Compound muscle action potential and motor function in children with spinal muscular atrophy

Lewelt, Aga J.; Krosschell, Kristin J.; Scott, Charles; Sakonju, Ai; Kissel, John T.; Crawford, Thomas O.; Acsádi, Gyula; D’Anjou, Guy; Elsheikh, Bakri; Reyna, Sandra P.; Schroth, Mary K.; Maczulski, Jo Anne; Stoddard, Gregory J.; Elovic, Elie P.; Swoboda, Kathryn J.

doi:10.1002/mus.21838

Cited by 94 publications

(84 citation statements)

References 12 publications

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“…CMAP responses were reliably lower in SMA infants than controls and correlated with MFS in SMA infants, consistent with previous reports (22, 40–42). Given its promise in SMA animal model studies (43, 44), future studies in infants who receive effective disease-modifying therapy may indicate that CMAP is, if not a prognostic biomarker, a predictive biomarker of treatment response.…”

Section: Discussionsupporting

confidence: 92%

Natural history of infantile‐onset spinal muscular atrophy

Kolb

Coffey

Yankey

et al. 2017

Annals of Neurology

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294

224

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Objective Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. Methods A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. Results Motor function scores (MFS) and CMAP decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17). Interpretation These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated.

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Section: Discussionsupporting

confidence: 92%

Natural history of infantile‐onset spinal muscular atrophy

Kolb

Coffey

Yankey

et al. 2017

Annals of Neurology

Self Cite

294

224

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“…In EMG studies on type 3 cases, there is evidence of sprouting of the surviving motor neurons [48]. Large CMAPs are often found in type 3 patients for a particular muscle [49]. …”

Section: Discussionmentioning

confidence: 99%

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

Iyer¹,

McGovern²,

Wise³

et al. 2014

Neuromuscular Disorders

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Spinal Muscular Atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx−/−–SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1.

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“…The biggest challenge to the CMAP is its reliability, which is sensitively dependent on electrode positioning, limb and hand positioning, and temperature. Not surprisingly several studies that have looked at CMAP reliability have shown mixed results [48,49]. However, by carefully trying to maximize the CMAP value and being consistent about electrode placement and limb position, it may be possible to more effectively use the CMAP as a primary marker of disease progression.…”

Section: Compound Motor Action Potential and The Neurophysiological Imentioning

confidence: 99%

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

Rutkove

2015

Neurotherapeutics

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Progressive weakness remains the clinical hallmark of amyotrophic lateral sclerosis (ALS). Accordingly, a variety of tools has been developed to capture this disease feature, including questionnaires, such as the ALS-functional rating scale, strength testing, pulmonary function tests, electrophysiologic measures, including motor unit number estimation, and imaging techniques. Despite this plethora of approaches, there is little agreement as to what measures to use in a given clinical trial or in the clinic during routine patient care. Part of the reason for this uncertainty is that ALS is a remarkably protean disease. Some individuals progress rapidly, others slowly; some patients have considerable upper motor neuron dysfunction, whereas others have little; and there is considerable variation in the sequence of body regions affected, in some the disease beginning in the bulbar musculature and in others in one arm or one leg. Here, I present a variety of basic and more complex clinical measures for potential use in therapeutic trials with the aim of offering a balanced and practical set of recommendations, as well as considerations for future studies.

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Compound muscle action potential and motor function in children with spinal muscular atrophy

Abstract: Introduction-Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials.

Cited by 94 publications

References 12 publications

Natural history of infantile‐onset spinal muscular atrophy

Natural history of infantile‐onset spinal muscular atrophy

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

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