The RESISTANT study (Respiratory Muscle Training in Patients with Spinal Muscular Atrophy): study protocol for a randomized controlled trial.

BACKGROUND: Spinal Muscular Atrophy (SMA) is characterized by progressive and predominantly proximal and axial muscle atrophy and weakness. Respiratory muscle weakness results in impaired cough with recurrent respiratory tract infections, nocturnal hypoventilation, and may ultimately lead to fatal respiratory failure in the most severely affected patients. Treatment strategies to either slow down the decline or improve respiratory muscle function are wanting. OBJECTIVE: The aim of this study is to assess the feasibility and efficacy of respiratory muscle training (RMT) in patients with SMA and respiratory muscle weakness. METHODS: The effect of RMT in patients with SMA, aged ≥ 8 years with respiratory muscle weakness (maximum inspiratory mouth pressure [PImax] ≤ 80 Centimeters of Water Column [cmH2O]), will be investigated with a single blinded randomized sham-controlled trial consisting of a 4-month training period followed by an 8-month open label extension phase. INTERVENTION: The RMT program will consist of a home-based, individualized training program involving 30-breathing cycles through an inspiratory and expiratory muscle training device. Patients will be instructed to perform 10 training sessions over 5-7 days per week. In the active training group, the inspiratory and expiratory threshold will be adjusted to perceived exertion (measured on a Borg scale). The sham-control group will initially receive RMT at the same frequency but against a constant, non-therapeutic resistance. After four months the sham-control group will undergo the same intervention as the active training group (i.e., delayed intervention). Individual adherence to the RMT protocol will be reviewed every two weeks by telephone/video call with a physiotherapist. MAIN STUDY PARAMETERS/ENDPOINTS: We hypothesize that the RMT program will be feasible (good adherence and good acceptability) and improve inspiratory muscle strength (primary outcome measure) and expiratory muscle strength (key secondary outcome measure) as well as lung function, patient reported breathing difficulties, respiratory infections, and health related quality of life (additional secondary outcome measures, respectively) in patients with SMA. DISCUSSION: RMT is expected to have positive effects on respiratory muscle strength in patients with SMA. Integrating RMT with recently introduced genetic therapies for SMA may improve respiratory muscle strength in this patient population. TRIAL REGISTRATION: Retrospectively registered at clinicaltrial.gov: NCT05632666.

The characteristics of self-care in children with spinal muscular atrophy: an integrative review.

INTRODUCTION: Spinal muscular atrophy (SMA) is one of the most common genetic causes of death in children. Recently, European Commission (EU) has approved a new gene therapy based on onasemnogene abeparvovec (Zolgensma) for the treatment of patients with SMA. It is essential that children suffering from SMA also apply self-care methods to maintain their health, monitor their weight and food intake, and use appropriate remedies. Indeed, self-care is a crucial element in the health care system because it is able to improve survival and prevent hospitalizations. The purpose of this review is to systematically explore the characteristics of self- care in children with SMA and the relationship with their parents and the collaboration of health- care professionals. EVIDENCE ACQUISITION: An integrative review of the literature has been conducted. The electronic databases CINAHL, Embase, PubMed, and SCOPUS were searched. EVIDENCE SYNTHESIS: Thirteen articles met the inclusion criteria and were reviewed using Whittemore and Knalf's integrative review methodology. The analysis of the 13 articles selected for the review show that previous literature has focused on six prevalent themes: problem solving and care behavior, decision making, optimizing living with an illness, high quality, child-focused homecare, healthcare professionals, and monitoring behaviors. CONCLUSIONS: This paper highlights how self-management behaviors depend on four basic aspects: the person (individual, cognitive, and social perceptions), the patient's family (level of knowledge of the pathology, involvement in the management and quality of relationship with the patient), the community (relationships with external social contexts, such as school and other organizations), and the healthcare system (availability of resources and the degree of evolution of healthcare).

Three years pilot of spinal muscular atrophy newborn screening turned into official program in Southern Belgium.

Three new therapies for spinal muscular atrophy (SMA) have been approved by the United States Food and Drug Administration and the European Medicines Agency since 2016. Although these new therapies improve the quality of life of patients who are symptomatic at first treatment, administration before the onset of symptoms is significantly more effective. As a consequence, newborn screening programs have been initiated in several countries. In 2018, we launched a 3-year pilot program to screen newborns for SMA in the Belgian region of Liège. This program was rapidly expanding to all of Southern Belgium, a region of approximately 55,000 births annually. During the pilot program, 136,339 neonates were tested for deletion of exon 7 of SMN1, the most common cause of SMA. Nine SMA cases with homozygous deletion were identified through this screen. Another patient was identified after presenting with symptoms and was shown to be heterozygous for the SMN1 exon 7 deletion and a point mutation on the opposite allele. These ten patients were treated. The pilot program has now successfully transitioned into the official neonatal screening program in Southern Belgium. The lessons learned during implementation of this pilot program are reported.

Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

Therapeutic interventions for Pisa syndrome in idiopathic Parkinson's disease. A Scoping Systematic Review.

Pisa syndrome (PS) is a postural deformity characterized by marked and reversible lateral trunk flexion. PS can be seen in Parkinson's disease (PD) and several neurodegenerative diseases. A scoping systematic review was conducted to view the therapeutic interventions for PS in PD, their effectiveness, outcome measurements, and related cofactors. Databases and manual searches were performed. Studies that evaluate the effect of interventions on PS were included. Data were extracted and categorized by the main applied therapeutic intervention. A total of 19 published and 2 unpublished studies met the inclusion criteria. Wall and traditional goniometer, kinematic analysis, and clinical observations were used to detect PS. The included studies applied the following therapeutic protocols: Deep brain stimulation (DBS), Botulinum toxin injection, posture exercises, lidocaine injection, oculomotor correction, and spinal cord stimulation. The outcomes measurements of the included studies were linked to International Classification of Functioning, Disability and Health (ICF) model. The therapeutic interventions variously improve PS outcomes at short and long-term follow-up. The interventions did not report side effects or adverse events except DBS. PS severity was related to the DBS voltage amount in one study, and one participant in another study relapsed due to DBS. There are missing reported data in terms of participants' characteristics, medication status, and side effects. The current evidence shows the available interventions for PS, outcomes measurements, and related cofactors. The interventions may be safe and beneficial for PS. Further powerful studies are required.

Enhancing GABAergic Transmission Improves Locomotion in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by degeneration of spinal motor neurons resulting in variable degrees of muscular wasting and weakness. It is caused by a loss-of-function mutation in the survival motor neuron (SMN1) gene. Caenorhabditis elegans mutants lacking SMN recapitulate several aspects of the disease including impaired movement and shorted life span. We examined whether genes previously implicated in life span extension conferred benefits to C. elegans lacking SMN. We find that reducing daf-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this C. elegans model of SMA. The locomotor dysfunction in C. elegans lacking SMN correlated with structural and functional abnormalities in GABAergic neuromuscular junctions (NMJs). Moreover, we demonstrated that reduction in daf-2 signaling reversed these abnormalities. Remarkably, enhancing GABAergic neurotransmission alone was able to correct the locomotor dysfunction. Our work indicated that an imbalance of excitatory/inhibitory activity within motor circuits and underlies motor system dysfunction in this SMA model. Interventions aimed at restoring the balance of excitatory/inhibitory activity in motor circuits could be of benefit to individuals with SMA.

[Healing of Amyotrophic Lateral Sclerosis: A Case Report].

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to death within 3-5 years in most cases. New approaches to treating this disease are needed. Here, we report a successful therapy. CASE REPORT: In a 49-year-old male patient suffering from muscle weakness and fasciculations, progressive muscular atrophy, a variant of ALS, was diagnosed after extensive examinations ruling out other diseases. Due to supposed mercury exposure from residual amalgam, the patient's teeth were restored. Then, the patient received sodium 2,3-dimercaptopropanesulfate (DMPS; overall 86 × 250 mg in 3 years) in combination with α-lipoic acid and followed by selenium. In addition, he took vitamins and micronutrients and kept a vegetarian diet. The excretion of metals was monitored in the urine. The success of the therapy was followed by scoring muscle weakness and fasciculations and finally by electromyography (EMG) of the affected muscles. First improvements occurred after the dental restorations. Two months after starting therapy with DMPS, the mercury level in the urine was increased (248.4 µg/g creatinine). After 1.5 years, EMG confirmed the absence of typical signs of ALS. In the course of 3 years, the patient recovered completely. CONCLUSIONS: The therapy described here is a promising approach to treating some kinds of motor neuron disease and merits further evaluation in rigorous trials.

Antisense Oligonucleotide-Based Therapy for Neuromuscular Disease.

Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness and wasting. Until recently there were no effective therapies for these conditions, but antisense oligonucleotides, a new class of synthetic single stranded molecules of nucleic acids, have demonstrated promising experimental results and are at different stages of regulatory approval. The antisense oligonucleotides can modulate the protein expression via targeting hnRNAs or mRNAs and inducing interference with splicing, mRNA degradation, or arrest of translation, finally, resulting in rescue or reduction of the target protein expression. Different classes of antisense oligonucleotides are being tested in several clinical trials, and limitations of their clinical efficacy and toxicity have been reported for some of these compounds, while more encouraging results have supported the development of others. New generation antisense oligonucleotides are also being tested in preclinical models together with specific delivery systems that could allow some of the limitations of current antisense oligonucleotides to be overcome, to improve the cell penetration, to achieve more robust target engagement, and hopefully also be associated with acceptable toxicity. This review article describes the chemical properties and molecular mechanisms of action of the antisense oligonucleotides and the therapeutic implications these compounds have in neuromuscular diseases. Current strategies and carrier systems available for the oligonucleotides delivery will be also described to provide an overview on the past, present and future of these appealing molecules.

Investigational therapies for the treatment of spinal muscular atrophy.

INTRODUCTION: Currently, there is no cure available for the hereditary neurodegenerative disease proximal spinal muscular atrophy (SMA), which is the number one genetic killer in early childhood. However, growing knowledge of SMA pathophysiology has opened new avenues for potential therapeutic interventions. AREAS COVERED: This review summarizes a variety of investigational therapeutic approaches for SMA. Focusing on the current state-of-the-art applications, the authors discuss the outcome of the first clinical interventions and compare the first results from the newest strategies. The achievements of the investigational drugs highlighted in this article were deduced from original articles, pharmaceutical company press releases and clinical trial results. EXPERT OPINION: Nearly two decades after the discovery of the disease causing gene survival motor neuron 1, many therapeutic options for SMA have been developed, some of which made it to clinical trials but could not prove their promising experimental results. Recently, big research efforts from academia, government and the pharmaceutical industry have led to the development of highly promising compounds that are currently in clinical trials, and which could lead to feasible treatment options in the future.

Immediate effect of spinal magnetic stimulation on camptocormia in Parkinson's disease.

OBJECTIVES: Spinal cord stimulation is a potential therapeutic option for the treatment of Parkinson's disease (PD)-associated symptoms. Repetitive trans-spinal magnetic stimulation (rTSMS) is a non-invasive and safe alternative for stimulation of spinal pathways that has not been studied for therapeutic efficacy in PD. We assessed the benefits of rTSMS on camptocormia, an often treatment-resistant postural abnormality observed in PD patients. METHODS: We compared rTSMS to sham stimulation in PD patients with camptocormia in a single-centre, randomised, single-blind, crossover, placebo-controlled study. PD patients with camptocormia were administered a single trial of rTSMS (a train of 40 stimuli) or sham treatment followed 1 week later by the alternate treatment. Primary outcome measure was thoracolumbar spine flexion angle in the standing position immediately after the trial. RESULTS: Of 320 PD patients examined, 37 had concomitant camptocormia and were randomly assigned to either the rTSMS first group (n=19) or sham first group (n=18). Flexion angle in the standing position decreased by a mean of 10.9° (95% CI 8.1 to 13.65) after rTSMS but remained unchanged after sham stimulation (mean, -0.1°; 95% CI -0.95 to 0.71). The flexion angle while sitting (secondary outcome) decreased by 8.1° (95% CI 5.89 to 10.25) after rTSMS, whereas sham treatment had no significant effect (mean, -0.8°; 95% CI -1.62 to 0.05). CONCLUSIONS: We found an immediate beneficial effect of rTSMS on camptocormia in PD patients. Although the effect was transient, this successful trial justifies further studies to test if repeated rTSMS treatments can induce longer term improvements in camptocormia associated with PD. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry: UMIN000011495.

Spinal muscular atrophy: from animal model to clinical trial.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration and loss of lower motor neurons in the spinal cord and brainstem. Clinically, SMA has been classified into four types, according to the maximum function attained. The disease is caused by deletion or mutation of the telomeric copy of the SMN gene (SMN1), and the clinical severity is in part determined by the copy number of the centromeric SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in reduced production of the full-length SMN protein. Treatment of SMA consists of supportive care, although many drugs have been demonstrated to improve muscle strength and motor function of patients. The development of animal models of SMA has led to better interpretation of the physiopathology of the disease and testing of potential drug targets. Several mechanisms have been targeted in SMA drug trials, including neuroprotection, neurogenesis, energy metabolism improvement, anabolic stimulation and increment of SMN2 transcripts. Gene therapy and cell transplantation have also been tested in murine SMA.

Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition.

Early treatment with the histone deacetylase inhibitor, trichostatin A, plus nutritional support extended median survival of spinal muscular atrophy mice by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after trichostatin A was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe spinal muscular atrophy. Early spinal muscular atrophy disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of histone deacetylase inhibitor treatment in human patients.

Restoring Bcl-x(L) levels benefits a mouse model of spinal muscular atrophy.

Currently, no curative treatment is available for spinal muscular atrophy (SMA). Since the degeneration of spinal motor neurons in SMA is mediated by apoptosis, over-expression of an anti-apoptotic factor, Bcl-x(L), may benefit SMA. Here, we crossed a mouse model of SMA with Bcl-x(L) transgenic mice to create SMA/Bcl-x(L) mice. The Bcl-x(L) expression in the spinal neurons of SMA/Bcl-x(L) mice was nearly double that in SMA mice. SMA/Bcl-x(L) mice showed preserved motor function, normalized electrophysiological tests, diminished muscle atrophy, and less motor neuron degeneration. In addition, the life span of SMA/Bcl-x(L) mice was 1.5 times longer than that of SMA mice. Therefore, over-expression of Bcl-x(L) has a potential for amelioration of SMA, and Bcl-x(L) may be another attractive therapeutic target other than survival motor neuron (SMN) protein for use in future drug screening for SMA.

Dose-dependent effects of inspiratory muscle training in neuromuscular disorders.

The goal of this study was to show whether a correlation exists between the intensity of specific respiratory muscle training and the improvement of strength and endurance in inspiratory musculature in patients with neuromuscular disorders (NMD). Sixteen patients with NMD (13 with Duchenne muscular dystrophy and 3 with spinal muscular atrophy) performed inspiratory muscle training (IMT) at home with a special training apparatus for 9 months. Maximal inspiratory mouth pressure (PI(MAX)) and 12s-maximum voluntary ventilation (12s-MVV) test served as parameters for inspiratory muscle strength and endurance, respectively. In patients whose inspiratory vital capacity (VC(in)) declined by less than 10% during the year before training began (n = 10), a significant positive correlation was found between the number of successfully completed strength and endurance exercises and the improvement of PI(MAX) (P < 0.05) and 12s-MVV (P < 0.05). In patients whose VC(in)-decline exceeded 10% (n = 6), indicating more progressive respiratory system involvement of the disease, no significant correlation between the improvement of PI(MAX) and 12s-MVV and the intensity of training was found. In patients with NMD, the effects of IMT-runs are dose-dependent, provided that the respiratory system involvement of the disease is only slowly progressive.

Cervical radiculopathy: a case for ancillary therapies?

OBJECTIVE: To present two cases, one of a patient with a radicular syndrome and another of a patient with a pseudoradicular syndrome. CLINICAL FEATURES: A 45-yr-old man visited one chiropractic clinic complaining of a "pinched nerve" in his neck, with pain and paresthesia in his left hand. He reported that these symptoms began after a work accident 1 month before, when he lifted a heavy object. Radiographs revealed disk space thinning at C4-5, C5-6 and C6-7. CT scans revealed foraminal narrowing with a minor disk bulging at the level of C5-6 and a large disk protrusion at C7-T1. The second patient is a 60-yr-old man with left shoulder and cervical spine pain. The patient stated that the shoulder pain felt like an ache and had begun 2 wk earlier when he had awakened with pain in the shoulder and a stiff neck. X-ray evaluation revealed a moderate level of degenerative change at the the C4-5, C5-6 and C7-T1 region. CONCLUSION: This article identifies the similarities and variations between two syndromes receiving chiropractic intervention that included ancillary therapy. Certain conditions, including cervical radiculopathy, seem to respond well to chiropractic spinal manipulative therapy. However, in other conditions with similar symptomatology, appropriate referral may be necessary for the condition to respond. Alternatively, adjunctive or ancillary therapy may be indicated to improve the effect of the chiropractic intervention.

Gold bead implants.

Gold bead implantation is an experimental area of study in the acupuncture field dealing with chronic diseases. Special acupuncture techniques are required to implant the gold beads successfully in the proper location. Gold beads are used to treat degenerative joint disease, osteochondritis, osteochondritis dessicans, ventral spondylosis, and seizures.