Correction: Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Mendili, Mohamed-Mounir El; Lenglet, Timothée; Stojkovic, Tanya; Béhin, Anthony; Guimarães‐Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaëlle; Forestier, Nadine Le; Laforêt, Pascal; Lehericy, Stéphane; Benali, Habib

doi:10.1371/journal.pone.0167886

Cited by 3 publications

(4 citation statements)

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“…We found a clear difference in total CSA of the SC between SMA patients and HCs at TP3, in substantial agreement with previous studies ( 27 – 29 ). SMA patients showed a smaller CSA than HCs, with the largest discrepancy being observed in correspondence of the cervical vertebrae.…”

Section: Discussionsupporting

confidence: 93%

“…Advanced techniques such as magnetization transfer (MT) and diffusion tensor imaging (DTI) of the SC can be used for in vivo quantification of possible pathology-related microstructural changes occurring within the SC (26). qMRI of the cervical SC has been recently applied in three recent cross-sectional studies focusing on pediatric and adult SMA patients not under therapy (27)(28)(29). El Mendili et al (27) reported a significant cord atrophy gradient with a more evident reduction of SC CSA between C3 and C6 levels of adult SMA patients compared to HCs; Querin et al (28) investigated both WM and GM, showing a significant reduction of the CSA of both total SC and GM (but not of WM) at each cervical level (from C2 to C7) in adult untreated SMA patients (SMA 3a, 3b, and 4); finally, in the third study, both pediatric and adult SMA patients (type 2 and 3) showed lower SC CSA values than HCs, though the difference was not statistically significant (29).…”

Section: Introductionmentioning

confidence: 99%

“…qMRI of the cervical SC has been recently applied in three recent cross-sectional studies focusing on pediatric and adult SMA patients not under therapy (27)(28)(29). El Mendili et al (27) reported a significant cord atrophy gradient with a more evident reduction of SC CSA between C3 and C6 levels of adult SMA patients compared to HCs; Querin et al (28) investigated both WM and GM, showing a significant reduction of the CSA of both total SC and GM (but not of WM) at each cervical level (from C2 to C7) in adult untreated SMA patients (SMA 3a, 3b, and 4); finally, in the third study, both pediatric and adult SMA patients (type 2 and 3) showed lower SC CSA values than HCs, though the difference was not statistically significant (29). Two of the studies mentioned above also explored the diffusion properties of SC in SMA: Stam et al (29) reported significantly higher axial diffusivity (AD) in the GM of SMA patients than HCs, while Querin et al (28) found preserved diffusion properties of SC WM.…”

Section: Introductionmentioning

confidence: 99%

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Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Savini¹,

Asteggiano

Paoletti³

et al. 2021

Front. Neurol.

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Introduction: Nusinersen is a recent promising therapy approved for the treatment of spinal muscular atrophy (SMA), a rare disease characterized by the degeneration of alpha motor neurons (αMN) in the spinal cord (SC) leading to progressive muscle atrophy and dysfunction. Muscle and cervical SC quantitative magnetic resonance imaging (qMRI) has never been used to monitor drug treatment in SMA. The aim of this pilot study is to investigate whether qMRI can provide useful biomarkers for monitoring treatment efficacy in SMA.Methods: Three adult SMA 3a patients under treatment with nusinersen underwent longitudinal clinical and qMRI examinations every 4 months from baseline to 21-month follow-up. The qMRI protocol aimed to quantify thigh muscle fat fraction (FF) and water-T2 (w-T2) and to characterize SC volumes and microstructure. Eleven healthy controls underwent the same SC protocol (single time point). We evaluated clinical and imaging outcomes of SMA patients longitudinally and compared SC data between groups transversally.Results: Patient motor function was stable, with only Patient 2 showing moderate improvements. Average muscle FF was already high at baseline (50%) and progressed over time (57%). w-T2 was also slightly higher than previously published data at baseline and slightly decreased over time. Cross-sectional area of the whole SC, gray matter (GM), and ventral horns (VHs) of Patients 1 and 3 were reduced compared to controls and remained stable over time, while GM and VHs areas of Patient 2 slightly increased. We found altered diffusion and magnetization transfer parameters in SC structures of SMA patients compared to controls, thus suggesting changes in tissue microstructure and myelin content.Conclusion: In this pilot study, we found a progression of FF in thigh muscles of SMA 3a patients during nusinersen therapy and a concurrent slight reduction of w-T2 over time. The SC qMRI analysis confirmed previous imaging and histopathological studies suggesting degeneration of αMN of the VHs, resulting in GM atrophy and demyelination. Our longitudinal data suggest that qMRI could represent a feasible technique for capturing microstructural changes induced by SMA in vivo and a candidate methodology for monitoring the effects of treatment, once replicated on a larger cohort.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Savini¹,

Asteggiano

Paoletti³

et al. 2021

Front. Neurol.

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“…Central nervous quantitative MR imaging has exposed cervical spinal cord atrophy in treatment-naïve adult SMA patients compared to healthy controls [ 191 ] and these changes might be based on gray matter atrophy [ 192 , 193 ]. A longitudinal pilot study with three adult SMA patients found stable gray matter volumes in two out of three patients under nusinersen and increasing volumes in the third patient [ 193 ].…”

Section: Biomarkersmentioning

confidence: 99%

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Lapp¹,

Freigang²,

Hagenacker³

et al. 2023

J Neurol

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Abstract5q-associated spinal muscular atrophy (SMA) is a rare genetic disease caused by mutations in the SMN1 gene, resulting in a loss of functional SMN protein and consecutive degeneration of motor neurons in the ventral horn. The disease is clinically characterized by proximal paralysis and secondary skeletal muscle atrophy. New disease-modifying drugs driving SMN gene expression have been developed in the past decade and have revolutionized SMA treatment. The rise of treatment options led to a concomitant need of biomarkers for therapeutic guidance and an improved disease monitoring. Intensive efforts have been undertaken to develop suitable markers, and numerous candidate biomarkers for diagnostic, prognostic, and predictive values have been identified. The most promising markers include appliance-based measures such as electrophysiological and imaging-based indices as well as molecular markers including SMN-related proteins and markers of neurodegeneration and skeletal muscle integrity. However, none of the proposed biomarkers have been validated for the clinical routine yet. In this narrative review, we discuss the most promising candidate biomarkers for SMA and expand the discussion by addressing the largely unfolded potential of muscle integrity markers, especially in the context of upcoming muscle-targeting therapies. While the discussed candidate biomarkers hold potential as either diagnostic (e.g., SMN-related biomarkers), prognostic (e.g., markers of neurodegeneration, imaging-based markers), predictive (e.g., electrophysiological markers) or response markers (e.g., muscle integrity markers), no single measure seems to be suitable to cover all biomarker categories. Hence, a combination of different biomarkers and clinical assessments appears to be the most expedient solution at the time.

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Mild SMN missense alleles are only functional in the presence of SMN2 in mammals

Iyer

Corlett

Massoni-Laporte

et al. 2018

Human Molecular Genetics

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Spinal muscular atrophy (SMA) is caused by reduced levels of full-length SMN (FL-SMN). In SMA patients with one or two copies of the Survival Motor Neuron 2 (SMN2) gene there are a number of SMN missense mutations that result in milder-than-predicted SMA phenotypes. These mild SMN missense mutation alleles are often assumed to have partial function. However, it is important to consider the contribution of FL-SMN as these missense alleles never occur in the absence of SMN2. We propose that these patients contain a partially functional oligomeric SMN complex consisting of FL-SMN from SMN2 and mutant SMN protein produced from the missense allele. Here we show that mild SMN missense mutations SMND44V, SMNT74I or SMNQ282A alone do not rescue mice lacking wild-type FL-SMN. Thus, missense mutations are not functional in the absence of FL-SMN. In contrast, when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL-SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish. Here we demonstrate that the heteromeric SMN complex formed with FL-SMN is functional and sufficient to rescue small nuclear ribonucleoprotein assembly, motor neuron function and rescue the SMA mice. We conclude that mild SMN missense alleles are not partially functional but rather they are completely non-functional in the absence of wild-type SMN in mammals.

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Correction: Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

Cited by 3 publications

References 1 publication

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Pilot Study on Quantitative Cervical Cord and Muscular MRI in Spinal Muscular Atrophy: Promising Biomarkers of Disease Evolution and Treatment?

Biomarkers in 5q-associated spinal muscular atrophy—a narrative review

Mild SMN missense alleles are only functional in the presence of SMN2 in mammals

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