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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 -
Gene Therapy Feb 2023Loss or deletion of survival motor neuron 1 gene (SMN1) is causative for a severe and devastating neuromuscular disease, Spinal Muscular Atrophy (SMA). SMN1 produces... (Review)
Review
Loss or deletion of survival motor neuron 1 gene (SMN1) is causative for a severe and devastating neuromuscular disease, Spinal Muscular Atrophy (SMA). SMN1 produces SMN, a ubiquitously expressed protein, that is essential for the development and survival of motor neurons. Major advances and developments in SMA therapeutics are shifting the natural history of the disease. With three relatively new available therapies, nusinersen (Spinraza), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi), patients survive longer and have improved outcomes. However, patients and families continue to face many challenges associated with use of these therapies, including poor treatment response and a variability in the benefits to those that do respond, suggesting that the quest for the SMA cure is not over. In this review, we discuss the current therapies, their limitations, and highlight necessary gaps that need to be addressed to guarantee the best outcomes for SMA patients.
Topics: Humans; Muscular Atrophy, Spinal; Motor Neurons; Genetic Therapy
PubMed: 35614235
DOI: 10.1038/s41434-022-00349-y -
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 -
Cells May 2023Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.
Topics: Humans; Amyotrophic Lateral Sclerosis; Riluzole; Motor Neurons; Biomarkers; Disease Progression
PubMed: 37296644
DOI: 10.3390/cells12111523 -
Journal of Neurology, Neurosurgery, and... Apr 2020Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the...
Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.
Topics: Amyotrophic Lateral Sclerosis; Consensus; Delayed Diagnosis; Diagnosis, Differential; Humans; Motor Neuron Disease; Motor Neurons
PubMed: 32029539
DOI: 10.1136/jnnp-2019-322541 -
Handbook of Clinical Neurology 2023This chapter considers the principles that underlie neurophysiological studies of upper motor neuron or lower motor neuron lesions, based on an understanding of the... (Review)
Review
This chapter considers the principles that underlie neurophysiological studies of upper motor neuron or lower motor neuron lesions, based on an understanding of the normal structure and function of the motor system. Human motor neurophysiology consists of an evaluation of the active components of the motor system that are relevant to volitional movements. Relatively primitive motor skills include locomotion, much dependent on the spinal cord central pattern generator, reaching, involving proximal and distal muscles activation, and grasping. Humans are well prepared to perform complex movements like writing. The role of motor cortex is critical for the motor activity, very dependent on the continuous sensory feedback, and this is essential for adapting the force and speed control, which contributes to motor learning. Most corticospinal neurons in the brain project to brainstem and spinal cord, many with polysynaptic inhibitory rather than excitatory connections. The monosynaptic connections observed in humans and primates constitute a specialized pathway implicated in fractional finger movements. Spinal cord has a complex physiology, and local reflexes and sensory feedback are essential to control adapted muscular contraction during movement. The cerebellum has a major role in motor coordination, but also consistent roles in sensory activities, speech, and language, in motor and spatial memory, and in psychological activity. The motor unit is the final effector of the motor drive. The complex interplay between the lower motor neuron, its axon, motor end-plates, and muscle fibers allows a relevant plasticity in the movement output.
Topics: Animals; Humans; Neurophysiology; Spinal Cord; Motor Neurons; Spinal Cord Injuries; Motor Cortex
PubMed: 37562869
DOI: 10.1016/B978-0-323-98818-6.00018-2 -
Muscle & Nerve Sep 2022Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder characterized by progressive degeneration of cortical, bulbar, and spinal motor...
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disorder characterized by progressive degeneration of cortical, bulbar, and spinal motor neurons. When a patient presents with a progressive upper and/or lower motor syndrome, clinicians must pay particular attention to any atypical features in the history and/or clinical examination suggesting an alternate diagnosis, as up to 10% percent of patients initially diagnosed with ALS have a mimic of ALS. ALS is a clinical diagnosis and requires the exclusion of other disorders that may have similar presentations but a more favorable prognosis or an effective therapy. Because there is currently no specific diagnostic biomarker that is sensitive or specific for ALS, understanding the spectrum of clinical presentations of ALS and its mimics is paramount. While true mimics of ALS are rare, the clinician must correctly identify these disorders to avoid the misdiagnosis of ALS and to initiate effective treatment where available.
Topics: Adult; Amyotrophic Lateral Sclerosis; Humans; Motor Neuron Disease; Motor Neurons; Prognosis; Syndrome
PubMed: 35607838
DOI: 10.1002/mus.27567 -
Brain : a Journal of Neurology Nov 2023Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with... (Review)
Review
Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.
Topics: Adult; Humans; Amyotrophic Lateral Sclerosis; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Muscle Weakness
PubMed: 37327376
DOI: 10.1093/brain/awad202 -
Molecular Neurobiology Mar 2022Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation.... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting "dying back" hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS.
Topics: Amyotrophic Lateral Sclerosis; Humans; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Superoxide Dismutase-1; Synapses
PubMed: 34997540
DOI: 10.1007/s12035-021-02658-6 -
Cells Feb 2023Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.
Topics: Humans; Amyotrophic Lateral Sclerosis; Neurodegenerative Diseases; Delayed Diagnosis; Motor Neurons; Biomarkers
PubMed: 36899872
DOI: 10.3390/cells12050736