Progressive Muscular Weakness Research Articles

Anaesthesia management of a patient with Bethlem Myopathy for elective tonsillectomy: a case report

BackgroundBethlem Myopathy is a collagen VI-related myopathy presenting as a rare hereditary muscular disorder with progressive muscular weakness and joint contractures. Despite its milder clinical course relative to other myopathies, anaesthetic management can be challenging. High arched palates and fixed flexion deformities may contribute to a difficult airway. A progressive decline in pulmonary function can present later into adulthood. This respiratory decline can carry secondary cardiovascular consequences due to the progressive nature of restrictive lung disease, including right sided heart disease and pulmonary hypertension. We describe a case of a male patient with Bethlem Myopathy undergoing anaesthesia, to contribute to the limited body of literature on this condition and enhance awareness and guidance amongst anaesthesiologists on approaching patients with this condition. This is the first case report within the literature of its kind.Case presentationThis case details a 33-year-old male with Bethlem Myopathy undergoing tonsillectomy. Diagnosed in childhood following developmental delays, the patient had no prior anaesthetic exposure and no family history of anaesthetic complications. Anaesthetic induction was achieved without complications, avoiding depolarizing muscle relaxants and careful airway management. Extreme care was taken in patient positioning to prevent complications. The surgery proceeded without incident and muscle paralysis was reversed with Suggammadex, resulting in no adverse post-operative respiratory complications. The patient was discharged on the first post-operative day without any respiratory or cardiovascular compromise.ConclusionsBethlem Myopathy, while often exhibiting a mild clinical course, can present anaesthetic challenges. Awareness of potential complications including a difficult airway, cardiovascular and respiratory implications as well as the need for specialised monitoring and positioning is crucial to ensure a safe peri-operative course.

A Post-Marketing Surveillance Study of Nusinersen for Spinal Muscular Atrophy in Routine Medical Practice in China: Interim Results.

Spinal muscular atrophy (SMA) is a rare, autosomal recessive, neuromuscular disease that leads to progressive muscular weakness and atrophy. Nusinersen, an antisense oligonucleotide, was approved for SMA in China in February 2019. We report interim results from a post-marketing surveillance phase 4 study, PANDA (NCT04419233), that collects data on the safety, efficacy, and pharmacokinetics of nusinersen in children with SMA in routine clinical practice in China. Participants enrolled in PANDA will be observed for 2years following nusinersen treatment initiation. The primary endpoint is the incidence of adverse events (AEs)/serious AEs (SAEs) during the treatment period. Efficacy assessments include World Health Organization (WHO) Motor Milestones assessment, the Hammersmith Infant Neurological Examination (HINE), and ventilation support. Plasma and cerebrospinal fluid (CSF) concentrations of nusinersen are measured at each dose visit. Fifty participants were enrolled as of the January 4, 2023, data cutoff: 10 with infantile-onset (≤ 6months) and 40 with later-onset (> 6months) SMA. All 50 participants have received at least one dose of nusinersen; 6 have completed the study. AEs were experienced by 45 (90%) participants and were mostly mild/moderate; no AEs led to nusinersen discontinuation or study withdrawal. Eleven participants experienced SAEs, most commonly pneumonia (n = 9); none were considered related to study treatment. Stability or gain of WHO motor milestone was observed and mean HINE-2 scores improved in both subgroups throughout the study. No serious respiratory events occurred,and no permanent ventilation support was initiated during the study. Pre-dose nusinersen CSF concentrations increased steadily through the loading-dose period, with no accumulation in plasma after multiple doses. Nusinersen was generally well tolerated with an acceptable overall safety profile, consistent with the known safety of nusinersen. Efficacy, safety, and nusinersen exposure are consistent with prior observations. These results support continuing PANDA and evaluation of nusinersen in Chinese participants with SMA. ClinicalTrials.gov identifier, NCT04419233.

Disturbance of the human gut microbiota in patients with Myotonic Dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant genetic disorder. Although DM1 is primarily characterized by progressive muscular weakness, it exhibits many multisystemic manifestations, such as cognitive deficits, cardiac conduction abnormalities, and cataracts, as well as endocrine and reproductive issues. Additionally, the gastrointestinal (GI) tract is frequently affected, encompassing the entire digestive tract. However, the underlying causes of these GI symptoms remain uncertain, whether it is biomechanical problems of the intestine, involvement of bacterial communities, or both. The primary objective of this study is to investigate the structural changes in the gut microbiome of DM1 patients. To achieve this purpose, 35 patients with DM1 were recruited from the DM-Scope registry of the neuromuscular clinic in the Saguenay–Lac-St-Jean region of the province of Québec, Canada. Stool samples from these 35 patients, including 15 paired samples with family members living with them as controls, were collected. Subsequently, these samples were sequenced by 16S MiSeq and were analyzed with DADA2 to generate taxonomic signatures. Our analysis revealed that the DM1 status correlated with changes in gut bacterial community. Notably, there were differences in the relative abundance of Bacteroidota, Euryarchaeota, Fusobacteriota, and Cyanobacteria Phyla compared to healthy controls. However, no significant shift in gut microbiome community structure was observed between DM1 phenotypes. These findings provide valuable insights into how the gut bacterial community, in conjunction with biomechanical factors, could potentially influence the gastrointestinal tract of DM1 patients.

Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

Self-Reported Health-Related Quality of Life of Children with Spinal Muscular Atrophy: Preliminary Insights from a Nationwide Patient Registry in Germany.

Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness. The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA. Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5-16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between -0.02 and 0.96. The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population.

Design requirements of upper extremity supports for daily use in Duchenne muscular dystrophy with severe muscle weakness.

People with Duchenne muscular dystrophy (DMD) cope with progressive muscular weakness and consequential upper extremity function loss. They benefit from arm supports, or arm exoskeletons, to assist arm function. Especially for severe muscle weakness (DMD ≥ Brooke Scale 4), the design of such arm support is challenging. This study aims to structurally develop functional and technical design requirements of arm supports for people with DMD Brooke Scale 4. An overview of clinical characteristics and a classification of clinically meaningful activities were derived from data from the Dutch Dystrophinopathy Database and available literature. Based on these, functional and technical design requirements of arm supports were developed and matched to the achievable needs of the user. First, the clinical characteristics of the target population, such as strength, range of motion, and functional ability, are given. Next, clinically relevant activities of daily living are translated to functional requirements categorised in a 'must,' 'should,' and 'could' category. Last, the technical requirements to realise these functional goals are presented. The recommendations following from the functional user needs, technical requirements, and safety considerations can be used to make the development of assistive arm supports for people with DMD Brooke Scale 4 more user-centred.

Ayurvedic Management of Duchenne Muscular Dystrophy in Children: A Narrative Review

Duchenne Muscular Dystrophy (DMD) is the most common primary myopathy of children. There are many muscular diseases in children which are inherited through generations. All those are known as congenital myopathy. This disease is an X-linked recessive disorder produced by the abnormality of the gene Xp21. It is a severe condition that poses a life-threatening risk and significantly reduces a patient's lifespan. It is characterised by progressive symmetrical muscular weakness, with proximal muscles being more affected than distal ones. Additionally, individuals with DMD often exhibit pseudohypertrophy of the calf muscles. The compilation of data from classical Ayurvedic texts contributes to a holistic understanding of potential interventions, aiming to improve patient quality of life and prevent contractures. The study is crucial in bridging traditional and contemporary healthcare practices, offering valuable insights for clinicians and the wider medical community in addressing the multifaceted challenges posed by DMD. This research underscores the need for an integrative and comprehensive approach to enhance therapeutic strategies for this prevalent X-linked recessive disorder. In pursuit of this objective, concerted efforts have been directed towards raising awareness among both the general public and the medical community. Furthermore, the review delves into the exploration of various Panchakarma treatments, a traditional therapeutic approach rooted in Ayurveda. By consolidating and synthesising data derived from classical Ayurvedic texts pertaining to DMD, this review seeks to provide a holistic understanding of potential interventions. The goal is to contribute to the advancement of therapeutic strategies that can ameliorate the impact of DMD on patients' lives, fostering a more comprehensive and integrated approach to managing this challenging condition.

The congenital muscular dystrophies

AbstractBackgroundCongenital muscular dystrophies (CMDs) are genetically and clinically heterogeneous inherited conditions. Onset is typically within the first year of life. Most CMDs are autosomal recessive, except for de novo dominant mutations in LMNA‐related muscular dystrophy and some collagen‐6‐associated disorders.ResultsCMD is characterized by progressive muscular weakness, hypotonia, multiple contractures with a variable degree, spinal stiffness, delay in motor milestones acquisition, and histologically dystrophic lesions. Also, some forms of CMD may feature structural and myelination abnormalities on brain magnetic resonance imaging, intellectual impairment, and structural abnormalities of the eye. Muscle biopsy specimens exhibit a dystrophic pattern, but the appearance is quite variable depending on the different stages and severity of the disorder. The prevalence of CMD is estimated to be one in 100 000 people. Over the last few years, with advances in molecular genetic diagnostics, knowledge about neuromuscular disorders, particularly CMDs, has increased dramatically. Thus, the incidence may be higher than originally thought.ConclusionThis article reviews the recent achievements related to the clinical, diagnostic, pathogenic, and therapeutic aspects of CMDs.

SGCD Missense Variant in a Lagotto Romagnolo Dog with Autosomal Recessively Inherited Limb-Girdle Muscular Dystrophy.

An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and progressive muscular weakness and evolving to tetraparesis, which persuaded the owner to request euthanasia. A primary muscle pathology was supported by necropsy and histopathological findings. Macroscopically, the muscles were moderately atrophic, except for the diaphragm and the neck muscles, which were markedly thickened. Histologically, all the skeletal muscles examined showed atrophy, hypertrophy, necrosis with calcification of the fibers, and mild fibrosis and inflammation. On immunohistochemistry, all three dystrophin domains and sarcoglycan proteins were absent. On Western blot analysis, no band was present for delta sarcoglycan. We sequenced the genome of the affected dog and compared the data to more than 900 control genomes of different dog breeds. Genetic analysis revealed a homozygous private protein-changing variant in the SGCD gene encoding delta- sarcoglycan in the affected dog. The variant was predicted to induce a SGCD:p.(Leu242Pro) change in the protein. In silico tools predicted the change to be deleterious. Other 770 Lagotto Romagnolo dogs were genotyped for the variant and all found to be homozygous wild type. Based on current knowledge of gene function in other mammalian species, including humans, hamsters, and dogs, we propose the SGCD missense variant as the causative variant of the observed form of muscular dystrophy in the index case. The absence of the variant allele in the Lagotto Romagnolo breeding population indicates a rare allele that has appeared recently.

Advancing Epidemiology and Genetic Approaches for the Treatment of Spinal and Bulbar Muscular Atrophy: Focus on Prevalence in the Indigenous Population of Western Canada.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease among the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on gene therapy and antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.

Effects of intensive rehabilitation on functioning in patients with mild and moderate Charcot-Marie-Tooth disease: a real-practice retrospective study.

Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neuropathies and can lead to progressive muscular weakness, pes cavus, loss of deep tendon reflexes, distal sensory loss, and gait impairment. There are still no effective drugs or surgical therapies for CMT, and supportive treatment is limited to rehabilitative therapy and surgical treatment of skeletal deformities. Many rehabilitative therapeutic approaches have been proposed, but timing and cadence of rehabilitative intervention are not clearly defined, and long-term follow-up is lacking in literature. The aim of this real-practice retrospective study was to assess the effectiveness of an intensive neurorehabilitation protocol on muscle strength and functioning in CMT patients. We analyzed data of patients with diagnosis of mild to moderate CMT. The rehabilitation program lasted 2-4 h a day, 5 days a week, for 3 weeks and consisted of manual treatments, strengthening exercises, stretching, core stability, balance and resistance training, aerobic exercises, and tailored self-care training. Data were collected at baseline (T0), after treatment (T1), and at the 12-month mark (T2) in terms of the following outcome measures: muscle strength, pain, fatigue, cramps, balance, walking speed, and ability. We included 37 CMT patients with a median age of 50.72 ± 13.31 years, with different forms: demyelinating (n = 28), axonal (n = 8), and mixed (n = 1). After intensive rehabilitation treatment, all outcomes significantly improved. This improvement was lost at the 1-year mark. Taken together, these findings suggest that an intensive rehabilitation program improves short-term symptoms and functional outcomes in a cohort of inpatients affected by mild to moderate CMT.

Severe myopathy in a patient with chronic neurological disease – diagnostic challenges

Polymyositis is a rare disease that belongs to the idiopathic inflammatory myopathies (IIMs) group, characterized by chronic muscle inflammation, and in rare cases a life-threatening condition due to extra-muscular involvement. Even though steroids constitute the building block of treatment of this disease, in severe cases, escalation treatment should be considered in order to obtain good clinical outcomes. We report a clinical case of a 22-year-old female who developed progressive severe systemic muscular weakness, dysphagia and dysphonia, accompanied by elevated serum muscle enzymes, positive myositis-specific antibodies, and muscle biopsy suggestive of inflammatory myopathy. The clinical features and laboratory results led us to the diagnosis of polymyositis. On additional laboratory tests the patient tested positive for Borrelia burgdorferi (Borrelia b) specific antibodies. Due to life-threatening organ involvement the immunosuppressive treatment, immunoglobulin intravenous infusion and pulse therapy with methylprednisolone were initiated and she needed nasogastric tube in order to be fed. Furthermore antibiotic treatment was administrated. The patient improved almost completely after 3 months of treatment.

Детекция различных форм потери гена SMN1 с помощью набора для ПЦР-РВ

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease characterized by progressive skeletal muscular weakness and atrophy. The newborn screening for spinal muscular atrophy should define all molecular forms of SMA. The aim of this study is to compare a PCR-based test for detection of homozygous SMN1 loss with multiple ligation probe amplification (MPLA) in patients with spinal muscular atrophy and other numerical changes of the SMN1 gene. PCR-based test was used to detect exon 7 of SMN1 gene homozygous loss. The study included 341 samples of patients with clinical suspicion of SMA from Biobank of Centre of Molecular Medicine of Pavlov State Medical University (Saint-Petersburg, Russia). Group 1 included 206 whole blood samples and Group 2 included 135 dried blood spot (DBS) samples. Copy number of the SMN1 and SMN2 genes had been evaluated with MLPA as a reference method. The results showed that kit was able to detect homozygous SMN1 loss in all samples from group 1 and 2 (Group 1: n = 67; 33%; Group 2: n = 19; 14%). At the same time in all samples with 1–3 copies of the SMN1 gene, the results of the kit were negative for homozygous loss of SMN1 gene (Group 1: n = 139; 67%; Group 2: n = 116; 86%). Kit showed high effectiveness in the detection of homozygous loss SMN1 gene. The kit detects all possible molecular forms of homozygous SMN1 gene loss in both DNA samples extracted from the whole blood and DBS.

1044 Spinal Muscular Atrophy and Sleep: Double-Trouble

Abstract Introduction Spinal muscular atrophy (SMA) is a rare neuromuscular disorder which leads to progressive muscular weakness and respiratory impairment. Affected patients experience a variety of sleep problems including obstructive sleep apnea, nocturnal hypoventilation, and increased sleep disturbances. As of 2019, the first gene therapy was approved to treat patients with SMA under the age of 2, onasemnogene abeparvovec-xioi (ZolgensmaTM), with expedited approval due to findings of improved motor function and milestone achievement as well as survivability. We describe an unusual case of twins with SMA whom developed worsening obstructive sleep apnea after gene therapy. Report of case(s) The patients are a set of 3-year-old male twins with past medical history significant for premature lung disease related to extreme prematurity at 24-weeks and SMA type 2. They were initially referred for polysomnography (PSG) at 1 year of age for evaluation of snoring and as a precaution related to their underlying diagnosis. Physical examination findings were significant for tongue atrophy with fasciculations and generalized muscular weakness which spared the face. Neither twin achieved gross motor milestones of standing or walking to that point. Both patients would receive the gene therapy infusion at 1 year, 8 months with subsequent improvement in hypotonia and ability to ambulate independently. For twin A, baseline PSG at age 1 showed mild obstructive sleep apnea (apnea-hypopnea index (AHI)= 3.24 events per hour) without any signs of hypoxemia or hypoventilation. By comparison, the patient’s post-gene therapy PSG (around 1.5 years post-infusion) at age 3, showed progression to moderate obstruction (obstructive AHI of 6.03 events per hour). For twin B, baseline PSG showed moderate obstructive sleep apnea (AHI=9.09 events per hour) which progressed into the severe range (AHI= 11.90 events per hour) over the same time course. Conclusion Sleep-disordered breathing in SMA is a commonly diagnosed entity. While airway obstruction related to hypotonia would be an expected contributor, our case suggests that despite recovery of motor function through use of gene therapy, clinicians should maintain a high level of suspicion for sleep problems with strong consideration for PSG due to the risk of sub-clinical progression of sleep obstruction. Support (if any)

Treatment of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that predominantly affects motor neurons, resulting in progressive muscular atrophy and weakness. SMA arises due to insufficient levels of the survival motor neuron (SMN) protein as a result of homozygous disruption of the SMN1 gene. The SMN protein is also produced by the paralogous gene SMN2, but the amount of SMN produced is minimal due to a defect in the splicing process. Nusinersen, an antisense oligonucleotide, and risdiplam, an oral small molecule, have been developed to repair SMN2 splicing failures to facilitate adequate production of the SMN protein. Onasemnogene abeparvovec utilizes a nonreplicating adeno-associated virus 9 to provide a copy of the gene encoding the SMN protein. This therapy has led to a dramatic advancement in SMA treatment. Here, we introduce current treatment strategies for SMA.

Design of a Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Nipocalimab in Participants with Active Idiopathic Inflammatory Myopathies (SPIREA) (P10-5.007)

Design of a Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Nipocalimab in Participants with Active Idiopathic Inflammatory Myopathies (SPIREA) (P10-5.007)

ERK MAPK signaling pathway inhibition as a potential target to prevent autophagy alterations in Spinal Muscular Atrophy motoneurons

Spinal Muscular Atrophy (SMA) is a severe genetic neuromuscular disorder that occurs in childhood and is caused by misexpression of the survival motor neuron (SMN) protein. SMN reduction induces spinal cord motoneuron (MN) degeneration, which leads to progressive muscular atrophy and weakness. The link between SMN deficiency and the molecular mechanisms altered in SMA cells remains unclear. Autophagy, deregulation of intracellular survival pathways and ERK hyperphosphorylation may contribute to SMN-reduced MNs collapse, offering a useful strategy to develop new therapies to prevent neurodegeneration in SMA. Using SMA MN in vitro models, the effect of pharmacological inhibition of PI3K/Akt and ERK MAPK pathways on SMN and autophagy markers modulation was studied by western blot analysis and RT-qPCR. Experiments involved primary cultures of mouse SMA spinal cord MNs and differentiated SMA human MNs derived from induced pluripotent stem cells (iPSCs). Inhibition of the PI3K/Akt and the ERK MAPK pathways reduced SMN protein and mRNA levels. Importantly, mTOR phosphorylation, p62, and LC3-II autophagy markers protein level were decreased after ERK MAPK pharmacological inhibition. Furthermore, the intracellular calcium chelator BAPTA prevented ERK hyperphosphorylation in SMA cells. Our results propose a link between intracellular calcium, signaling pathways, and autophagy in SMA MNs, suggesting that ERK hyperphosphorylation may contribute to autophagy deregulation in SMN-reduced MNs.

Clinical and functional characterization of a long survivor congenital titinopathy patient with a novel metatranscript-only titin variant

Congenital titinopathies are an emerging group of a potentially severe form of congenital myopathies caused by biallelic mutations in titin, encoding the largest existing human protein involved in the formation and stability of sarcomeres. In this study we describe a patient with a congenital myopathy characterized by multiple contractures, a rigid spine, non progressive muscular weakness, and a novel homozygous TTN pathogenic variant in a metatranscript-only exon: the c.36400A > T, p.Lys12134*. Muscle biopsies showed increased internalized nuclei, variability in fiber size, mild fibrosis, type 1 fiber predominance, and a slight increase in the number of satellite cells. RNA studies revealed the retention of intron 170 and 171 in the open reading frame, and immunoflourescence and western blot studies, a normal titin content. Single fiber functional studies showed a slight decrease in absolute maximal force and a cross-sectional area with no decreases in tension, suggesting that weakness is not sarcomere-based but due to hypotrophy. Passive properties of single fibers were not affected, but the observed increased calcium sensitivity of force generation might contribute to the contractural phenotype and rigid spine of the patient. Our findings provide evidence for a pathogenic, causative role of a metatranscript-only titin variant in a long survivor congenital titinopathy patient with distal arthrogryposis and rigid spine.

Clinical utilisation of multimodal quantitative magnetic resonance imaging in investigating muscular damage in Duchenne muscular dystrophy: a study on the association between gluteal muscle groups and motor function

BackgroundDuchennemuscular dystrophy (DMD) is a neuromuscular disease characterised by progressive muscular weakness and atrophy. Currently, studies on DMD muscle function mostly focus on individual muscles; little is known regarding the effect of gluteal muscle group damage on motor function.ObjectiveTo explore potential imaging biomarkers of hip and pelvic muscle groups for measuring muscular fat replacement and inflammatory oedema in DMD with multimodal quantitative magnetic resonance imaging (MRI).Materials and methodsOne hundred fifty-nine DMD boys and 32 healthy male controls were prospectively included. All subjects underwent MRI examination of the hip and pelvic muscles with T1 mapping, T2 mapping and Dixon sequences. Quantitatively measured parameters included longitudinal relaxation time (T1), transverse relaxation time (T2) and fat fraction. Investigations were all based on hip and pelvic muscle groups covering flexors, extensors, adductors and abductors. The North Star Ambulatory Assessment and stair climbing tests were used to measure motor function in DMD.ResultsT1 of the extensors (r = 0.720, P < 0.01), flexors (r = 0.558, P < 0.01) and abductors (r = 0.697, P < 0.001) were positively correlated with the North Star Ambulatory Assessment score. In contrast, T2 of the adductors (r = -0.711, P < 0.01) and fat fraction of the extensors (r = -0.753, P < 0.01) were negatively correlated with the North Star Ambulatory Assessment score. Among them, T1 of the abductors (b = 0.013, t = 2.052, P = 0.042), T2 of the adductors (b = -0.234, t = -2.554, P = 0.012) and fat fraction of the extensors (b = -0.637, t = − 4.096, P < 0.001) significantly affected the North Star Ambulatory Assessment score. Moreover, T1 of the abductors was highly predictive for identifying motor dysfunction in DMD, with an area under the curve of 0.925.ConclusionMagnetic resonance biomarkers of hip and pelvic muscle groups (particularly T1 values of the abductor muscles) have the potential to be used as independent risk factors for motor dysfunction in DMD.