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Cited by (646)
Validation of SMA screening kits with SMN1 gene analysis in a Turkish cohort
2024, Clinica Chimica ActaIt is crucial to start early treatment in Spinal Muscular Atrophy (SMA) with available drugs to stop the progression of the disease, therefore making SMA screening preferable. This study assessed Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) compared to Multiplex Ligation-dependent Probe Amplification (MLPA) for detecting Spinal Muscular Atrophy (SMA) through SMN1 gene copy number analysis in a Turkish cohort.
We analyzed 249 DNA samples, previously tested for SMN1 and SMN2 gene deletion via MLPA, using qRT-PCR kits from three different companies. Accuracy, sensitivity, and specificity of qRT-PCR in identifying deletions of SMN1 copy number variations.
High accuracy (96.2–98.7%) achieved with qRT-PCR for detecting homozygous deletions, heterozygous deletions, and copy number variations in the SMN1 gene. Minor discrepancies between qRT-PCR and MLPA were observed, possibly due to single nucleotide polymorphisms affecting primer binding.
The qRT-PCR method proved to be a rapid, cost-effective, and accurate technique, aligning well with the demands of routine SMA screening, suggesting its general suitability for application in SMA screening programs. This research highlights the importance of improving molecular methodologies and the value of collaborations between government and relevant sectors to overcome rare diseases, particularly through the enhancement of screening initiatives which is the first and most effective strategy to protect the public health.
Evaluation of the therapeutic efficacy and tolerability of current drug treatments on the clinical outcomes of paediatric spinal muscular atrophy type 1: A systematic review
2023, Paediatric Respiratory ReviewsSpinal muscular atrophy (SMA) is a severe hereditary lower motor neuron disorder characterised by degeneration of alpha motor neurons in the spinal cord, resulting in progressive weakness and paralysis of proximal muscles. A systematic literature search was carried out by using PRISMA guidelines and searching through different databases that could provide findings of evidence on the health outcomes of the approved therapies for the management of paediatric SMA type 1 regarding efficacy with follow-up in terms of motor and respiratory functions and the tolerability and incidence of adverse drug reactions (ADRs) post-treatment from real-world publications. Half of the publications (50%) had a prospective observational design. Eight studies (66.7%) assessed nusinersen, and three studies (25%) assessed onasemnogene abeparvovec with a duration of follow-up ranging from 6 months to 3 years to evaluate the motor and respiratory functions using different assessment tools, hospitalisation rates, and the tolerability and incidence of ADRs post-treatment. The three currently approved treatments for SMA type 1 provided good support and health outcomes in terms of motor function, respiratory outcomes, reduction of hospitalisations, and improvement of survival. Nevertheless, uncertainties regarding continued improvement after long-term illness and the generalizability of results are still unknown.
Digital measures of respiratory and upper limb function in spinal muscular atrophy: design, feasibility, reliability, and preliminary validity of a smartphone sensor-based assessment suite
2023, Neuromuscular DisordersSpinal muscular atrophy (SMA) is characterized by progressive muscle weakness and paralysis. Motor function is monitored in the clinical setting using assessments including the 32-item Motor Function Measure (MFM-32), but changes in disease severity between clinical visits may be missed. Digital health technologies may assist evaluation of disease severity by bridging gaps between clinical visits. We developed a smartphone sensor-based assessment suite, comprising nine tasks, to assess motor and muscle function in people with SMA. We used data from the risdiplam phase 2 JEWELFISH trial to assess the test–retest reliability and convergent validity of each task. In the first 6 weeks, 116 eligible participants completed assessments on a median of 6.3 days per week. Eight of the nine tasks demonstrated good or excellent test–retest reliability (intraclass correlation coefficients >0.75 and >0.9, respectively). Seven tasks showed a significant association (P < 0.05) with related clinical measures of motor function (individual items from the MFM-32 or Revised Upper Limb Module scales) and seven showed significant association (P < 0.05) with disease severity measured using the MFM-32 total score. This cross-sectional study supports the feasibility, reliability, and validity of using smartphone-based digital assessments to measure function in people living with SMA.
Muscle Ultrasound Changes Correlate With Functional Impairment in Spinal Muscular Atrophy
2023, Ultrasound in Medicine and BiologyWe investigated ultrasound patterns of muscle involvement in different types of spinal muscular atrophy (SMA) and their correlation with functional status to determine the pattern of muscle compromise in patients with SMA and the potential role of ultrasound to evaluate disease progression.
We examined muscles (biceps brachii, rectus femoris, diaphragm, intercostals and thoracic multifidus) of 41 patients with SMA (types 1 to 4) and 46 healthy age- and sex-matched control individuals using B-mode ultrasound for gray-scale analysis (GSA), area (biceps brachii and rectus femoris) and diaphragm thickening ratio. Functional scales were applied to patients only. We analyzed ultrasound abnormalities in specific clinical subtypes and correlated findings with functional status.
Compared with controls, patients had reduced muscle area and increased mean GSA for all muscles (p < 0.001), with an established correlation between the increase in GSA and the severity of SMA for biceps brachii, rectus femoris and intercostals (p = 0.03, 0.01 and 0.004 respectively) when using the Hammersmith Functional Motor Scale Expanded. Diaphragm thickening ratio was normal in the majority of patients, and intercostal muscles had higher GSA than diaphragm in relation to the controls.
Ultrasound is useful for quantifying muscular changes in SMA and correlates with functional status. Diaphragm thickening ratio can be normal even with severe compromise of respiratory muscles in quantitative analysis, and intercostal muscles were more affected than diaphragm.
Challenges and future perspective of antisense therapy for spinal muscular atrophy: A review
2023, European Journal of Cell BiologySpinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the death of motor neurons and progressive muscle weakness. SMN1 normally produces an essential protein called SMN. Although humans possess a paralogous gene called SMN2, ∼90% of the SMN it produces is non-functional. This is due to a mutation in SMN2 that causes the skipping of a required exon during splicing of the pre-mRNA. The first treatment for SMA, nusinersen (brand name Spinraza), was approved by the FDA in 2016 and by the EMU in 2017. Nusinersen is an antisense oligonucleotide-based therapy that alters the splicing of SMN2 to make functional full-length SMN protein. Despite the recent advancements in antisense oligonucleotide therapy and SMA treatment development, nusinersen is faced with a multitude of challenges, such as intracellular and systemic delivery. In recent years, the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) in antisense therapy has gained interest. These are antisense oligonucleotides conjugated to cell-penetrating peptides such as Pips and DG9, and they have the potential to address the challenges associated with delivery. This review focuses on the historic milestones, development, current challenges, and future perspectives of antisense therapy for SMA.
Childhood spinal muscular atrophy
2023, Handbook of Clinical NeurologySpinal muscular atrophy (SMA) is caused by biallelic mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13.2, which leads to a progressive degeneration of alpha motor neurons in the spinal cord and in motor nerve nuclei in the caudal brainstem. It is characterized by progressive proximally accentuated muscle weakness with loss of already acquired motor skills, areflexia and, depending on the phenotype, varying degrees of weakness of the respiratory and bulbar muscles. Over the past decade, disease-modifying therapies have become available based on splicing modulation of the SMN2 with SMN1 gene replacement, which if initiated significantly modifies the natural course of the disease. Newborn screening for SMA has been implemented in an increasing number of centers; however, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage.