Spectrum of Neuropathophysiology in Spinal Muscular Atrophy Type I

Harding, Brian; Kariya, Shingo; Monani, Umrao R.; Chung, Wendy K.; Benton, Maryjane; Yum, Sabrina W.; Tennekoon, Gihan; Finkel, Richard S.

doi:10.1097/nen.0000000000000144

Cited by 95 publications

(90 citation statements)

References 60 publications

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“…Whether these changes are due to deficiency of SMN or are a secondary effect of motor neuron dysfunction is currently unknown. Delay in maturation of the acetylcholine receptor was described, as has also been published by other investigators [14,15].…”

Section: Human Pathology In Sma Typementioning

confidence: 71%

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

Finkel

Bertini²,

Muntoni

et al. 2015

Neuromuscular Disorders

175

198

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Section: Human Pathology In Sma Typementioning

confidence: 71%

209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7–9 November 2014, Heemskerk, The Netherlands

Finkel

Bertini²,

Muntoni

et al. 2015

Neuromuscular Disorders

175

198

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“…In contrast to human SMA, mouse models of SMA demonstrate several additional pathological features that are only rarely reported in a few patients with the most severe forms of the disease (type 0 SMA with a single copy of SMN2 ) (Araujo et al, 2009; Bevan et al, 2010; Distefano et al, 1994; Harding et al, 2015; Rudnik-Schoneborn et al, 2010; Shababi et al, 2012; Shababi et al, 2014). Therefore, loss of motor neuron function and degeneration is the most clinically relevant feature in SMA models.…”

Section: Discussionmentioning

confidence: 99%

The neuromuscular impact of symptomatic SMN restoration in a mouse model of spinal muscular atrophy

Arnold

McGovern

Sanchez

et al. 2016

Neurobiology of Disease

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Background Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMNΔ7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. Methods SMAΔ7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12 days for comparison. Results Electrophysiological measures and electrical impedance myography detected significant differences at 12 days between control and late-treated (4 or 6 days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2 days(p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit number estimation (r=0.61 and r=0.50, respectively, p<0.01). Longitudinal measures at 21 and 30 days show that symptomatic therapy results in reduced motor unit number estimation associated with delayed normalization of compound muscle action potential. Conclusions The incomplete effect of symptomatic treatment is accurately identified by both electrophysiological measures and electrical impedance myography. There is strong correlation between these measures and with weight and righting reflex. This study predicts that measures of compound muscle action potential, motor unit number estimation, and electrical impedance myography are promising biomarkers of treatment stratification and effect for future spinal muscular atrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard electrophysiological measures may be particularly valuable in future pediatric clinical trials.

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“…4 Most of these latter patients die in the first weeks of life. [11][12][13][14][15] In this work, we present 3 patients (pts) with clinical and genetic diagnosis of SMA type 0 who survived longer than expected and presented similar progressive brain imaging changes over time. 6,7 Several studies have demonstrated a strong inverse correlation between the number of SMN2 copies (a homologous gene of SMN1) and SMA severity.…”

mentioning

confidence: 88%