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BMC Pediatrics Nov 2022Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that... (Review)
Review
Spinal muscular atrophy (5q-SMA; SMA), a genetic neuromuscular condition affecting spinal motor neurons, is caused by defects in both copies of the SMN1 gene that produces survival motor neuron (SMN) protein. The highly homologous SMN2 gene primarily expresses a rapidly degraded isoform of SMN protein that causes anterior horn cell degeneration, progressive motor neuron loss, skeletal muscle atrophy and weakness. Severe cases result in limited mobility and ventilatory insufficiency. Untreated SMA is the leading genetic cause of death in young children. Recently, three therapeutics that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza, Zolgensma, and Evrysdi have a clinically significant impact, they are not curative. For many patients, there remains a significant disease burden. A potential combination therapy under development for SMA targets myostatin, a negative regulator of muscle mass and strength. Myostatin inhibition in animal models increases muscle mass and function. Apitegromab is an investigational, fully human, monoclonal antibody that specifically binds to proforms of myostatin, promyostatin and latent myostatin, thereby inhibiting myostatin activation. A recently completed phase 2 trial demonstrated the potential clinical benefit of apitegromab by improving or stabilizing motor function in patients with Type 2 and Type 3 SMA and providing positive proof-of-concept for myostatin inhibition as a target for managing SMA. The primary goal of this manuscript is to orient physicians to the evolving landscape of SMA treatment.
Topics: Animals; Child; Child, Preschool; Humans; Motor Neurons; Muscular Atrophy, Spinal; Myostatin; Clinical Trials, Phase II as Topic
PubMed: 36329412
DOI: 10.1186/s12887-022-03671-x -
Neurologic Clinics Nov 2015Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival... (Review)
Review
Spinal muscular atrophy is an autosomal-recessive disorder characterized by degeneration of motor neurons in the spinal cord and caused by mutations in the survival motor neuron 1 gene, SMN1. The severity of SMA is variable. The SMN2 gene produces a fraction of the SMN messenger RNA (mRNA) transcript produced by the SMN1 gene. There is an inverse correlation between SMN2 gene copy number and clinical severity. Clinical management focuses on multidisciplinary care. Preclinical models of SMA have led to an explosion of SMA clinical trials that hold great promise of effective therapy in the future.
Topics: Animals; DNA Copy Number Variations; Disease Management; Humans; Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein
PubMed: 26515624
DOI: 10.1016/j.ncl.2015.07.004 -
Muscle & Nerve Feb 2015Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form... (Review)
Review
Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q-SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produces reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early-phase clinical trials.
Topics: DNA, Antisense; Electromyography; Genetic Therapy; Humans; Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein
PubMed: 25346245
DOI: 10.1002/mus.24497 -
International Journal of Molecular... Jul 2023Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the... (Review)
Review
Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, , was identified. Genetic testing of has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, -deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.
Topics: Infant, Newborn; Humans; Muscular Atrophy, Spinal; Genetic Testing; Homozygote; Neonatal Screening; Inheritance Patterns
PubMed: 37569314
DOI: 10.3390/ijms241511939 -
Journal of Comparative Effectiveness... Apr 2022To conduct indirect treatment comparisons between risdiplam and other approved treatments for spinal muscular atrophy (SMA). Individual patient data from risdiplam... (Review)
Review
To conduct indirect treatment comparisons between risdiplam and other approved treatments for spinal muscular atrophy (SMA). Individual patient data from risdiplam trials were compared with aggregated data from published studies of nusinersen and onasemnogene abeparvovec, accounting for heterogeneity across studies. In Type 1 SMA, studies of risdiplam and nusinersen included similar populations. Indirect comparison results found improved survival and motor function with risdiplam versus nusinersen. Comparison with onasemnogene abeparvovec in Type 1 SMA and with nusinersen in Types 2/3 SMA was challenging due to substantial differences in study populations; no concrete conclusions could be drawn from the indirect comparison analyses. Indirect comparisons support risdiplam as a superior alternative to nusinersen in Type 1 SMA.
Topics: Azo Compounds; Humans; Muscular Atrophy, Spinal; Pyrimidines; Spinal Muscular Atrophies of Childhood
PubMed: 35040693
DOI: 10.2217/cer-2021-0216 -
European Journal of Paediatric... Jul 2022This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated... (Review)
Review
Mid- and long-term (at least 12 months) follow-up of patients with spinal muscular atrophy (SMA) treated with nusinersen, onasemnogene abeparvovec, risdiplam or combination therapies: A systematic review of real-world study data.
OBJECTIVES
This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated with any of the approved drugs or combination therapies.
METHODS
A systematic literature search was carried out in five databases. Two authors selected the studies based on pre-defined selection criteria and independently graded the risk of bias at study level.
RESULTS
Five hundred forty-six records were identified in the literature search and 22 studies (in 26 publications) were included in the analysis. Nusinersen, onasemnogene abeparvovec and combination therapies improved motor endpoints in SMA type 1 patients. SMA type 2 to type 4 patients treated with nusinersen showed stabilisation or small improvements in motor endpoints with some deterioration observed. Quality of life endpoints, such as respiratory and nutritional support were poorly reported on. Drug-related adverse events occurred rarely in all types of SMA patients with all assessed drugs. Mid- and long-term studies on risdiplam could not be identified.
CONCLUSIONS
The large quantity of missing data and heterogeneity of studies hinder comparability. Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease.
Topics: Follow-Up Studies; Humans; Muscular Atrophy, Spinal; Oligonucleotides; Quality of Life; Spinal Muscular Atrophies of Childhood
PubMed: 35533607
DOI: 10.1016/j.ejpn.2022.04.006 -
Seminars in Pediatric Neurology Jul 2021Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder characterized by loss of motor neurons leading to muscle weakness and atrophy. The United States'... (Review)
Review
Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder characterized by loss of motor neurons leading to muscle weakness and atrophy. The United States' Food and Drug Administration's (FDA) approval of nusinersen, onasemnogene abeparvovec, and risdiplam for SMA has challenged existing treatment paradigms with multiple treatment options, a new natural history of the disease, and an emerging understanding of the importance of early and pre-symptomatic treatment. The profound impact of early, pre-symptomatic treatment has led to the creation of a neurogenetics urgency for newly identified patients with SMA, a novel problem for neurologists more accustomed to a more methodical approach to diagnosis and care. Implementation of newborn screening programs has helped facilitate early diagnosis and treatment, but challenges remain in overcoming administrative and procedural hurdles that can lead to treatment delays. Herein I discuss 2 cases that highlight the importance of early treatment, as well as gaps in our understanding of the progression of SMA in pre-symptomatic infants.
Topics: Genetic Therapy; Humans; Infant; Infant, Newborn; Muscular Atrophy, Spinal; Neonatal Screening; Neurosciences; Spinal Muscular Atrophies of Childhood; United States
PubMed: 34183144
DOI: 10.1016/j.spen.2021.100899 -
Orphanet Journal of Rare Diseases Nov 2011Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in... (Review)
Review
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic severity going from high mortality within the first year for SMA type 1 to no mortality for the chronic and later onset forms.
Topics: Adult; Animals; Child, Preschool; Genetic Counseling; Humans; Infant; Infant, Newborn; Mice; Muscular Atrophy, Spinal; Prenatal Diagnosis; Survival of Motor Neuron 1 Protein
PubMed: 22047105
DOI: 10.1186/1750-1172-6-71 -
European Journal of Pediatrics Jul 2023The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying... (Review)
Review
The natural history of spinal muscular atrophy has been radically changed by the advent of improved standards of care and the availability of disease-modifying therapies. The aim of this paper is to provide the current therapeutic scenario including new perspectives and to report the challenges related to new phenotypes a few years after the therapies have become available. The paper also includes a review of real-world data that provides information on safety and efficacy in individuals that were not included in clinical trials. Special attention is paid to future perspectives both in terms of new drugs that are currently investigated in clinical trials or providing details on current developments in the use of the available drugs, including combination therapies or new modalities of dose or administration. Conclusion: Clinical trials and real world data support the efficacy and safety profiles of the available drugs. At the moment there is not enough published evidence about the superiority of one product compared to the others. What is Known: • Safety and efficacy results of clinical trials have led in the last 6 years to the marketing of three drugs for spinal muscular atrophy, with different mechanisms of action. What is New: • Since the drug's approval, real-world data allow us to have data on bigger and heterogeneous groups of patients in contrast with those included in clinical trials. • In addition to the new molecules, combinations of therapies are currently being evaluated.
Topics: Humans; Muscular Atrophy, Spinal
PubMed: 37067602
DOI: 10.1007/s00431-023-04883-8 -
Frontiers in Bioscience (Landmark... Jun 2022Spinal muscular atrophy (SMA) is a progressive neurological disease with autosomal recessive transmission that affects motor neurons, causing their loss and resulting in...
INTRODUCTION
Spinal muscular atrophy (SMA) is a progressive neurological disease with autosomal recessive transmission that affects motor neurons, causing their loss and resulting in muscle waste and motor deficiency. Nusinersen, the first SMN2 pre-mRNA targeted therapy approved by the Food and Drug Administration and the European Medicines Agency, has demonstrated high efficacy in improving motor function, as well as respiratory and nutritional statuses.
MATERIALS AND METHODS
We observed 55 patients (children/adolescents) diagnosed with spinal muscular atrophy (SMA), who received nusinersen therapy. To investigate the benefits of physical therapy on rehabilitation outcomes, we compared the motor evolution of patients who received nusinersen and performed daily physical therapy (study group) to those of the control group, who received only nusinersen therapy.
RESULTS
Motor skill improvements were statistically significantly ( < 0.001) higher in the study group, being almost four times better (12.66%), effect size, in comparison to the control group (3.18%).
CONCLUSIONS
Physical therapy has provided superior results for those who receive it on a regular basis. These results include the correction of posture, reduction in stiffness, expansion of the range of motion and strengthening of muscles, thus allowing patients to do more movements and boosting their ability to perform everyday tasks.
Topics: Adolescent; Child; Humans; Muscular Atrophy, Spinal; Oligonucleotides; Physical Therapy Modalities; Treatment Outcome; United States
PubMed: 35748255
DOI: 10.31083/j.fbl2706179