-
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 -
Nature Reviews. Disease Primers Aug 2022Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in SMN1 (encoding survival motor neuron protein (SMN)). Reduced expression of SMN leads... (Review)
Review
Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in SMN1 (encoding survival motor neuron protein (SMN)). Reduced expression of SMN leads to loss of α-motor neurons, severe muscle weakness and often early death. Standard-of-care recommendations for multidisciplinary supportive care of SMA were established in the past few decades. However, improved understanding of the pathogenetic mechanisms of SMA has led to the development of different therapeutic approaches. Three treatments that increase SMN expression by distinct molecular mechanisms, administration routes and tissue biodistributions have received regulatory approval with others in clinical development. The advent of the new therapies is redefining standards of care as in many countries most patients are treated with one of the new therapies, leading to the identification of emerging new phenotypes of SMA and a renewed characterization of demographics owing to improved patient survival.
Topics: Humans; Motor Neurons; Muscular Atrophy, Spinal; Mutation; Phenotype
PubMed: 35927425
DOI: 10.1038/s41572-022-00380-8 -
Seminars in Pediatric Neurology Apr 2021Spinal muscular atrophy is one of the most common neuromuscular disorders of childhood and has high morbidity and mortality. Three different disease-modifying... (Review)
Review
Spinal muscular atrophy is one of the most common neuromuscular disorders of childhood and has high morbidity and mortality. Three different disease-modifying treatments were introduced in the last 4 years: nusinersen, onasemnogene abeparvovec, and risdiplam. These agents have demonstrated safety and efficacy, but their long-term benefits require further study. Newborn screening programs are enabling earlier diagnosis and treatment and better outcomes, but respiratory care and other supportive measures retain a key role in the management of spinal muscular atrophy. Ongoing efforts seek to optimize gene therapy vectors, explore new therapeutic targets beyond motor neurons, and evaluate the role of combination therapy.
Topics: Genetic Therapy; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Neonatal Screening
PubMed: 33892848
DOI: 10.1016/j.spen.2021.100878 -
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 -
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 -
Journal of Neuromuscular Diseases 2020Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum... (Review)
Review
Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.
Topics: Genetic Therapy; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Neonatal Screening; Oligonucleotides, Antisense; Thionucleotides
PubMed: 31707373
DOI: 10.3233/JND-190424 -
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 -
Medicina Aug 2022Spinal muscular atrophy (SMA) has been known as a clinical entity for 130 yearsis still recognized today as the most severe autosomal recessive neuromuscular disease... (Review)
Review
Spinal muscular atrophy (SMA) has been known as a clinical entity for 130 yearsis still recognized today as the most severe autosomal recessive neuromuscular disease (5q,13,2) in pediatrics. Until 2015, SMA treatment was limited to ventilatory, nutritional, and physical therapy support. Currently, the existence of genetic treatments: gene modification by inclusion of exon 7 to the SMN2 gene (nusinersen and risdiplam) or insertion of the SMN1 gene through the adeno-associated viral transporter (onasemnogene) have radically modified the clinical evolution of children with SMA,especially if they are treated early. This review details the effects of the 3 treatments currently in use worldwide.
Topics: Child; Humans; Muscular Atrophy, Spinal
PubMed: 36054863
DOI: No ID Found -
Continuum (Minneapolis, Minn.) Oct 2023This article provides a comprehensive overview of the diagnostic assessment and treatment of individuals with spinal muscular atrophy (SMA) due to homozygous deletions... (Review)
Review
OBJECTIVE
This article provides a comprehensive overview of the diagnostic assessment and treatment of individuals with spinal muscular atrophy (SMA) due to homozygous deletions of SMN1 .
LATEST DEVELOPMENTS
In recent years, most states have incorporated SMA in their newborn screening panel. To provide the earliest diagnosis possible after symptom onset, vigilance is needed for births in states without newborn screening for SMA and when compound heterozygotes are missed by newborn screening programs. Supportive care for respiratory, nutritional, and orthopedic health impacts outcomes and is the cornerstone of care. Adaptive equipment, including assistive home technology, enables affected individuals to gain autonomy in their daily activities. Pharmacologic treatments approved by the US Food and Drug Administration (FDA) include three drugs that increase deficient survival motor neuron protein levels through SMN1 - or SMN2 - directed pathways: nusinersen, onasemnogene abeparvovec, and risdiplam. Efficacy for these trials was measured in event-free survival (survival without the need for permanent ventilation) and gains in functional motor outcomes. Earlier treatment is most effective across all treatments.
ESSENTIAL POINTS
The diagnostic and therapeutic landscapes for SMA have seen dramatic advancements in recent years, improving prognosis. Optimized supportive care remains essential, and vigilance is needed to define the new natural history of this disease.
Topics: Infant, Newborn; United States; Humans; Muscular Atrophy, Spinal; United States Food and Drug Administration
PubMed: 37851043
DOI: 10.1212/CON.0000000000001338 -
Continuum (Minneapolis, Minn.) Oct 2020This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US... (Review)
Review
PURPOSE OF REVIEW
This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug Administration (FDA)-approved gene-targeted therapies and mainstays of supportive SMA care.
RECENT FINDINGS
Over the past decades, an understanding of the role of SMN protein in the development and maintenance of the motor unit and the intricate genetics underlying SMA has led to striking developments in therapeutics with three FDA-approved treatments for SMA, one targeting SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most effective in infants treated at younger ages, and improvement is most striking in babies treated as neonates. Despite improvements in motor function, patients (especially those treated at older ages) continue to experience significant weakness and require continued close monitoring of respiratory and orthopedic symptoms.
SUMMARY
Striking therapeutic advancements have changed the clinical course of SMA dramatically, although supportive care continues to play an important role in patient care.
Topics: Azo Compounds; Biological Products; Genetic Therapy; Humans; Infant; Infant, Newborn; Muscular Atrophy, Spinal; Neuromuscular Agents; Oligonucleotides; Pyrimidines; Recombinant Fusion Proteins; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein
PubMed: 33003005
DOI: 10.1212/CON.0000000000000918