Enhanced Carrier Screening for Spinal Muscular Atrophy: Detection of Silent (SMN1: 2 + 0) Carriers Utilizing a Novel TaqMan Genotyping Method

2019 ◽  
Vol 51 (4) ◽  
pp. 408-415
Author(s):  
Abul Kalam Azad ◽  
Chih-Kang Huang ◽  
Hong Jin ◽  
Hongwei Zou ◽  
Lindsay Yanakakis ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Cost Effective ◽  
Carrier Screening ◽  
Laboratory Method ◽  
Survival Motor Neuron ◽  
Reference Laboratory ◽  
Allelic Discrimination ◽  
Detection Rates ◽  
Genotyping Assay

Abstract Background Individuals whose copies of the survival motor neuron 1 (SMN1) gene exist on the same chromosome are considered silent carriers for spinal muscular atrophy (SMA). Conventional screening for SMA only determines SMN1 copy number without any information regarding how those copies are arranged. A single nucleotide variant (SNV) rs143838139 is highly linked with the silent carrier genotype, so testing for this SNV can more accurately assess risk to a patient of having an affected child. Methods Using a custom-designed SNV-specific Taqman genotyping assay, we determined and validated a model for silent-carrier detection in the laboratory. Results An initial cohort of 21 pilot specimens demonstrated results that were 100% concordant with a reference laboratory method; this cohort was utilized to define the reportable range. An additional 177 specimens were utilized for a broader evaluation of clinical validity and reproducibility. Allelic-discrimination analysis demonstrated tight clustering of genotype groupings and excellent reproducibility, with a coefficient of variation for all genotypes ranging from 1% to 4%. Conclusion The custom-developed Taqman SNV genotyping assay we tested provides a rapid, accurate, and cost-effective method for routine SMA silent-carrier screening and considerably improves detection rates of residual risk for SMA carriers.

scholarly journals Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells

2015 ◽  
Vol 4 ◽  
pp. 351-356 ◽  
Author(s):  
Nur Imma Fatimah Harahap ◽  
Dian Kesumapramudya Nurputra ◽  
Mawaddah Ar Rochmah ◽  
Ai Shima ◽  
Naoya Morisada ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Protein Degradation ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Survival Motor Neuron Protein ◽  
Motor Neuron Protein

scholarly journals Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy

2020 ◽  
Vol 29 (16) ◽  
pp. 2674-2683 ◽  
Author(s):  
Anna A L Motyl ◽  
Kiterie M E Faller ◽  
Ewout J N Groen ◽  
Rachel A Kline ◽  
Samantha L Eaton ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Time Window ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Micro Computed Tomography ◽  
Developmental Abnormalities ◽  
Presymptomatic Stage ◽  
Cardiac Ventricles ◽  
Molecular Phenotypes ◽  
Preclinical And Clinical Studies

Abstract Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of whether SMA has presymptomatic, developmental components to disease pathogenesis. We have addressed this by combining micro-computed tomography (μCT) and comparative proteomics to examine systemic pre-symptomatic changes in a prenatal mouse model of SMA. Quantitative μCT analyses revealed that SMA embryos were significantly smaller than littermate controls, indicative of general developmental delay. More specifically, cardiac ventricles were smaller in SMA hearts, whilst liver and brain remained unaffected. In order to explore the molecular consequences of SMN depletion during development, we generated comprehensive, high-resolution, proteomic profiles of neuronal and non-neuronal organs in SMA mouse embryos. Significant molecular perturbations were observed in all organs examined, highlighting tissue-specific prenatal molecular phenotypes in SMA. Together, our data demonstrate considerable systemic changes at an early, presymptomatic stage in SMA mice, revealing a significant developmental component to SMA pathogenesis.

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.

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