Clinical Variability in Spinal Muscular Atrophy Type III.

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.

Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function.

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.

Gait assessment with solesound instrumented footwear in spinal muscular atrophy.

INTRODUCTION: Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over-ground walking has not been studied. METHODS: Nine SMA participants completed the 6-minute walk test (6MWT) and 10-meter walk/run wearing instrumented footwear (SoleSound). Data were simultaneously collected using a reference system (GAITRite). The root-mean-square error (RMSE) indicated criterion validity. The decrease in walking speed represented fatigue. Foot loading patterns were evaluated using force sensors. RESULTS: The RMSE for stride time, length, and velocity ranged from 1.3% to 1.7%. Fatigue was 11.6 ± 9.1%, which corresponded to an average deceleration of 0.37 ± 0.28 mm/s2 . Participants spent most of their stance without heel contact. Forefoot contact occurred early in the gait cycle. CONCLUSIONS: These results suggest that footwear-based devices are an alternative to specialized equipment for gait assessment. Better understanding of gait disturbances should inform ongoing treatment efforts and provide a more sensitive outcome measure. Muscle Nerve 56: 230-236, 2017.

Revised upper limb module for spinal muscular atrophy: Development of a new module.

INTRODUCTION: There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients. METHODS: An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale. RESULTS: Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups. CONCLUSIONS: The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi-center clinical research. Muscle Nerve 55: 869-874, 2017.

Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy.

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.

Six-minute walk test is reliable and valid in spinal muscular atrophy.

INTRODUCTION: The Six-Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. METHODS: Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. RESULTS: Test-retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand-held dynamometry, and inversely with 10-m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. CONCLUSIONS: This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836-842, 2016.

Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

INTRODUCTION: In this study we evaluated the suitability of a caregiver-reported functional measure, the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), for children and young adults with spinal muscular atrophy (SMA). METHODS: PEDI-CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. RESULTS: Unidimensional content for each domain was confirmed. The PEDI-CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. CONCLUSIONS: The PEDI-CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097-1107, 2016.

Old measures and new scores in spinal muscular atrophy patients.

INTRODUCTION: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale-Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items. METHODS: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients. RESULTS: The mean 12-month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar. CONCLUSIONS: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items.

Validity of remote live stream video evaluation of the North Star Ambulatory Assessment in patients with Duchenne muscular dystrophy.

Conducting functional assessments remotely can help alleviate the burden of in-person assessment on patients with Duchenne muscular dystrophy and their caregivers. The objective of this study was to evaluate whether scores from remote functional assessment of patients with Duchenne muscular dystrophy correspond to in-person scores on the same functional assessments. Remote live stream versus in-person scores on the North Star Ambulatory Assessment (including time [seconds] to complete the 10-meter walk/run and time to rise from the floor [supine to stand]) were assessed using statistical analyses, including intraclass correlation coefficient, and Pearson, Spearman, and Bland-Altman analyses. The remote and in-clinic assessments had to occur within 2 weeks of one another to be considered for this analysis. This analysis included patients with Duchenne muscular dystrophy, aged 4 to 7 years. Participants in this analysis received delandistrogene moxeparvovec (as part of SRP-9001-101 [Study 101; NCT03375164] or SRP-9001-102 [Study 102; NCT03769116]) or were randomized to receive placebo (in Part 1 of Study 102). This study evaluates score reproducibility between live stream remote scoring versus in-person functional assessments as determined by intraclass correlation coefficient, and Pearson, Spearman, and Bland-Altman analyses. The results showed that scores from remote functional assessment of patients with Duchenne muscular dystrophy strongly correlated with those obtained in person. These findings demonstrate congruence between live stream remote and in-person functional assessment and suggest that remote assessment has the potential to reduce the burden on a family by supplementing in-clinic visits.

Cross-sectional, quantitative analysis of motor function in females with HNRNPH2-related disorder.

AIMS: To describe the gross motor function of individuals with HNRNPH2-related disorder (OMIM 300986, Mental Retardation, X-linked, Syndrome, Bain Type; MRXSB) and determine the associations between clinician-measured motor function and caregiver-reported mobility scores. METHODS: Developmental histories of 17 female participants with HNRNPH2-related disorder (mean age 11.2 years, range 2.7-37.1 years) with various genotypes within and adjacent to the nuclear localization sequence (NLS) were analyzed. Participants performed the Gross Motor Function Measure-88 (GMFM-88) and caregivers completed developmental histories and the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT). RESULTS: All participants had measurable and quantifiable motor impairments. A strong positive correlation between the clinician-measured GMFM-88 total score and the caregiver-reported PEDI-CAT mobility domain score was established. Motor deficits were noted more often in individuals who were nonverbal. The 2 participants with genotypes adjacent to the NLS appear to have milder motor phenotypes. CONCLUSIONS: The GMFM-88 and PEDI-CAT are useful and feasible measures of mobility in individuals with HNRNPH2-related disorders. Convergent validity was established between the clinician-measured GMFM-88 raw scores and caregiver-reported PEDI-CAT mobility domain scores. Factors including verbal status and genotype may impact motor abilities.

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency.

We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.

Psychometric properties of the PEDI-CAT for children and youth with spinal muscular atrophy.

PURPOSE: The purpose of this study was to examine the psychometric properties of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT) in children and youth with Spinal Muscular Atrophy (SMA). METHODS: In this prospective cross-sectional study, caregivers of children and youth with SMA completed the PEDI-CAT Daily Activities and Mobility domains. A subset of caregivers completed a questionnaire about the measure. RESULTS: Mean ranks of scaled scores for Daily Activities (n = 96) and Mobility (n = 95) domains were significantly different across the three SMA types and across the three motor classifications. Normative scores indicated that 85 participants (89.5%) had limitations in Mobility and 51 in Daily Activities (53.1%). Floor effects were observed in≤10.4% of the sample for Daily Activities and Mobility. On average, caregivers completed the Mobility domain in 5.4 minutes and the Daily Activities domain in 3.3 minutes. Most caregivers reported that they provided meaningful information (92.1%), were willing to use the PEDI-CAT format again (79%), and suggested adding content including power wheelchair mobility items. CONCLUSION: Convergent validity was demonstrated for the Daily Activities and Mobility domains. Normative scores detected limitations in Mobility and Daily Activity performance for most participants with SMA. The PEDI-CATwas feasible to administer and caregivers expressed willingness to complete the PEDI-CAT in the future.

Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder.

OBJECTIVE: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals. METHODS: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures. RESULTS: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition. CONCLUSIONS: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

Scoliosis Surgery Significantly Impacts Motor Abilities in Higher-functioning Individuals with Spinal Muscular Atrophy1.

BACKGROUND: Weakness affects motor performance and causes skeletal deformities in spinal muscular atrophy (SMA). Scoliosis surgery decision-making is based on curve progression, pulmonary function, and skeletal maturity. Benefits include quality of life, sitting balance, and endurance. Post-operative functional decline has not been formally assessed. OBJECTIVE: To assess the impact of scoliosis surgery on motor function in SMA types 2 and 3. METHODS: Prospective data were acquired during a multicenter natural history study. Seventeen participants (12 type 2, 5 type 3 with 4 of the 5 having lost the ability to ambulate) had motor function assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) performed pre-operatively and at least 3 months post-operatively. Independent t-tests determined group differences based on post-operative HFMSE changes, age, and baseline HFMSE scores. RESULTS: Three participants had minimal HFMSE changes (±2 points) representing stability (mean change = -0.7). Fourteen participants lost >3 points, representing a clinically meaningful progressive change (mean change = -12.1, SD = 8.9). No participant improved >2 points. There were no age differences between stable and progressive groups (p = 0.278), but there were significant differences between baseline HFMSE (p = 0.006) and change scores (p = 0.001). Post-operative changes were permanent over time. CONCLUSIONS: Scoliosis surgery has an immediate impact on function. Baseline HFMSE scores anticipate post-operative loss as higher motor function scores were associated with worse decline. Instrumentation that includes fixation to the pelvis reduces flexibility, limiting the ability for compensatory maneuvers. These observations provide information to alert clinicians regarding surgical risk and to counsel families.

Exploring mTOR inhibition as treatment for mitochondrial disease.

Leigh syndrome and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) are two of the most frequent pediatric mitochondrial diseases. Both cause severe morbidity and neither have effective treatment. Inhibiting the mammalian target of rapamycin (mTOR) pathway has been shown in model mice of Leigh syndrome to extend lifespan and attenuate both the clinical and pathological progression of disease. Based on this observation, we treated two children with everolimus, a rapamycin analogue. The child with Leigh syndrome showed sustained benefit, while the child with MELAS failed to respond and died of progressive disease. We discuss possible mechanisms underlying these disparate responses to mTOR inhibition.

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression.

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool.

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

Temporal and spatial gait parameters in children with Cri du Chat Syndrome under single and dual task conditions.

AIM: To describe temporal and spatial gait characteristics in individuals with Cri du Chat syndrome (CdCS) and to explore the effects of performing concurrent manual tasks while walking. METHODS: The gait parameters of 14 participants with CdCS (mean age 10.3, range 3-20 years) and 14 age-matched controls (mean age 10.1, range 3-20 years) were collected using the GAITRite® instrumented walkway. All participants first walked without any concurrent tasks and then performed 2 motor dual task walking conditions (pitcher and tray). RESULTS: Individuals with CdCS took more frequent, smaller steps than controls, but, on average, had a comparable gait speed. In addition, there was a significant task by group interaction. Participants decreased gait speed, decreased cadence, decreased step length, and increased% time in double limb support under dual task conditions compared to single task conditions. However, the age-matched controls altered their gait for both manual tasks, and the participants with CdCS only altered their gait for the tray task. INTERPRETATION: Although individuals with CdCS ambulate with a comparable gait speed to age-matched controls under single task conditions, they did not significantly alter their gait when carrying a pitcher with a cup of water inside, like controls. It is not clear whether or not individuals with CdCS had difficulty attending to task demands or had difficulty modifying their gait.

Developmental milestones in type I spinal muscular atrophy.

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.

Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials.

The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients.