Methods/design An evaluator-blinded, randomized, controlled trial of aerobic and strengthening exercise in 14 ambulatory SMA patients aged 8-50 years. Patients will be randomized to either the exercise or control arm after the 1 month lead in period. During the first 6-months, the exercise group will receive the intervention while the other group serves as a control. After those 6 months, both groups will receive the intervention. The last 6-months of the study are designed to mimic real-world conditions where all participants are encouraged to continue on their own. Participants will be monitored throughout this 19 month study and will have in-person visits every three months. The primary outcome measure is the change in the total distance walked over 6-months on the six minute walk test (6MWT). Secondary outcome measures include maximal oxygen uptake (VO2 max), functional and strength assessments, pulmonary function, fatigue, and quality of life. Discussion The result of this prospective, single blinded, randomized and controlled clinical trial of exercise on an established functional outcome measure will have impact on clinical practice by providing important guidance to clinical management of SMA patients.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of skeletal muscle training on functional performance in people with spinal muscular atrophy (SMA) type 3 and to identify any adverse effects.

Preliminary validation of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) for motor skill assessment in spinal muscular atrophy type I.A total of 27 subjects 3 to 260 months old (mean = 49, SD = 69) with spinal muscular atrophy-I were evaluated with the CHOP INTEND. Subjects were evaluated as part of a multicenter natural history study.CHOP INTEND scores and age were significantly correlated (r = -0.51, P = .007; 2 survival of the motor neuron [SMN] 2 gene copies, n = 16, r = -0.60, 3 SMN2 gene copies, n = 9, r = -0.83). Respiratory support and CHOP INTEND scores were correlated (r = -0.74, P.0001, n = 26). The CHOP INTEND and age regression in patients with 2 copies versus 3 copies of SMN2 approached significance (P = .0711, n = 25). Subjects who required respiratory support scored significantly lower (mean = 15.5, SD = 10.2 vs mean = 31.2, SD = 4.2, P.0001, n = 27). Correlation with motor unit number estimation and combined motor unit activation were not significant.The CHOP INTEND reflects measures of disease severity and supports continued exploration of the CHOP INTEND.

The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith functional motor scale, expanded score into three cohorts: low-functioning non-ambulatory (type 2 with Hammersmith score n =19), high-functioning non-ambulatory (type 2 with Hammersmith score⩾12 or non-ambulatory type 3, n =17), and Ambulatory ( n =17). Lean and fat mass was estimated using dual-energy X-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg/stature in m 2 ) and fat (fat mass in kg/stature in m 2 ) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the high-functioning non-ambulatory cohort (10.4±4.5) compared with both the ambulatory (7.2±2.1, P =0.013) and low-functioning non-ambulatory (7.6±3.1, P =0.040) cohorts. 12 of 17 subjects (71%) in the high-functioning non-ambulatory cohort had fat mass index>85th percentile for age and gender (connoting "at risk of overweight") versus 9 of 19 subjects (47%) in the low-functioning non-ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA.

Background: In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children. Methods: To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale–Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes. Results: The 6MWT was associated with the HFMSE score (r 0.83, p 0.0001), 10-m walk/run (r 0.87, p 0.0001), and knee flexor strength (r 0.62, p 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p 0.0003). Conclusion: The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA. Neurology ® 2010;74:833–838

Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m2), fat-free (FFMI, lean mass/height in m2) and fat (FMI, fat mass/height in m2) mass indexes were estimated in 25 children (ages 5–18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was ≥ 50th percentile in 11 (44%) and ≥ 85th in 5 (20%). FFMI was reduced (p

The objective was to report on the creation, features and performance of a web-based data management system for a two-stage phase II randomized clinical trial of Co-Enzyme Q10 in ALS. We created a relatively comprehensive web-based data system that provided electronic data entry; patient management utilities; adverse event reporting, safety monitoring, and invoice generation; and standardized coding for medications and adverse events. In stage 1, clinical sites submitted 7207 forms reporting on 105 patients followed for 10 months. Less than 0.7% of submitted forms contained errors. At the time of the delivery of the analysis data set, only four errors remained unresolved. Data were available quickly, with a median time from event to data posting of two days. The data set was locked and the analysis data set produced nine days after the final patient visit. A survey of trial personnel yielded generally positive feedback, with 75% of respondents wishing to use a similar system in the future. Given sufficient resources, a comprehensive web-based data management system can meet the need for clean, available data in clinical trials in ALS and similar diseases, and can contribute significantly to their efficient execution.

Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMN Rx ), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory. Results: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9–14 months postdose (5.8 points; p = 0.008) during the extension study. Conclusions: Results from this study support continued development of nusinersen for treatment of SMA. Classification of evidence: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.