Abstract
ObjectiveRecent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age‐ and gender‐matched controls (n = 34).MethodsWe performed the first large‐scale whole blood transcriptomic screen with L1000, a rapid, high‐throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes.ResultsThe primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton,” and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT‐qPCR. SMA type 3 patient‐derived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first‐degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation.InterpretationOur findings from whole blood and patient‐derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.
Highlights
Spinal muscular atrophy (SMA) is characterized by progressive motor neuron denervation resulting in chronic muscle weakness and atrophy caused by mutations in the survival motor neuron 1 (SMN1) gene.[1,2] SMA is divided into three primary clinical subtypes based on age of onset and maximum achievement of key motor abilities
Ulnar compound muscle action potential (CMAP) amplitudes were typical of those previously reported for SMA type 3 patients (7.1 Æ 3.4), indicating less severe denervation in the ulnar-innervated abductor digiti minimi (ADM) muscle as compared to patients with SMA type 1 or type 2.4 Control subjects had at least one SMN1 copy and had no signs of muscle weakness or atrophy
We found 270 significantly downregulated genes and 287 significantly upregulated genes in SMA patients compared to healthy controls
Summary
Spinal muscular atrophy (SMA) is characterized by progressive motor neuron denervation resulting in chronic muscle weakness and atrophy caused by mutations in the survival motor neuron 1 (SMN1) gene.[1,2] SMA is divided into three primary clinical subtypes based on age of onset and maximum achievement of key motor abilities. Spinal muscular atrophy (SMA) is characterized by progressive motor neuron denervation resulting in chronic muscle weakness and atrophy caused by mutations in the survival motor neuron 1 (SMN1) gene.[1,2]. SMA is divided into three primary clinical subtypes based on age of onset and maximum achievement of key motor abilities. SMA type 3 patients achieve the ability to walk independently, progressive muscular weakness in the absence of diseasemodifying therapy results in progressive loss of predominantly proximal muscle strength and functional mobility. Despite significant improvement in survival and motor function in SMA infants and children treated with recently FDA-approved novel molecular and gene therapies,[1,6,7] further studies are needed to determine the benefits and risks of these novel strategies in adult patients with chronic denervation, atrophy, and weakness.
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