SMNT and NAIP mutations in Canadian families with spinal muscular atrophy (SMA): Genotype/phenotype correlations with disease severity

1997 ◽  
Vol 72 (1) ◽  
pp. 51-58 ◽  
Author(s):  
Louise R. Simard ◽  
Camille Rochette ◽  
Alexandre Semionov ◽  
Kenneth Morgan ◽  
Michel Vanasse
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy

SMN mRNA and protein levels in peripheral blood

Neurology ◽  
2006 ◽  
Vol 66 (7) ◽  
pp. 1067-1073 ◽  
Author(s):  
C. J. Sumner ◽  
S. J. Kolb ◽  
G. G. Harmison ◽  
N. O. Jeffries ◽  
K. Schadt ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Muscular Atrophy ◽  
Gene Copy ◽  
Blood Levels ◽  
Type I ◽  
Protein Levels ◽  
Smn Protein

Background: Clinical trials of drugs that increase SMN protein levels in vitro are currently under way in patients with spinal muscular atrophy.Objective: To develop and validate measures of SMN mRNA and protein in peripheral blood and to establish baseline SMN levels in a cohort of controls, carriers, and patients of known genotype, which could be used to follow response to treatment.Methods: SMN1 and SMN2 gene copy numbers were determined in blood samples collected from 86 subjects. Quantitative reverse transcription PCR was used to measure blood levels of SMN mRNA with and without exon 7. A cell immunoassay was used to measure blood levels of SMN protein.Results: Blood levels of SMN mRNA and protein were measured with high reliability. There was little variation in SMN levels in individual subjects over a 5-week period. Levels of exon 7-containing SMN mRNA and SMN protein correlated with SMN1 and SMN2 gene copy number. With the exception of type I SMA, there was no correlation between SMN levels and disease severity.Conclusion: SMN mRNA and protein levels can be reliably measured in the peripheral blood and used during clinical trials in spinal muscular atrophy, but these levels do not necessarily predict disease severity.

scholarly journals Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy

Neurology ◽  
2019 ◽  
Vol 94 (9) ◽  
pp. e921-e931 ◽  
Author(s):  
Christiano R.R. Alves ◽  
Ren Zhang ◽  
Alec J. Johnstone ◽  
Reid Garner ◽  
Pann H. Nwe ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Lean Mass ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Survival Motor Neuron ◽  
Mixed Effect

ObjectiveIdentifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA.MethodsWe examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 (SMN2) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE).ResultsPatients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93–2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52–1.82; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31–1.58; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57–2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24–1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21–1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE.ConclusionsThese findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.

scholarly journals Association of Plastin 3 Expression With Disease Severity in Spinal Muscular Atrophy Only in Postpubertal Females

2010 ◽  
Vol 67 (10) ◽  
Author(s):  
George Stratigopoulos ◽  
Patricia Lanzano ◽  
Liyong Deng ◽  
Jiancheng Guo ◽  
Petra Kaufmann ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy

scholarly journals Decreasing Disease Severity in Symptomatic,Smn−/−;SMN2+/+, Spinal Muscular Atrophy Mice Following scAAV9-SMN Delivery

2012 ◽  
Vol 23 (3) ◽  
pp. 330-335 ◽  
Author(s):  
Jacqueline J. Glascock ◽  
Erkan Y. Osman ◽  
Mary J. Wetz ◽  
Megan M. Krogman ◽  
Monir Shababi ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy

Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy

2009 ◽  
Vol 31 (1) ◽  
pp. 42-45 ◽  
Author(s):  
Mohd Shamshudin Watihayati ◽  
Hayati Fatemeh ◽  
Marzuki Marini ◽  
Amin Baig Atif ◽  
Wan Mohd Zahiruddin ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Copy Number ◽  
Muscular Atrophy

scholarly journals Glial Fibrillary Acidic Protein in Cerebrospinal Fluid of Nusinersen-Treated Patients with Spinal Muscular Atrophy

2021 ◽  
Author(s):  
Maren Freigang ◽  
Petra Steinacker ◽  
Claudia Diana Wurster ◽  
Olivia Schreiber-Katz ◽  
Alma Osmanovic ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Glial Fibrillary Acidic Protein ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy ◽  
Gene Replacement ◽  
Adult Patients ◽  
Acidic Protein ◽  
Specialist Care ◽  
Predict Treatment Response

Abstract BackgroundActivated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA-modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein (GFAP) concentrations as a marker of astrogliosis in the cerebrospinal fluid (CSF) of children and adult patients with SMA before and during treatment with nusinersen.Methods58 adult patients and 21 children with genetically confirmed 5q-associated SMA from 4 German motor neuron disease specialist care centers and 30 age- and sex-matched controls were prospectively included in this study. GFAP concentration was measured in CSF and motor performance and disease severity were assessed.ResultsCSF GFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients’ age. Within 14 months of nusinersen treatment, CSF GFAP concentrations did not change significantly.ConclusionsGFAP concentration in CSF of patients with long-standing SMA is not useful to assess disease severity or predict treatment response, but might support the hypothesis that glial activation is involved in SMA pathology.

scholarly journals Correlation of PLS3 expression with disease severity in children with spinal muscular atrophy

2013 ◽  
Vol 59 (1) ◽  
pp. 24-27 ◽  
Author(s):  
Cao Yanyan ◽  
Qu Yujin ◽  
Bai Jinli ◽  
Jin Yuwei ◽  
Wang Hong ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy

scholarly journals Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy

2020 ◽  
Vol 6 (1) ◽  
pp. e386 ◽  
Author(s):  
Renske I. Wadman ◽  
Marc D. Jansen ◽  
Chantall A.D. Curial ◽  
Ewout J.N. Groen ◽  
Marloes Stam ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Muscular Atrophy ◽  
Clinical Effects ◽  
Severe Phenotype ◽  
Splice Enhancer ◽  
Expression Levels ◽  
Exonic Splice Silencer ◽  
Exonic Splice ◽  
Intronic Variants

ObjectiveTo investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.MethodsWe performed a hypothesis-based search into the presence of variants in fused in sarcoma (FUS), transactive response DNA-binding protein 43 (TDP-43), plastin 3 (PLS3), and profilin 2 (PFN2) in a cohort of 153 patients with SMA types 1–4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.ResultsWe identified 2 exonic variants in FUS exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in PLS3 in 33 patients. Five PLS3 variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in PFN2 and TDP-43 with no correlation with clinical phenotype or effects on splicing.ConclusionsPLS3 and FUS sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.

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