Muscle Fatigability Research Articles

Biallelic variants in AGRN with recurrent pregnancy losses in a family with a fetal akinesia deformation sequence.

Agrin, encoded by AGRN, plays a vital role in the acetylcholine receptor clustering pathway, and any defects in this pathway are known to cause congenital myasthenic syndrome (CMS) 8 in early childhood with variable fatigable muscle weakness. The most severe or lethal form of CMS manifests as a fetal akinesia deformation sequence (FADS). To date, only one family has been reported with an association of null variants in AGRN and a lethal FADS. We identified a nonconsanguineous couple with recurrent pregnancy loss. Detailed phenotyping of fetuses was performed via perinatal autopsy. Genetic evaluation was performed along with split-read analysis to identify variants. Perinatal phenotyping revealed an FADS in the family, and genomic testing identified novel null variants in AGRN. First, whole-exome sequencing revealed the maternally inherited heterozygous variant c.952+1_952+3del in AGRN in fetuses. Split-read analysis of the exome led to the identification of the paternally inherited second variant, a heterozygous deletion of 41.33 kb, encompassing exons 1 and 2 of AGRN. This study highlights the importance of incorporating split-read analysis in clinical practice and emphasizes the association of null variants in AGRN with the FADS. To the best of our knowledge, this is the second report explaining FADS and null variants in AGRN.

A rare case of myopathy with fatigability due to PYROXD1 variation

Introduction: Congenital myopathies are a group of heterogenous inherited muscle diseases. With advances in genetics, newer genes with novel features are being described. Pyridine nucleotide-disulfide oxidoreductase domain 1 ( PYROXD1) related myopathy is an ultrarare congenital myopathy. Only few cases have been reported worldwide till now. We report the first interesting case of PYROXD1 related myopathy from India. Methods: This is a retrospective study done from a quaternary neurology referral centre from southern India. All clinical, laboratory and electrophysiological data were collected from the medical records. Institutional ethics approval and informed consent from patient were obtained. Results: A 9 year-old-boy of non-consanguineous parentage presented with progressive fatigable proximo-distal weakness of upper and lower limbs with facial weakness from the age of 4 years. This was followed by chewing and swallowing difficulty. However speech was normal. There was profound proximal and distal joint hyperextensibility along with hip and ankle contractures. There was facial dysmorphism with high arched palate and retrognathism. Investigations showed normal serum creatine kinase levels. Nerve conduction studies showed axonal sensorimotor neuropathy. There was significant decremental response in tibialis anterior. Muscle biopsy showed both myopathic and neurogenic changes with novel findings of mitochondrial aggregates in subsarcolemmal and perinuclear regions. Next generation sequencing revealed a missense variant NM_024854.5:c.394C > T (NP_079130.2:p.Arg132Cys) of uncertain significance in exon 4 of PYROXD1 gene. Conclusion: This is the first report of PYROXD1 related myopathy from India. There were novel features of muscle fatigability, contractures, novel muscle biopsy features and a variant of uncertain significance expanding the phenotypic and genotypic spectrum of this rare myopathy.

Changes in lower extremity muscle coordination over a 30-minute walk do not differ by muscle fatigability

Muscle fatigue, the transient decrease in muscle power, leads to low levels of physical activity and an inability to perform activities of daily living. Altered muscle coordination in response to fatigue may contribute to impaired physical performance. We sought to determine whether lower extremity muscle coordination during gait changes differently depending on susceptibility to fatigue (i.e., fatigability). Thirty-one older adults completed muscle power testing before and after a 30-min walk, with the change in power used to categorize participants as more or less fatigable. We used non-negative matrix factorization to identify muscle modules from electromyography (EMG) from the 2nd minute as our measure of baseline muscle coordination. Changes in muscle coordination were determined by computing the variance in the 30th minute’s EMG accounted for by the baseline modules across all muscles (tVAF) and in individual muscles (mVAF). We compared tVAF between the 2nd and 30th minutes of the walk in individuals who were more and less fatigable. We used mVAF to explore the contribution of changes in individual muscle activity to tVAF. There was a decrease in tVAF overall in response to the walk (p < 0.001; 92.3 ± 1.6 % vs. 89.0 ± 4.3 %) but this did not differ between groups (interaction p = 0.66). There were significant associations between mVAF and tVAF for knee extensor, knee flexor, and ankle dorsiflexor muscles. Our results suggest that muscle coordination changes over the course of a walk in older adults but that this change does not differ between more and less fatigable older adults.

Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).

Greater perceived physical fatigability and lower skeletal muscle energetics are bothpredictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher = greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher = greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N = 873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo) were associated with lower perceived physical fatigability, all p < 0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE Fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability ≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p < 0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the ex vivomeasures (p < 0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

Increased fatigability and impaired skeletal muscle microvascular reactivity in adults with obstructive sleep apnea: a cross-sectional study

BackgroundSympathetic nervous system hyperactivity and chronic intermittent nocturnal hypoxia in individuals with obstructive sleep apnea (OSA) predispose them to microvascular impairment, which may contribute to increased daytime muscle fatigue. This study aimed to assess microvascular reactivity of the skeletal muscle, examine fatigability, and determine the relationship between fatigability and microvascular reactivity in adults with OSA.MethodsTwenty-six participants were allocated into two groups—those with OSA and those without i.e. non-OSA. Each group comprised of 13 individuals who underwent an arterial occlusion test on their non-dominant leg. The percentage change of maximal hyperemic response (MHR) and the time to achieve MHR (tM) of both the total myoglobin/hemoglobin (∆[Hbtot]) and the oxygenated myoglobin/hemoglobin (∆[HbO2]) signals from near-infrared spectroscopy were calculated to examine microvascular reactivity. In addition, a 10-min walk test was performed to assess performance and perceived fatigability.ResultsThe OSA group demonstrated a reduced in ∆[Hbtot]MHR (150.9 ± 16.2% vs. 235.8 ± 72.7%, p = 0.006), ∆[HbO2]MHR (131.4 ± 8% vs. 161.7 ± 10.6%, p = 0.001) and increased ∆[Hbtot]tM (80.5 ± 13.1 s vs. 47.7 ± 9.9 s, p < 0.001), ∆[HbO2]tM (85.2 ± 22.4 s vs. 52.1 ± 5.9 s, p = 0.001) compared to the non-OSA group. In addition, participants in the OSA group experienced greater perceived (6 ± 1 vs. 2.8 ± 0.1, p = 0.001) and performance fatigability (1.1 ± 0.1 vs. 0.9 ± 0.1, p = 0.001) compared to adults in the non-OSA group. Moreover, both performance and perceived fatigability were significantly associated with microvascular reactivity parameters (all p < 0.05).ConclusionMicrovascular dysfunction, as determined by an attenuated post-occlusive reactive hyperemia, is observed in individuals with OSA that may contribute to increased fatigability in these individuals.

A Deficiency in Glutamine-Fructose-6-Phosphate Transaminase 1 (Gfpt1) in Skeletal Muscle Results in Reduced Glycosylation of the Delta Subunit of the Nicotinic Acetylcholine Receptor (AChRδ).

The neuromuscular junction (NMJ) is the site where the motor neuron innervates skeletal muscle, enabling muscular contraction. Congenital myasthenic syndromes (CMS) arise when mutations in any of the approximately 35 known causative genes cause impaired neuromuscular transmission at the NMJ, resulting in fatigable muscle weakness. A subset of five of these CMS-causative genes are associated with protein glycosylation. Glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) is the rate-limiting enzyme within the hexosamine biosynthetic pathway (HBP), a metabolic pathway that produces the precursors for glycosylation. We hypothesized that deficiency in Gfpt1 expression results in aberrant or reduced glycosylation, impairing the proper assembly and stability of key NMJ-associated proteins. Using both in vitro and in vivo Gfpt1-deficient models, we determined that the acetylcholine receptor delta subunit (AChRδ) has reduced expression and is hypo-glycosylated. Using laser capture microdissection, NMJs were harvested from Gfpt1 knockout mouse muscle. A lower-molecular-weight species of AChRδ was identified at the NMJ that was not detected in controls. Furthermore, Gfpt1-deficient muscle lysates showed impairment in protein O-GlcNAcylation and sialylation, suggesting that multiple glycan chains are impacted. Other key NMJ-associated proteins, in addition to AChRδ, may also be differentially glycosylated in Gfpt1-deficient muscle.

Mitochondrial dysfunction in myasthenia gravis: Exploring directions for future immunotherapy? A review.

Myasthenia gravis (MG) is an acquired autoimmune disease characterized by impaired transmission at the neuromuscular junction, primarily manifesting as fluctuating muscle weakness, fatigability, and partial paralysis. Due to its long disease course, treatment resistance, and frequent relapses, it places a significant burden on patients and their families. In recent years, advances in molecular biology have provided growing evidence that mitochondrial dysfunction impairs muscle function and affects immune cell proliferation and differentiation in patients. Mitochondria, as the cell's energy source, play a critical role in various pathological processes in MG, including oxidative stress, dynamic abnormalities, mitophagy, and mitochondrial metabolism. The role of mitochondrial dysfunction in the pathogenesis of MG has garnered increasing attention. This manuscript primarily explores mitochondrial function and abnormal morphological changes in MG, as well as mitochondrial quality control, metabolic reprogramming, and their potential mechanisms in the pathological changes of the disease. It also reviews the current status of drug therapies aimed at improving mitochondrial function. The goal is to provide novel perspectives and strategies for future mitochondrial-targeted therapies in MG.

ARGX-119 is an agonist antibody for human MuSK that reverses disease relapse in a mouse model of congenital myasthenic syndrome.

Muscle-specific kinase (MuSK) is essential for the formation, function, and preservation of neuromuscular synapses. Activation of MuSK by a MuSK agonist antibody may stabilize or improve the function of the neuromuscular junction (NMJ) in patients with disorders of the NMJ, such as congenital myasthenia (CM). Here, we generated and characterized ARGX-119, a first-in-class humanized agonist monoclonal antibody specific for MuSK, that is being developed for treatment of patients with neuromuscular diseases. We performed in vitro ligand-binding assays to show that ARGX-119 binds with high affinity to the Frizzled-like domain of human, nonhuman primate, rat, and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc region, ARGX-119 harbors L234A and L235A mutations to diminish potential immune-activating effector functions. Its mode of action is to activate MuSK, without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model of DOK7 CM, ARGX-119 prevented early postnatal lethality and reversed disease relapse in adult Dok7 CM mice by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic studies in nonhuman primates, rats, and mice revealed a nonlinear PK behavior of ARGX-119, indicative of target-mediated drug disposition and in vivo target engagement. On the basis of this proof-of-concept study, ARGX-119 has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function, warranting further clinical development.

Non-Coding RNAs in Myasthenia Gravis: From Immune Regulation to Personalized Medicine.

Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder characterized by altered neuromuscular transmission, which causes weakness and fatigability in the skeletal muscles. The etiology of MG is complex, being associated with multiple genetic and environmental factors. Over recent years, progress has been made in understanding the immunological alterations implicated in the disease, but the exact pathogenesis still needs to be elucidated. A pathogenic interplay between innate immunity and autoimmunity contributes to the intra-thymic MG development. Epigenetic changes are critically involved in both innate and adaptive immune response regulation. They can act as (i) pathological factors besides genetic predisposition and (ii) co-factors contributing to disease phenotypes or patient-specific disease course/outcomes. This article reviews the role of non-coding RNAs (ncRNAs) as epigenetic factors implicated in MG. Particular attention is dedicated to microRNAs (miRNAs), whose expression is altered in MG patients' thymuses and circulating blood. The long ncRNA (lncRNA) contribution to MG, although not fully characterized yet, is also discussed. By summarizing the most recent and fast-growing findings on ncRNAs in MG, we highlight the therapeutic potential of these molecules for achieving immune regulation and their value as biomarkers for the development of personalized medicine approaches to improve disease care.

Suspension training improves bilateral isometric strength asymmetry of knee muscles in people with multiple sclerosis

IntroductionMost people with multiple sclerosis are diagnosed with bilateral strength asymmetry in the lower limbs. Strength asymmetry increases muscle metabolic cost, muscle fatigability, postural instability, gait disturbance, imbalance, and risk of falling, and negatively affects the quality of life in PwMS. So far, the effects of rehabilitation exercises on reducing the asymmetric index in this population has not been studied convincingly. The purpose of this study was to investigate the effect of suspension exercise on bilateral isometric strength asymmetry of knee muscles in patients with multiple sclerosis. Materials & methodsIn this randomized controlled trial, twenty-seven female patients were purposively selected as the statistical sample and randomly divided into the control (n = 13, age: 34.72 ± 5.01 years) and exercise (n = 14, age: 37.62 ± 4.58 years) groups. The control group received routine care while the exercise group received the suspension exercise protocol. Isometric muscle strength and bilateral asymmetry were measured at baseline and after 8 weeks. The Biodex isokinetic dynamometer was used to measure the maximal voluntary isometric contraction of the flexor and extensor muscles of the knee. The analysis of covariance was used to analyze the data. ResultsThe isometric strength of the knee extensor muscles in the weak leg at the angle of 20° and in both legs at the angle of 70° in the exercise group improved significantly. Furthermore, the strength of the knee flexor muscles in the exercise group was increased. The amount of bilateral strength asymmetry in the knee flexor and extensor muscles at the angle of 70° significantly decreased in the exercise group. Discussions & conclusionsThese data suggest that suspension training is a practical approach to manage bilateral asymmetry in knee flexor and extensor muscle strength in patients with an EDSS of less than four.

Comparative Analysis of Intravenous Immunoglobulins (IVIg) vs Plasmapheresis (PLEX) in the Management of Myasthenic Crisis.

Myasthenia gravis (MG) is an autoimmune disorder affecting postsynaptic membranes in neuromuscular junctions, presenting as fatigable muscle weakness. Myasthenic crisisis a life-threatening complication characterized by severe respiratory insufficiency necessitating invasive or noninvasive ventilation. Two rapid therapiesused to manage myasthenic crisesare intravenous immunoglobulins (IVIg) and plasmapheresis (PLEX). Their comparative effectiveness remains equivocal. Our article examines evidence from several clinical trials and observational studies, in order to determine the superiority of one treatment over the other. Multiple factors can complicate the choices between two treatments. We concluded that the choice between PLEX and IVIg is multifaceted, guided by individual patient characteristics, institutional resources, and clinician preference. While PLEX can be consideredasfirst-linefor rapid clinical outcomes, it is hard to pick one treatment over the other, and careful consideration of comorbiditiesand resource availability is crucial. Our article highlights the need for further research to establish definitive guidelines and enhance patient outcomes in myasthenic crisis patients.

Characterization of Clinical Phenotypes in Congenital Myasthenic Syndrome Associated with the c.1327delG Frameshift Mutation in CHRNE Encoding the Acetylcholine Receptor Epsilon Subunit.

Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.

Congenital myasthenic syndrome secondary to pathogenic variants in the SLC5A7 gene: report of two cases

BackgroundCongenital Myasthenic Syndromes (CMS) are rare genetic diseases, which share as a common denominator muscle fatigability due to failure of neuromuscular transmission. A distinctive clinical feature of presynaptic CMS variants caused by defects of the synthesis of acetylcholine is the association with life-threatening episodes of apnea. One of these variants is caused by mutations in the SLC5A7 gene, which encodes the sodium-dependent HC-3 high-affinity choline transporter 1 (CHT1). To our knowledge there are no published cases of this CMS type in Latin America.Case presentationWe present two cases of CHT1-CMS. Both patients were males presenting with repeated episodes of apnea, hypotonia, weakness, ptosis, mild ophthalmoparesis, and bulbar deficit. The first case also presented one isolated seizure, while the second case showed global developmental delay. Both cases, exhibited incomplete improvement with treatment with pyridostigmine.ConclusionsThis report emphasizes the broad incidence of CMS with episodic apnea caused by mutations in the SLC5A7 gene and the frequent association of this condition with serious manifestations of central nervous system involvement.

Sex differences in human performance.

Sex as a biological variable is an underappreciated aspect of biomedical research, with its importance emerging in more recent years. This review assesses the current understanding of sex differences in human physical performance. Males outperform females in many physical capacities because they are faster, stronger and more powerful, particularly after male puberty. This review highlights key sex differences in physiological and anatomical systems (generally conferred via sex steroids and puberty) that contribute to these sex differences in human physical performance. Specifically, we address the effects of the primary sex steroids that affect human physical development, discuss insight gained from an observational study of 'real-world data' and elite athletes, and highlight the key physiological mechanisms that contribute to sex differences in several aspects of physical performance. Physiological mechanisms discussed include those for the varying magnitude of the sex differences in performance involving: (1) absolute muscular strength and power; (2) fatigability of limb muscles as a measure of relative performance; and (3) maximal aerobic power and endurance. The profound sex-based differences in human performance involving strength, power, speed and endurance, and that are largely attributable to the direct and indirect effects of sex-steroid hormones, sex chromosomes and epigenetics, provide a scientific rationale and framework for policy decisions on sex-based categories in sports during puberty and adulthood. Finally, we highlight the sex bias and problem in human performance research of insufficient studies and information on females across many areas of biology and physiology, creating knowledge gaps and opportunities for high-impact studies.

Testing the predictive capacity of a muscle fatigue model on electrically stimulated adductor pollicis.

Based on the critical power (Pc or critical force; Fc) concept, a recent mathematical model formalised the proportional link between the decrease in maximal capacities during fatiguing exercises and the amount of impulse accumulated above Fc. This study aimed to provide experimental support to this mathematical model of muscle fatigability in the severe domain through testing (i) the model identifiability using non-exhausting tests and (ii) the model ability to predict time to exhaustion (tlim)and maximal force (Fmax)decrease. The model was tested on eight participants using electrically stimulated adductor pollicis muscle force. The Fmax was recorded every 15s for all tests, including five constant tests to estimate the initial maximal force (Fi), Fc, and a time constant (τ). The model's parameters were used to compare the predicted and observed tlim values of the incremental ramp test and Fmax(t) of the sine test. The results showed that the model accurately estimated Fi, Fc, and τ (CI95% = 2.7%Fi and 9.1s for Fc and τ, respectively; median adjusted r2 = 0.96) and predicted tlim and Fmax with low systematic and random errors (11 ± 20% and -1.8 ± 7.7%Fi, respectively). This study revealed the potential applications of a novel mathematical formalisation that encompasses previous research on the critical power concept. The results indicated that the model's parameters can be determined from non-exhaustive tests, as long as maximal capacities are regularly assessed. With these parameters, the evolution of maximal capacities (i.e. fatigability) at any point during a known exercise and the time to exhaustion can be accurately predicted.

Potential of a New, Flexible Electrode sEMG System in Detecting Electromyographic Activation in Low Back Muscles during Clinical Tests: A Pilot Study on Wearables for Pain Management.

While low back pain (LBP) is the leading cause of disability worldwide, its clinical objective assessment is currently limited. Part of this syndrome arises from the abnormal sensorimotor control of back muscles, involving increased muscle fatigability (i.e., assessed with the Biering-Sorensen test) and abnormal muscle activation patterns (i.e., the flexion-extension test). Surface electromyography (sEMG) provides objective measures of muscle fatigue development (median frequency drop, MDF) and activation patterns (RMS amplitude change). This study therefore assessed the sensitivity and validity of a novel and flexible sEMG system (NSS) based on PEVA electrodes and potentially embeddable in textiles, as a tool for objective clinical LBP assessment. Twelve participants wearing NSS and a commercial laboratory sEMG system (CSS) performed two clinical tests used in LBP assessment (Biering-Sorensen and flexion-extension). Erector spinae muscle activity was recorded at T12-L1 and L4-L5. NSS showed sensitivity to sEMG changes associated with fatigue development and muscle activations during flexion-extension movements (p < 0.05) that were similar to CSS (p > 0.05). Raw signals showed moderate cross-correlations (MDF: 0.60-0.68; RMS: 0.53-0.62). Adding conductive gel to the PEVA electrodes did not influence sEMG signal interpretation (p > 0.05). This novel sEMG system is promising for assessing electrophysiological indicators of LBP during clinical tests.

Clinical meaningfulness and psychometric robustness of the MG Symptoms PRO scales in clinical trials in adults with myasthenia gravis.

The objective of this research was to generate psychometric evidence supporting the myasthenia gravis (MG) symptoms patient-reported outcome (PRO) scales as a fit-for-purpose measure of severity of core symptoms of MG and provide information allowing their meaningful interpretation using data from a phase 3 study in MG. Data from the MycarinG study, a phase 3 study of rozanolixizumab in patients with generalized MG who experience moderate to severe symptoms (ClinicalTrials.gov Identifier: NCT03971422) were analyzed with both classical test theory (CTT) and Rasch measurement theory (RMT). Meaningful within-individual change and group-level meaningful change were estimated for three MG Symptoms PRO scales using anchor- and distribution-based methods. Anchor-based methods used patient global impression of severity (PGIS) and change (PGIC) in MG symptoms as anchors. Good measurement properties of the MG Symptoms PRO scales were shown in the sample of 200 participants: good to excellent reliability (test-retest and internal consistency reliability) and validity (associations between items and scores within the MG Symptoms PRO scales and between the MG Symptoms PRO scores and other clinical outcomes-MG ADL, QMG score, MGC score, and MGFA classes-were as expected); and the items showed good coverage of the continuum and fit to the Rasch model. Triangulation of the anchor- and distribution-based method results led to the definition of clinically meaningful within-patient improvement in scores for Muscle Weakness Fatigability (-16.67), Physical Fatigue (-20.00), and Bulbar Muscle Weakness (-20.00), with associated ranges. Benchmarks are also proposed for the interpretation of group-level results. The strong psychometric performance of the MG Symptoms PRO scales and the information generated to guide its interpretation supports its use in clinical trials for demonstrating the clinical benefits of new treatments targeting core symptoms of MG (muscle weakness fatigability, physical fatigue, bulbar muscle weakness, respiratory muscle weakness, and ocular muscle weakness).

Upper-Limb Muscle Fatigability in Para-Athletes Quantified as the Rate of Force Development in Rapid Contractions of Submaximal Amplitude.

This study aimed to compare neuromuscular fatigability of the elbow flexors and extensors between athletes with amputation (AMP) and athletes with spinal cord injury (SCI) for maximum voluntary force (MVF) and rate of force development (RFD). We recruited 20 para-athletes among those participating at two training camps (2022) for Italian Paralympic veterans. Ten athletes with SCI (two with tetraplegia and eight with paraplegia) were compared to 10 athletes with amputation (above the knee, N = 3; below the knee, N = 6; forearm, N = 1). We quantified MVF, RFD at 50, 100, and 150 ms, and maximal RFD (RFDpeak) of elbow flexors and extensors before and after an incremental arm cranking to voluntary fatigue. We also measured the RFD scaling factor (RFD-SF), which is the linear relationship between peak force and peak RFD quantified in a series of ballistic contractions of submaximal amplitude. SCI showed lower levels of MVF and RFD in both muscle groups (all p values ≤ 0.045). Despite this, the decrease in MVF (Cohen's d = 0.425, p < 0.001) and RFDpeak (d = 0.424, p = 0.003) after the incremental test did not show any difference between pathological conditions. Overall, RFD at 50 ms showed the greatest decrease (d = 0.741, p < 0.001), RFD at 100 ms showed a small decrease (d = 0.382, p = 0.020), and RFD at 150 ms did not decrease (p = 0.272). The RFD-SF decreased more in SCI than AMP (p < 0.0001). Muscle fatigability impacted not only maximal force expressions but also the quickness of ballistic contractions of submaximal amplitude, particularly in SCI. This may affect various sports and daily living activities of wheelchair users. Early RFD (i.e., ≤50 ms) was notably affected by muscle fatigability.

Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.

Congenital Myasthenic Syndromes in Belgium: Genetic and Clinical Characterization of Pediatric and Adult Patients

BackgroundCongenital myasthenic syndromes (CMS) are a group of genetic disorders characterized by impaired neuromuscular transmission. CMS typically present at a young age with fatigable muscle weakness, often with an abnormal response after repetitive nerve stimulation (RNS). Pharmacologic treatment can improve symptoms, depending on the underlying defect. Prevalence is likely underestimated. This study reports on patients with CMS followed in Belgium in 2022. MethodsData were gathered retrospectively from the medical charts. Only likely pathogenic and pathogenic variants were included in the analysis. ResultsWe identified 37 patients, resulting in an estimated prevalence of 3.19 per 1,000,000. The patients harbored pathogenic variants in CHRNE, RAPSN, DOK7, PREPL, CHRNB1, CHRNG, COLQ, MUSK, CHRND, GFPT1, and GMPPB. CHRNE was the most commonly affected gene. Most patients showed disease onset at birth, during infancy, or during childhood. Symptom onset was at adult age in seven patients, caused by variants in CHRNE, DOK7, MUSK, CHRND, and GMPPB. Severity and distribution of weakness varied, as did the presence of respiratory involvement, feeding problems, and extraneuromuscular manifestations. RNS was performed in 23 patients of whom 18 demonstrated a pathologic decrement. Most treatment responses were predictable based on the genotype. ConclusionsThis is the first pooled characterization of patients with CMS in Belgium. We broaden the phenotypical spectrum of pathogenic variants in CHRNE with adult-onset CMS. Systematically documenting larger cohorts of patients with CMS can aid in better clinical characterization and earlier recognition of this rare disease. We emphasize the importance of establishing a molecular genetic diagnosis to tailor treatment choices.