Stander Use in Spinal Muscular Atrophy: Results From a Large Natural History Database.

PURPOSE: The purpose of this study was to describe stander use in a natural history cohort of drug therapy-naïve children with spinal muscular atrophy (SMA) who are not walking and identify factors associated with consistent stander use. METHODS: Data from 397 children with SMA types 1 and 2 characterized the prevalence and frequency of stander use. Predictors of consistent stander use explored were SMA type, survival motor neuron 2 gene (SMN2) copy number, respiratory support, and motor performance. RESULTS: Prevalence of consistent stander use was 13% in type 1 and 68% in type 2. SMA type, SMN2 copy number, respiratory support, and head rotation control each predicted consistent stander use. CONCLUSIONS: Findings characterize stander use in children with SMA who are not walking, address important safety considerations, identify factors that may inform physical therapists' clinical decision-making related to standing program prescription, and provide guidance for future prospective studies.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Natural history of 10-meter walk/run test performance in spinal muscular atrophy: A longitudinal analysis.

As trials and treatments for spinal muscular atrophy (SMA) rapidly evolve, understanding the natural history and potential utility of the 10-meter walk/run test (10MWRT) in ambulant individuals is critical. Study aims were to: 1) establish change over time and across age for 10MWRT time in an untreated natural history cohort of young, ambulatory participants with SMA and 2) identify relations between 10MWRT time and age, SMA type, SMN2 copy number and anthropometrics. Untreated individuals (n = 56) age 2 to 21 years who were enrolled in a long-term natural history study between 2005 and 2014 and met inclusion criteria were included. Linear mixed effects models were used to assess changes in 10MWRT time with age and associations with SMA type, SMN2 copy number, and body mass. SMA type 3b (versus 3a), SMN2 copy number 4 (versus 3) and lower body mass were associated with faster 10MWRT. 10MWRT performance improved between 3 and 8 years of age, was stable between 9 and 10, and gradually declined from 11 to 18. Findings provide the first longitudinal natural history report of 10MWRT time in young individuals with SMA and offer a critical foundation for interpreting childhood change in short distance walking speed with pharmacologic treatment.

Prospective Cohort Study of Nusinersen Treatment in Adults with Spinal Muscular Atrophy.

BACKGROUND: The impact of nusinersen therapy on outcomes in adults with Spinal Muscular Atrophy (SMA) remains uncertain. OBJECTIVE: To demonstrate whether nusinersen therapy, at currently prescribed doses, can stabilize or improve motor function in adults with SMA using existing outcome measures. METHODS: A single-center prospective cohort study of 6 adults with SMA type 3, with inclusion/exclusion criteria intended to optimize the ability to demonstrate change using established outcome measures. Primary outcomes were the Hammersmith Functional Motor Scale-Expanded (HFMSE) and the Revised Upper Limb Measure (RULM). Secondary outcomes were the PedsQL Fatigue scale, the SMA Functional Rating Scale (SMAFRS), and the 6-minute and 10-meter walk tests (6 MWT and 10 MWT). Estimates of change in HFMSE and RULM mean scores across visits were calculated using a linear mixed effects model. Change from baseline was used for other outcome measures. RESULTS: HFMSE and RULM scores over 12 months were stable or improved in all participants, with a mean increase of 2 points in each. Other measures showed high intra-individual variability. Adverse events related to the primary diagnosis, including injury and infection, significantly impacted the ability to reliably perform walk tests in the four ambulatory participants. CONCLUSIONS: HFMSE and RULM show potential as responsive outcome measures of motor function in ambulatory and non-ambulatory adults with SMA type 3. A time-dependent accrual of benefit of nusinersen on motor function was apparent in this cohort. More sensitive alternative measures of quality of life, fatigue, exercise tolerance, stability and ADLs are clearly needed for adults with SMA.