Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Kariyawasam, Didu; D’Silva, Arlene M; Howells, James; Herbert, Karen; Geelan-Small, Peter; Lin, Cindy S.‐Y.; Farrar, Michelle A.

doi:10.1136/jnnp-2020-324254

Cited by 39 publications

(64 citation statements)

References 40 publications

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“…One prior study in children with later onset SMA treated with nusinersen, showed decreased MUNE and stable CMAP, but data in this study showed variability possibly reflecting the difficulty of electrophysiological assessments in children (14). Another recent study used the technique of MScanFit MUNE to investigate motor unit response in children undergoing nusinersen treatment and showed recovery of smaller motor units (28). This is in contrast to what we show here in that adults undergoing nusinersen demonstrated enlargement of average motor unit size (amplitude) without change in MUNE.…”

Section: Discussioncontrasting

confidence: 99%

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

et al. 2021

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Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1–C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21–64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.

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Section: Discussioncontrasting

confidence: 99%

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

et al. 2021

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“…In a parallel study in non-ambulatory adults with SMA, we found a similar pattern of increases in CMAP and SMUP and stable MUNE ( 31 ). Interestingly, in a recent study that used MscanFit MUNE to estimate motor unit number in children with SMA treated with nusinersen, it was shown that nusinersen induced recovery of smaller motor units ( 32 ). Whether these differences are related to variability of biological response in children vs. adults or are explained by differences in technique requires further research.…”

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

et al. 2021

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Objective: To determine the safety and tolerability of nusinersen treatment in ambulatory adults with spinal muscular atrophy (SMA) and investigate the treatment effect on muscle strength, physical function, and motor unit physiology.Methods: Individuals aged 18 years or older with genetically confirmed 5q SMA, three or more copies of the SMN2 gene, and the ability to ambulate 30 feet were enrolled. Safety outcomes included the number of adverse events and serious adverse events, clinically significant vital sign or laboratory parameter abnormalities. Outcome assessments occurred at baseline (prior to the first dose of nusinersen) and then 2, 6, 10, and 14 months post-treatment.Results: Six women, seven men (mean age: 37 ± 11, range: 18–59 years) were included for analyses. The most common side effects were headache and back pain, but overall procedures and treatments were well-tolerated. No serious adverse events were reported. Maximal Voluntary Isometric Muscle Contraction Testing (MVICT) and 6-min walk test (6MWT) both showed overall stability with significant increases at 2, 6, and 10 months for the 6MWT. More consistent significant treatment effects were noted on the Hammersmith Functional Motor Scale Expanded, SMA-Functional Rating Scale, and forced vital capacity. Treatment resulted in progressively increased ulnar compound muscle action potential and average single motor unit potential amplitudes, but motor unit number estimation remained stable.Conclusions: Nusinersen treatment is safe and well-tolerated in ambulatory adults with SMA. Treatment resulted in improved motor function and electrophysiological findings suggest that this improvement may be occurring via improved motor unit reinnervation capacity.

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“…In a prospective study of 20 symptomatic SMA children (ages 4 months-16 years) undergoing nusinersen treatment, individuals with shorter disease durations showed greater increases in CMAP and MUNE, and these measures correlated with functional changes assessed by CHOP-INTEND and HFMSE. 123 In children with later-onset SMA (ages 2-15 years), CMAP and MUNE fluctuated slightly but were generally stable over 3 years of nusinersen treatment. 124 SMA type 2 children (n = 11, average age 15.4 months at diagnosis) showed progressive improvements in motor function and the majority demonstrated clinically meaningful improvements by the end of the study, while SMA type 3 children (n = 17, average age 43.6 months at diagnosis) showed only modest, and few clinically meaningful, functional improvements.…”

Section: Electrophysiology and Imaging Biomarkersmentioning

confidence: 95%

“…Disease progression, prognostic, predictive Kolb et al, 31 Kolb et al, 32 Arnold et al, 79 Swoboda et al, 114 David et al, 118 Weng et al, 119 Al-Zaidy et al, 122 Kariyawasam et al, 123 Darras et al 124 Motor unit number estimation (MUNE) Disease progression, prognostic, predictive Swoboda et al, 114 David et al, 118 Al-Zaidy et al, 122 Kariyawasam et al, 123 Darras et al 124 Motor unit number index (MUNIX) and motor unit size index (MUSIX)…”

Section: Physiologicmentioning

confidence: 99%

Update on Biomarkers in Spinal Muscular Atrophy

2021

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The availability of disease modifying therapies for spinal muscular atrophy (SMA) has created an urgent need to identify clinically meaningful biomarkers. Biomarkers present a means to measure and evaluate neurological disease across time. Changes in biomarkers provide insight into disease progression and may reveal biologic, physiologic, or pharmacologic phenomena occurring prior to clinical detection. Efforts to identify biomarkers for SMA, a genetic motor neuron disease characterized by motor neuron degeneration and weakness, have culminated in a number of putative molecular and physiologic markers that evaluate biological media (eg, blood and cerebrospinal fluid [CSF]) or nervous system function. Such biomarkers include SMN2 copy number, SMN mRNA and protein levels, neurofilament proteins (NFs), plasma protein analytes, creatine kinase (CK) and creatinine (Crn), and various electrophysiology and imaging measures. SMN2 copy number inversely correlates with disease severity and is the best predictor of clinical outcome in untreated individuals. SMN mRNA and protein are commonly measured in the blood or CSF of patients receiving SMA therapies, particularly those aimed at increasing SMN protein expression, and provide insight into current disease state. NFs have proven to be robust prognostic, disease progression, and pharmacodynamic markers for SMA infants undergoing treatment, but less so for adolescents and adults. Select plasma proteins are altered in SMA individuals and may track response to therapy. CK and Crn from blood correlate with motor function and disease severity status and are useful for predicting which individuals will respond to therapy. Electrophysiology measures comprise the most reliable means for monitoring motor function throughout disease course and are sensitive enough to detect neuromuscular changes before overt clinical manifestation, making them robust predictive and pharmacodynamic biomarkers. Finally, magnetic resonance imaging and muscle ultrasonography are non-invasive techniques for studying muscle structure and physiology and are useful diagnostic tools, but cannot reliably track disease progression. Importantly, biomarkers can provide information about the underlying mechanisms of disease as well as reveal subclinical disease progression, allowing for more appropriate timing and dosing of therapy for individuals with SMA. Recent therapeutic advancements in SMA have shown promising results, though there is still a great need to identify and understand the impact of biomarkers in modulating disease onset and progression.

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Motor unit changes in children with symptomatic spinal muscular atrophy treated with nusinersen

Cited by 39 publications

References 40 publications

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy

Safety, Tolerability, and Effect of Nusinersen Treatment in Ambulatory Adults With 5q-SMA

Update on Biomarkers in Spinal Muscular Atrophy

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