Severe Form Of Spinal Muscular Atrophy Research Articles

Concomitant telomere attrition is associated with spinal muscular atrophy in highly inbred region of North India: unraveling the thread in Kashmir region

Spinal muscular atrophy (SMA) is a rare genetic disorder that unequivocally results in the degeneration of motor neurons, leading to muscle weakness and atrophy. This condition is caused by a mutation in the survival motor neuron 1 (SMN1) gene, which inevitably results in a deficiency of the SMN protein. In present study, we investigated the potential role of telomere attrition in SMA patients. Relative telomere length in peripheral blood lymphocytes was measured by Monochrome Multiplex Quantitative Polymerase Chain Reaction (MMQPCR) in 98 subjects and we conclusively found that SMA cases exhibit telomere attrition compared to healthy controls (P = 4 × 10− 2). Moreover, significant attrition was also observed in severe form of SMA, i.e. SMA type 0 (P = 0.04) as well.Although, the exact mechanism through which telomere shortening contributes to the pathogenesis of SMA is not fully understood and is yet to be delineated. However, one possibility is that telomere shortening leads to genomic instability and DNA damage, which can contribute to motor neuron degeneration. Another possibility is that telomere shortening leads to cellular senescence, which can impair the ability of motor neurons to regenerate and repair themselves. Recent studies have suggested that telomere shortening may be a potential therapeutic target in SMA. Thus, understanding the role of SMN1 gene in disease pathogenesis & its effect on telomere length will aid in estimating the risk & prognosis of SMA in genetically less explored & highly inbred region of Kashmir, Northern India.

Real-World Data on Access to Standards of Care for People With Spinal Muscular Atrophy in the UK.

Spinal Muscular Atrophy (SMA) is characterized by muscle atrophy and weakness and has an incidence of 1:11. 000 live births which projects an estimated population in the UK of 650–1,300 affected patients. Standards of Care (SoC) were updated in 2017 and they have been widely adopted as a reference for implementation of care in SMA across the globe. The effectiveness of implementation and adherence to these standards across different countries is unclear. The aim of this study is to describe the experience of individuals with SMA regarding their care in the UK. An online anonymised survey was sent out via patient organizations, the UK SMA Patient Registry, professional networks, and social media to reach across the UK. The survey captured demographic profile, professionals involved in a patient's care, Interventions and access to mobility aids and home adaptations. Participants responded about their access to services and to rate how important each professional and intervention was for their health and wellbeing. One hundred and twenty-eight responses were collected with a median age of 34 years (1–81). Seventy-three percent of participants were adults and 60% men. Overall good access to neurologist (>90%) but limited to nurse specialist (48%) and physiotherapist (57%). Good access to respiratory support was reported but limited for interventions for positioning and bracing and exercise. This survey highlights that access to certain professionals for people with SMA is limited in the UK. Striking differences were noted between pediatric and adult populations. Limited access to care were regularly reported, with half of the study population consistently not accessing full multidisciplinary care. Access to interventions for contracture management were recorded to have significant limitations. Mobility aids and home adaptations are widely available and were also reported as the most valued interventions. Access to nutritional support or speech and language therapy appears only to be available for a small proportion of the participants. Access to respiratory care was good especially in severe forms of SMA. We found pockets of good practice in the UK that align with the SoC. However, access is not equal for adults and children and access to certain professionals is significantly limited.

Spinal Muscular Atrophy: Diagnosis, Incidence, and Newborn Screening in Japan.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs—nusinersen and onasemnogene abeparvovec—improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000–40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture.

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive, neurodegenerative disease caused by biallelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is characterized by motor neuron degeneration, resulting in progressive muscle atrophy and weakness. Before the emergence of disease‐modifying therapies, children with the most severe form of SMA would never achieve the ability to sit independently. Only 8% survived beyond 20 months of age without permanent ventilator support. One such therapy, onasemnogene abeparvovec, an adeno‐associated virus–based gene replacement therapy, delivers functional human SMN through a one‐time intravenous infusion. In addition to substantially improving survival, onasemnogene abeparvovec was found to increase motor milestone attainment and reduce the need for respiratory or nutritional support in many patients. This expert opinion provides recommendations and practical considerations on the patient‐centered decisions to use onasemnogene abeparvovec. Recommendations include the need for patient‐centered multidisciplinary care and patient selection to identify those with underlying medical conditions or active infections to reduce risks. We also describe the importance of retesting patients with elevated anti–adeno‐associated virus serotype 9 antibodies. Recommendations for prednisolone tapering and monitoring for potential adverse events, including hepatotoxicity and thrombotic microangiopathy, are described. The need for caregiver education on managing day‐to‐day care at time of treatment and patient‐ and family‐centered discussions on realistic expectations are also recommended. We detail the importance of following standard‐of‐care guidance and long‐term monitoring of all children with SMA who have received one or more disease‐modifying therapy using registries. We also highlight the need for presymptomatic or early symptomatic treatment of this disorder.

Onasemnogene Abeparvovec-xioi: World’s most expensive and approved therapy for spinal muscular atrophy

On May 24, 2019, the U.S. Food and Drug Administration approved Onasemnogene Abeparvovec-xioi (Zolgensma), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality. It is priced in the United States at $2.1m (£1.6m; €1.9m) the world’s most expensive drug. Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure. Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival. This review summarized the clinical guidelines for the Onasemnogene Abeparvovec-xioi use and may be useful to healthcare professionals.

Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review.

To summarize the current knowledge on brain involvement in spinal muscular atrophy (SMA) type 1, focusing on brain pathology, cognition, and speech/language development. A scoping review was performed using the methodology of the Joanna Briggs Institute. Five databases and references from relevant articles were searched up to December 2019. Articles were screened on the basis of titles and abstracts. Full-text papers published in peer-reviewed journals in English were selected. Nineteen articles met eligibility criteria. Eight case series/reports on brain pathology showed abnormalities in few SMA type 0/1 cases, supported by findings in three post-mortem examinations in mice. Four studies (three case-control, one cross-sectional) on cognition reported contradictory results, with impaired cognitive performances in recent, small groups with SMA type 1. Four studies (three cross-sectional, one observational) on speech/language showed that untreated SMA type 1 patients rarely achieve functional and intelligible speech, with data limited to parent reports/non-formal evaluations. Brain involvement is an under-investigated aspect of SMA type 1, requiring further exploration in longitudinal studies. A deeper knowledge of brain involvement would improve the interpretation of clinical phenotypes and the personalization of rehabilitation programmes supporting patients' autonomies and quality of life. Additionally, it may help to define further outcome measures testing the efficacy of current and new developing drugs on this domain. Brain involvement is under-investigated in spinal muscular atrophy (SMA) type 1. Neuropathological data suggest progressive brain involvement in severe forms of SMA. Impaired cognitive performances are reported in small groups with SMA type 1. Data on language in those with SMA type 1 are limited to parent reports and non-formal assessments.

Yeo and Darras: Extraneuronal Phenotypes of Spinal Muscular Atrophy.

Yeo and Darras: Extraneuronal Phenotypes of Spinal Muscular Atrophy.

Quality of life data for individuals affected by spinal muscular atrophy: a baseline dataset from the Cure SMA Community Update Survey

BackgroundIndividuals and/or caregivers of individuals affected by spinal muscular atrophy (SMA) completed the 2019 Cure SMA Community Update Survey, online, assessing health-related quality of life (HRQoL), loss of work productivity, and fatigue using the Health Utilities Index Questionnaire (HUI), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Patient Reported Outcomes Measurement Information System Fatigue Short Form (PROMIS Fatigue SF), respectively. The purpose was to collect baseline quality of life results among individuals affected by SMA using the above Patient Reported Outcome Measures (PROMs).ResultsOf 666 surveys completed between March and May 2019, 478 were included in this analysis, accounting for duplicates, missing data, or deaths. The breakdown across SMA type I, II and III was 25, 47 and 28%, respectively. Responses were characterized by current functional status/milestone, with subsets for “permanent ventilation,” “non-sitters,” “sitters,” “walk with support,” and “walk alone.” WPAI and HUI respondents included affected adults and caregivers. The PROMIS Fatigue SF was completed by the primary caregiver of affected children.Overall, those affected by a less severe form of SMA and with a higher functional status reported higher HRQoL and lower work productivity and activity impairment. All affected individuals reported higher fatigue levels than the general population.ConclusionsThis study offers useful insights into the burden of SMA among affected individuals and their caregivers. The results provide a baseline picture of the patient and caregiver experience with SMA in a post-treatment era from which to measure year-over-year changes in quality of life scores from new therapies and improved care. The WPAI demonstrates the significant impact of work productivity among SMA populations. Aspects of the HUI seem more appropriate to certain SMA sub-populations than others. Measures from the PROMIS Fatigue SF appear to under-represent the burden of fatigue often reported by SMA individuals and caregivers; this may, perhaps be due to a lack of sensitivity in the questions associated with fatigue in the SMA affected population, when compared with other studies on this topic. Overall, these results suggest the need for SMA-specific quality of life outcome measures to fully capture clinically meaningful change in the SMA population.

Implementing a Global Expanded Access Program (EAP) for Infantile-Onset Spinal Muscular Atrophy (Type I): Understanding the Imperative, Impact and Challenges.

Nusinersen is the first disease-modifying therapy approved for the treatment of spinal muscular atrophy (SMA), a rare genetic disorder characterized by severe progressive muscular atrophy and weakness. An expanded access program (EAP) provides investigational treatment to patients without other treatment options. An EAP providing nusinersen treatment to individuals with the most severe form of SMA, infantile-onset SMA (consistent with SMA Type I), has enrolled over 800 participants as of September 2018, making it one of the largest in rare disease history. The successes, challenges experienced and opportunities for future consideration during the implementation of the nusinersen EAP are discussed.

Activin Receptor Type IIB Inhibition Improves Muscle Phenotype and Function in a Mouse Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a devastating neurodegenerative disorder that causes progressive muscle atrophy and weakness. Using adeno-associated virus-mediated gene transfer, we evaluated the potential to improve skeletal muscle weakness via systemic, postnatal inhibition of either myostatin or all signaling via the activin receptor type IIB (ActRIIB). After demonstrating elevated p-SMAD3 content and differential content of ActRIIB ligands, 4-week-old male C/C SMA model mice were treated intraperitoneally with 1x1012 genome copies of pseudotype 2/8 virus encoding a soluble form of the ActRIIB extracellular domain (sActRIIB) or protease-resistant myostatin propeptide (dnMstn) driven by a liver specific promoter. At 12 weeks of age, muscle mass and function were improved in treated C/C mice by both treatments, compared to controls. The fast fiber type muscles had a greater response to treatment than did slow muscles, and the greatest therapeutic effects were found with sActRIIB treatment. Myostatin/activin inhibition, however, did not rescue C/C mice from the reduction in motor unit numbers of the tibialis anterior muscle. Collectively, this study indicates that myostatin/activin inhibition represents a potential therapeutic strategy to increase muscle mass and strength, but not neuromuscular junction defects, in less severe forms of SMA.

Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is due to the loss of the survival motor neuron gene 1 (SMN1), resulting in motor neuron (MN) degeneration, muscle atrophy and loss of motor function. While SMN2 encodes a protein identical to SMN1, a single nucleotide difference in exon 7 causes most of the SMN2-derived transcripts to be alternatively spliced resulting in a truncated and unstable protein (SMNΔ7). SMA patients retain at least one SMN2 copy, making it an important target for therapeutics. Many of the existing SMA models are very severe, with animals typically living less than 2 weeks. Here, we present a novel intermediate mouse model of SMA based upon the human genomic SMN2 gene. Genetically, this model is similar to the well-characterized SMNΔ7 model; however, we have manipulated the SMNΔ7 transgene to encode a modestly more functional protein referred to as SMN read-through (SMN(RT)). By introducing the SMN(RT) transgene onto the background of a severe mouse model of SMA (SMN2(+/+);Smn(-/-)), disease severity was significantly decreased based upon a battery of phenotypic parameters, including MN pathology and a significant extension in survival. Importantly, there is not a full phenotypic correction, allowing for the examination of a broad range of therapeutics, including SMN2-dependent and SMN-independent pathways. This novel animal model serves as an important biological and therapeutic model for less severe forms of SMA and provides an in vivo validation of the SMN(RT) protein.

Bifunctional RNAs Targeting the Intronic Splicing Silencer N1 Increase SMN Levels and Reduce Disease Severity in an Animal Model of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of survival motor neuron-1 (SMN1). A nearly identical copy gene, SMN2, is present in all SMA patients. Although the SMN2 coding sequence has the potential to produce full-length SMN, nearly 90% of SMN2-derived transcripts are alternatively spliced and encode a truncated protein. SMN2, however, is an excellent therapeutic target. Previously, we developed antisense-based oligonucleotides (bifunctional RNAs) that specifically recruit SR/SR-like splicing factors and target a negative regulator of SMN2 exon-7 inclusion within intron-6. As a means to optimize the antisense sequence of the bifunctional RNAs, we chose to target a potent intronic repressor downstream of SMN2 exon 7, called intronic splicing silencer N1 (ISS-N1). We developed RNAs that specifically target ISS-N1 and concurrently recruit the modular SR proteins SF2/ASF or hTra2β1. RNAs were directly injected in the brains of SMA mice. Bifunctional RNA injections were able to elicit robust induction of SMN protein in the brain and spinal column of neonatal SMA mice. Importantly, hTra2β1-ISS-N1 and SF2/ASF-ISS-N1 bifunctional RNAs significantly extended lifespan and increased weight in the SMNΔ7 mice. This technology has direct implications for SMA therapy and provides similar therapeutic strategies for other diseases caused by aberrant splicing.

Impaired minor tri-snRNP assembly generates differential splicing defects of U12-type introns in lymphoblasts derived from a type I SMA patient

The survival of motor neuron (SMN) protein is essential for cytoplasmic assembly of spliceosomal snRNPs. Although the normal proportion of endogenous snRNAs is unevenly altered in spinal muscular atrophy (SMA) tissues, the biogenesis of individual snRNPs is not dramatically affected in SMN-deficient cells. The SMN protein is also required for normal Cajal body (CB) formation, but the functional consequences of CB disruption upon SMN deficiency have not yet been analyzed at the level of macromolecular snRNPs assembly. Here, we show that the SMN protein is required for tri-snRNPs formation and that the level of the minor U4atac/U6atac/U5 tri-snRNPs is dramatically decreased in lymphoblasts derived from a patient suffering from a severe form of SMA. We found also that splicing of some, but not all, minor introns is inhibited in these cells, demonstrating links between SMN deficiency and differential alterations of splicing events mediated by the minor spliceosome. Our results suggest that SMA might result from the inefficient splicing of one or only a few pre-mRNAs carrying minor introns and coding for proteins required for motor neurons function and/or organization.

SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA.

Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy mice

There is currently no treatment for the inherited motor neuron disease, spinal muscular atrophy (SMA). Severe SMA causes lower motor neuron loss, impaired myofiber development, profound muscle weakness and early mortality. Myostatin is a transforming growth factor-beta family member that inhibits muscle growth. Loss or blockade of myostatin signaling increases muscle mass and improves muscle strength in mouse models of primary muscle disease and in the motor neuron disease, amyotrophic lateral sclerosis. In this study, we evaluated the effects of blocking myostatin signaling in severe SMA mice (hSMN2/delta7SMN/mSmn(-/-)) by two independent strategies: (i) transgenic overexpression of the myostatin inhibitor follistatin and (ii) post-natal administration of a soluble activin receptor IIB (ActRIIB-Fc). SMA mice overexpressing follistatin showed little increase in muscle mass and no improvement in motor function or survival. SMA mice treated with ActRIIB-Fc showed minimal improvement in motor function, and no extension of survival compared with vehicle-treated mice. Together these results suggest that inhibition of myostatin may not be a promising therapeutic strategy in severe forms of SMA.

Letter to the Editor

Letter to the Editor

Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy

Motor neuron degeneration is the predominant pathological feature of spinal muscular atrophy (SMA). In patients with severe forms of the disease, additional sensory abnormalities have been reported. However, it is not clear whether the loss of sensory neurons is a common feature in severe forms of the disease, how many neurons are lost and how loss of sensory neurons compares with motor neuron degeneration. We have analysed dorsal root ganglionic sensory neurons in Smn-/-;SMN2 mice, a model of type I SMA. In contrast to lumbar motor neurons, no loss of sensory neurons in the L5 dorsal root ganglia is found at post-natal days 3-5 when these mice are severely paralyzed and die from motor defects. Survival of cultured sensory neurons in the presence of NGF and other neurotrophic factors is not reduced in comparison to wild-type controls. However, isolated sensory neurons have shorter neurites and smaller growth cones, and beta-actin protein and beta-actin mRNA are reduced in sensory neurite terminals. In footpads of Smn-deficient mouse embryos, sensory nerve terminals are smaller, suggesting that Smn deficiency reduces neurite outgrowth during embryogenesis. These data indicate that pathological alterations in severe forms of SMA are not restricted to motor neurons, but the defects in the sensory neurons are milder than those in the motor neurons.

Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific Disease

Spinal muscular atrophy (SMA) is a neurodegenerative disease in humans and the most common genetic cause of infant mortality. The disease results in motor neuron loss and skeletal muscle atrophy. Despite a range of disease phenotypes, SMA is caused by mutations in a single gene, the Survival of Motor Neuron 1 (SMN1) gene. Recent advances have shed light on functions of the protein product of this gene and the pathophysiology of the disease, yet, fundamental questions remain. This review attempts to highlight some of the recent advances made in the understanding of the disease and how loss of the ubiquitously expressed survival of motor neurons (SMN) protein results in the SMA phenotype. Answers to some of the questions raised may ultimately result in a viable treatment for SMA.

Deletion of Murine Smn Exon 7 Directed to Liver Leads to Severe Defect of Liver Development Associated with Iron Overload

Spinal muscular atrophy (SMA) is characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron 1 gene (SMN1). SMN is involved in various processes including the formation of the spliceosome, pre-mRNA splicing and transcription. To know whether SMN has an essential role in all mammalian cell types or an as yet unknown specific function in the neuromuscular system, deletion of murine Smn exon 7, the most frequent mutation found among SMA patients, has been restricted to liver. Homozygous mutation results in severe impairment of liver development associated with iron overload and lack of regeneration leading to dramatic liver atrophy and late embryonic lethality of mutant mice. These data strongly suggest an ubiquitous and essential role of full-length SMN protein in various mammalian cell types. In SMA patients, the residual amount of SMN allows normal function of various organs except motor neurons. However, data from mouse and human suggest that other tissues might be involved in severe form of SMA or during prolonged disease course which reinforce the need of therapeutic approaches targeted to all tissues. In addition, liver function of patients should be carefully investigated and followed up before and during therapeutic trials.

Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype.

Autosomal recessive spinal muscular atrophy (SMA) is a common motor neuron disease caused by absence or mutation in the survival motor neuron (SMN1) gene. SNM1 and a nearly identical copy, SMN2, encode identical proteins, but SMN2 only produces a little full length protein due to alternative splicing. The level of functional SMN protein and the number of SMN2 genes correlate with the clinical phenotype ranging from severe to very mild. Here, we report on premature termination mutations in SMN1 exon 3 (425del5 and W102X) which induce skipping of the mutated exon. The novel nonsense mutation W102X was detected in two patients with a relatively mild phenotype who had only two copies of the SMN2 gene, a number that has previously been found associated with the severe form of SMA. We show that the shortened transcripts are translated into predicted in frame protein isoforms. Aminoglycoside treatment suppressed the nonsense mutation in cultured cells and abolished exon skipping. Fibroblasts from both patients show a high number of nuclear structures containing SMN protein (gems). These findings suggest that the protein isoform lacking the exon 3 encoded region contributes to the formation of the nuclear protein complex which may account for the milder clinical phenotype.