Spinal Muscular Atrophy Functional Rating Research Articles

Psychometric evaluation of modified spinal muscular atrophy functional rating scale (SMAFRS) in adult patients using Rasch analysis.

The Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) was first developed as a secondary functional outcome measure to detect changes over time in patients with spinal muscular atrophy (SMA) in clinical trials. Its modified version evaluates 10 activities of daily living. The aim of the study was to analyze modified SMAFRS data using item response theory psychometric models. A total of 253 responses from 41 adult patients with ambulatory and non-ambulatory SMA types 2, 3, and 4 were analyzed. Rasch analysis was used to explore item-person targeting, fit statistics, category response functioning, dimensionality, and differential item functioning. Most items had good fitting with the exception of "toileting" and "respiratory." There were no major floor or ceiling effects, and most items covered a good range of disability with only a negligible breech of uni-dimensionality from eating, dressing, and respiratory items. Differential item function highlighted differences in toileting, turning, transferring, walking, and respiratory items between ambulatory and non-ambulatory populations. Despite subtle misfitting of certain items, mainly related to respiratory and bulbar function, overall modified SMAFRS remained a psychometrically stable and unidimensional outcome measure. There were some differences in measuring properties of certain functional items between ambulatory and non-ambulatory items that need to be taken into consideration in clinical trial design. Overall, the modified SMAFRS is a psychometrically reliable tool in assessment of adult patients with SMA.

Clinical and radiological profile of patients with spinal muscular atrophy type 4.

Spinal muscular atrophy (SMA) is the most important cause of motor neuron disease in childhood, and continues to represent the leading genetic cause of infant death. Adulthood-onset SMA (SMA type 4) is rare, with few isolated cases reported. The objective of the present study was to describe a cohort of patients with SMA type 4. A cross-sectional study was conducted to characterize clinical, genetic, radiological and neurophysiological features of patients with adulthood-onset SMA. Correlation analysis of functional assessment with genetic, radiological and neurophysiological data was performed. Twenty patients with SMA type 4 were identified in a Brazilian cohort of 227 patients with SMA. The most common clinical symptom was limb-girdle muscle weakness, observed in 15 patients (75%). The most frequent neurological findings were absent tendon reflexes in 18 (90%) and fasciculations in nine patients (45%). Sixteen patients (80%) had the homozygous deletion of exon 7 in the SMN1 gene, with 12 patients (60%) showing four copies of the SMN2 gene. The functional scales Hammersmith Functional Motor Scale Expanded, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised, Revised Upper Limb Module and Spinal Muscular Atrophy Functional Rating Scale, as well as the six-minute walk and the Time Up and Go tests showed a correlation with duration of disease. Motor Unit Number Index was correlated both with duration of disease and with performance in functional assessment. Radiological studies exhibited a typical pattern, with involvement of biceps femoris short head and gluteus minimus in all patients. This study represents the largest cohort of patients with SMA type 4 and provides functional, genetic, radiological and neurophysiological features that can be used as potential biomarkers for the new specific genetic therapies for SMA.

SMA THERAPIES I: P.176Experience using Spinraza to treat adults with spinal muscular atrophy

Evaluate effectiveness of spinraza clinical protocol in adults with SMA and determine post-treatment functional changes. Natural history data of functional and clinical measures prospectively collected from adults in a SMA network, PNCRN, were compared with spinraza treated adults. Visits included medical & genetic history, establishing standards of care, evaluating anatomic and radiologic findings, and assessing insurance. A minimal data set included at least one of the following: modified CHOP-INTEND, RULM, HFMSE, TUG, 6MWT. We also monitored pulmonary function, limb strength, patient reports, safety labs and adverse events. Natural history was collected from 170 evaluations of 57 untreated adults. Assessments included 39 patients wanting spinraza, 27 treated. None were denied treatment due to insurance, but others have not yet received treatment due to lack of access via fluoroscopy (n=5), and patient choice (n=1). Treated individuals were: 18-65 years old, non-ambulatory (n=20), male (n=16), requiring day and night ventilatory support (n=7), and spinal fusion (n=8). Attestations of qualitative improvements were frequent (85%) but were not reflected in the spinal muscular atrophy functional rating scale (SMAFRS). Baseline measures (median and ranges) included for ambulatory (n=7): 6MWT (342.7m, 69.2-466.0m), TUG (9.9s, 8.4-44.2s) and for non-Ambulatory RULM (n=14) (6, 0-37), FVC (n=12) (1.6L, 0.28-3.8L);(%predicted 40%, 9-90%)). Spinraza has been well tolerated and improvement trends are emerging in multiple measures; data continue to be collected. Analyses of clinical outcomes, to be presented, will define Spinraza efficacy for adults with SMA.

Reliability of Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) in Ambulatory Adults with Spinal Muscular Atrophy. (P4.452)

Reliability of Spinal Muscular Atrophy Functional Rating Scale (SMAFRS) in Ambulatory Adults with Spinal Muscular Atrophy. (P4.452)

Dysfunction of axonal membrane conductances in adolescents and young adults with spinal muscular atrophy

Spinal muscular atrophy is distinct among neurodegenerative conditions of the motor neuron, with onset in developing and maturing patients. Furthermore, the rate of degeneration appears to slow over time, at least in the milder forms. To investigate disease pathophysiology and potential adaptations, the present study utilized axonal excitability studies to provide insights into axonal biophysical properties and explored correlation with clinical severity. Multiple excitability indices (stimulus–response curve, strength–duration time constant, threshold electrotonus, current–threshold relationship and recovery cycle) were investigated in 25 genetically characterized adolescent and adult patients with spinal muscular atrophy, stimulating the median motor nerve at the wrist. Results were compared with 50 age-matched controls. The Medical Research Council sum score and Spinal Muscular Atrophy Functional Rating Scale were used to define the strength and motor functional status of patients with spinal muscular atrophy. In patients with spinal muscular atrophy, there were reductions in compound muscle action potential amplitude (P < 0.0005) associated with reduction in stimulus response slope (P < 0.0005), confirming significant axonal loss. In the patients with mild or ambulatory spinal muscular atrophy, there was reduction of peak amplitude without alteration in axonal excitability; in contrast, in the non-ambulatory or severe spinal muscular atrophy cohort prominent changes in axonal function were apparent. Specifically, there were steep changes in the early phase of hyperpolarization in threshold electrotonus (P < 0.0005) that correlated with clinical severity. Additionally, there were greater changes in depolarizing threshold electrotonus (P < 0.0005) and prolongation of the strength-duration time constant (P = 0.001). Mathematical modelling of the excitability changes obtained in patients with severe spinal muscular atrophy supported a mixed pathology comprising features of axonal degeneration and regeneration. The present study has provided novel insight into the pathophysiology of spinal muscular atrophy, with identification of functional abnormalities involving axonal K+ and Na+ conductances and alterations in passive membrane properties, the latter linked to the process of neurodegeneration.

An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy

To evaluate the effect of SMN2 copy number on disease severity in spinal muscular atrophy (SMA), we stratified 45 adult SMA patients based on SMN2 copy number (3 vs. 4 copies). Patients with 3 copies had an earlier age of onset and lower spinal muscular atrophy functional rating scale (SMAFRS) scores and were more likely to be non-ambulatory. There was, however, no difference between the groups in quantitative muscle strength or pulmonary function testing. Functional scale may be a more discriminating outcome measure for SMA clinical trials.