Distal Muscles Research Articles

Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant.

Background: Sheldon-Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes). Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis. Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype. Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.

AAV1.NT-3 gene therapy prevents age-related sarcopenia.

Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness.

Introduction Hereditary sensory neuropathy (HSN) describes as a heterogeneous group of peripheral neuropathies. HSN type 1 (HSN1) is one subtype characterized by distal sensory impairment that occurs in the form of numbness, tingling, or pain. To date, only two variants in the atlastin GTPase 3 (ATL3) gene have been identified that result in hereditary sensory neuropathy type 1F (HSN1F) with autosomal dominantinheritance. Methods We sudied and examined who present with sensory disturbances and muscle weakness in their lower limb. Patients underwent Whole Exome Sequencing and Sanger sequencing was performed in families for validation of detected variant. Results Here, we identified two Iranian families carrying the novel heterozygous stop variant NM_015459.5: c.16C>T, p.Arg6Ter in ATL3 that led to disturbed pain and touch sensitivity. This variant in the ATL3 gene was detected in both families (NM_015459.5: c.16C>T, p.Arg6Ter) by whole-exome sequencing and confirmed by Sanger sequencing. Conclusion In this study, the subjects manifested weakness of distal limb muscles and numbness of the lower extremities. In addition, some unusual features, including hearing problems and inability to sit and walk presented in one of the patients. Eventually, we provide a case-based review of the clinical features associated with HSN1F. Hitherto, only 11 patients with HSN1F have been reported. We compared our findings to previously reported cases, suggesting that the clinical features are generally variable in the HSN1F patients.

Unravelling inclusion body myositis using a patient-derived fibroblast model.

Inclusion body myositis (IBM) is an inflammatory myopathy clinically characterized by proximal and distal muscle weakness, with inflammatory infiltrates, rimmed vacuoles and mitochondrial changes in muscle histopathology. There is scarce knowledge on IBM aetiology, and non-established biomarkers or effective treatments are available, partly due to the lack of validated disease models. We have performed transcriptomics and functional validation of IBM muscle pathological hallmarks in fibroblasts from IBM patients (n=14) and healthy controls (n=12), paired by age and sex. The results comprise an mRNA-seq, together with functional inflammatory, autophagy, mitochondrial and metabolic changes between patients and controls. Gene expression profile of IBM vs control fibroblasts revealed 778 differentially expressed genes (P-value adj<0.05) related to inflammation, mitochondria, cell cycle regulation and metabolism. Functionally, an increased inflammatory profile was observed in IBM fibroblasts with higher supernatant cytokine secretion (three-fold increase). Autophagy was reduced considering basal protein mediators (18.4% reduced), time-course autophagosome formation (LC3BII 39% reduced, P-value<0.05), and autophagosome microscopic evaluation. Mitochondria displayed reduced genetic content (by 33.9%, P-value<0.05) and function (30.2%-decrease in respiration, 45.6%-decline in enzymatic activity (P-value<0.001), 14.3%-higher oxidative stress, 135.2%-increased antioxidant defence (P-value<0.05), 11.6%-reduced mitochondrial membrane potential (P-value<0.05) and 42.8%-reduced mitochondrial elongation (P-value<0.05)). In accordance, at the metabolite level, organic acid showed a 1.8-fold change increase, with conserved amino acid profile. Correlating to disease evolution, oxidative stress and inflammation emerge as potential markers of prognosis. These findings confirm the presence of molecular disturbances in peripheral tissues from IBM patients and prompt patients' derived fibroblasts as a promising disease model, which may eventually be exported to other neuromuscular disorders. We additionally identify new molecular players in IBM associated with disease progression, setting the path to deepen in disease aetiology, in the identification of novel biomarkers or in the standardization of biomimetic platforms to assay new therapeutic strategies for preclinical studies.

Effect of varied dorsiflexion range of motion on landing biomechanics in chronic ankle instability.

Limited dorsiflexion range of motion (DFROM) is a risk factor for lateral ankle sprain. However, varied DFROM exists within the chronic ankle instability (CAI) population, and how the variability may influence altered movement patterns during landing is unclear. The purpose of this study was to identify different movement strategies during maximal jump landing/cutting among CAI patients classified by varied DFROM. One hundred CAI subjects were classified into 3 subgroups based on their DFROM, measured by the weight-bearing lunge test: a Hypo- (≤40°), Normal- (40-50°), and Hyper-DFROM group (≥50°). Participants completed five trials of maximal jump landing/cutting. Lower extremity joint angles and EMG activation of seven muscles were collected from initial contact to toe-off. Functional analyses of variance were used to evaluate between-group differences for these outcome variables. Hypo-DFROM group (14M, 10F) displayed the reduced ankle dorsiflexion and inversion angles with increased hip flexion angle as a compensatory kinematic chain movement strategy. In addition, motion restrictions of the ankle are associated with altered muscle activation in both distal and proximal muscles during landing/cutting. Normal-DFROM (25M, 30F) and Hyper-DFROM (11M, 10F) groups also have different movement strategies including greater inversion angle and less EMG activation, which could contribute to further ankle injuries. Our data suggest that limited DFROM negatively affects the ankle joint during demanding movement within the CAI population. These movement patterns in CAI patients with pathomechanical deficits could contribute to further ankle sprains.

Reliability of 3D freehand ultrasound to assess lower limb muscles in children with spastic cerebral palsy and typical development.

This study investigated the reliability of 3-dimensional freehand ultrasound (3DfUS) to quantify the size (muscle volume [MV] and anatomical cross-sectional area [aCSA]), length (muscle length [ML], tendon length [TL], and muscle tendon unit length [MTUL]), and echo-intensity (EI, whole muscle and 50% aCSA), of lower limb muscles in children with spastic cerebral palsy (SCP) and typical development (TD). In total, 13 children with SCP (median age 14.3 (7.3) years) and 13 TD children (median age 11.1 (1.7) years) participated. 3DfUS scans of rectus femoris, semitendinosus, medial gastrocnemius, and tibialis anterior were performed by two raters in two sessions. The intra- and inter-rater and intra- and inter-session reliability were defined with relative and absolute reliability measures, that is, intra-class correlation coefficients (ICCs) and absolute and relative standard error of measurement (SEM and SEM%), respectively. Over all conditions, ICCs for muscle size measures ranged from 0.818 to 0.999 with SEM%s of 12.6%-1.6%. For EI measures, ICCs varied from 0.233 to 0.967 with SEM%s of 15.6%-1.7%. Length measure ICCs ranged from 0.642 to 0.999 with SEM%s of 16.0%-0.5%. In general, reliability did not differ between the TD and SCP cohort but the influence of different muscles, raters, and sessions was not constant for all 3DfUS parameters. Muscle length and muscle tendon unit length were the most reliable length parameters in all conditions. MV and aCSA showed comparable SEM%s over all muscles, where tibialis anterior MV was most reliable. EI had low-relative reliability, but absolute reliability was better, with better reliability for the distal muscles in comparison to the proximal muscles. Combining these results with earlier studies describing muscle morphology assessed in children with SCP, 3DfUS seems sufficiently reliable to determine differences between cohorts and functional levels. The applicability on an individual level, for longitudinal follow-up and after interventions is dependent on the investigated muscle and parameter. Moreover, the semitendinosus, the acquisition, and processing of multiple sweeps, and the definition of EI and TL require further investigation. In general, it is recommended, especially for longitudinal follow-up studies, to keep the rater the same, while standardizing acquisition settings and positioning of the subject.

Vasculitic Neuropathies, its Varied Manifestations, and Associations

Vasculitic neuropathies are disorders that result from inflammation in the peripheral nerve's vascular supply, resulting in ischemic injury. These disorders may be confined to peripheral nerves or may be a result of systemic inflammation. It is imperative that we recognize these disorders early to prevent morbidity and mortality. Hereby, we describe three cases of vasculitic neuropathy with varied presentations and their outcomes with treatment. A 43-year-old male presented with burning paresthesia of 4-month duration along with facial nerve paresis and black discoloration of toes of lower limbs. On evaluation, he had features of facial palsy along with dry gangrene involving the toes and calf region. A 36-year-old woman presented with features of paresthesia of lower limbs with reduced perception of temperature and distal and proximal muscle weakness. A 49-year-old male presented with features of multisystem involvement including lower respiratory tract infection and gastrointestinal symptoms along with distal and proximal muscle weakness. Nerve, muscle, and skin biopsies in all these three cases confirmed the diagnosis of vasculitic neuropathy. The first two patients were treated with methylprednisolone and cyclophosphamide and showed very good improvement during follow-up. However, the third patient was unwilling to receive treatment. Vasculitic neuropathies present with varied presentations. Therefore, when evaluating patients with peripheral neuropathy, suspicion of vasculitic etiology should be heightened. Timely diagnosis is very important in the management of vasculitic neuropathy and also for a better outcome. It is also important to acknowledge that nerve biopsy is a confirmatory investigation and should be performed in cases of strong suspicion.

Agreement and reliability of lower limb muscle architecture measurements using a portable ultrasound device

Although ultrasonography is commonly used to assess muscle architecture, high-end ultrasonography devices lack in portability and are expensive. Recently, ultrasonography devices consisting solely of a probe, an app, and/or a mobile display were introduced. These devices have lower acquisition costs than high-end devices and demonstrate higher portability. Portable systems would allow for cost-effective, on-site athlete or patient screenings of muscle architecture as well as diagnosis of pathologies or injury. Furthermore, portable systems can be easily transported to allow for uncomplicated assessment of athletes belonging to different teams or patients in different hospital units. Nonetheless, the reliability of portable systems and the comparability to high-end devices for muscle architecture assessment have not been investigated.&#x0D; We investigated the agreement and reliability of a portable and handheld ultrasonography system for muscle architecture measurements in human lower limb muscles. We acquired images of the rectus femoris (RF), vastus lateralis (VL) and gastrocnemius medialis (GM) in 36 active healthy participants (15 female, 21 male) at 50% of muscle length using the handheld Lumify (L12-4, linear array 37 mm, Philips Healthcare, Amsterdam, Netherlands) and a high-end laboratory device (ACUSON Juniper, linear-array 54 mm, 12L3, SIEMENS Healthineers, Erlangen, Germany). Muscle length was determined as distance between the proximal and distal muscle tendon junction. We compared measurements of muscle fascicle length, pennation angle and thickness. To assess inter-session reliability of the Lumify system, participants were measured twice within 1 week.&#x0D; Comparing RF architecture measurements of both devices resulted in intra-class correlations (ICCs) ranging from 0.46–0.82 and standardized mean difference (SMDs) ranging from −0.45–0.05. For VL, ICCs ranged from 0.60–0.89 and SMDs ranged from −0.11–0.13. ICCs and SMDs for the GM ranged from 0.82–0.86 and −0.07–0.07. Calculating inter-session reliability for RF resulted in ICCs ranging from 0.44–0.76 and SMDs ranging from −0.38–0.15. For VL, ICCs and SMDs ranged from 0.57–0.75 and −0.13–0.02. ICCs for GM ranged from 0.75–0.92 and SMDs ranged from −0.15–0.16. The highest agreement (ICC ≥ 0.82) and reliability (ICC ≥ 0.75) across all muscles was demonstrated for the measurement of muscle thickness.&#x0D; The Lumify system was comparable to a high-end device and reliable for GM measurements. Nevertheless, agreement and reliability were lower for the RF and VL. Thus, when interpreting longitudinal observed changes in muscle architecture assessed with the Lumify system, measurement errors should be considered. Future investigations should consider including different participant populations, comparing the reliability of different portable systems for muscle architecture assessment as well as including different muscle groups.

A rare reason for hospital admission with muscle weakness in the Covid-19 rra: CPT-2 deficiency

Abstract Introduction Carnitine Palmitoyl Transferase-2 (CPT-2) is a mitochondrial enzyme involved in the pathway of long chain fatty acids. CPT-2 deficiency is a rare autosomal recessive disease. Except for neonatal and severe infantile hepatocardiomuscular forms, the myopathic form diagnosed at later ages often presents with attacks of muscle weakness and recurrent rhabdomyolysis attacks. Clinical Case A 27-year-old male patient who applied to the emergency department with complaints of pain all over the body, muscle weakness, nausea, vomiting, headache and decreased urine output in the last 2 days. He was consulted because of LDH: 456 U/L (0–248 U/L), CK: 5567 U/L (0–190 U/L), AST: 382 U/L (10–37), ALT: 89.8 U/L (10–40 U/L), creatinine: 1.23 mg/dL (0–1,2 mg/dL). He was interned with the prediagnosis of acute kidney injury secondary to rhabdomyolysis. It was learned that he had been fasting for 2 days and working at an intense physical pace. There were intensive care hospitalizations due to rhabdomyolysis at the age of 16 and 24 years and Reye's syndrome at the age of 15. It was not diagnosed at that time. His mother's cousin when he was 15 had sudden cardiac death. On physical examination, he was conscious and his general condition was poor. Blood pressure: 141/100mmHg, pulse: 76/min, and fever: 37.4. There were 4/5 muscle weakness in bilateral lower extremity proximal muscles 3/5, distal muscles 4/5, upper extremity proximal and distal muscles 4/5. Pre-diagnoses of very long chain fatty acid dehydration deficiency, CPT-2 deficiency, glutaric acidemia type-2 were considered, IV hydration and riboflavin 3×100mg, coenzyme-Q 2×100mg, carnitine 2×1gr mitochondrial cocktail were started. Tandem Mass and urine amino acid levels were requested from the patient who was in the attack period. During his hospitalization, he had increases of acute phase reactants and respiratory symptoms, Covid PCR+ was detected. Liver function tests increased under favipravir treatment. In the follow-up, the values of CK, creatinine and liver function tests ​​decreased with hydration. Homozygous c.338C&amp;gt;T(p.Ser113Leu) mutation was detected in the CPT-2 gene. Conclusion CPT-2 deficiency should be kept in mind as a rare cause of increased muscle weakness after fasting, intense exercise, and all infections, especially Covid and other upper respiratory tract infections. Intense hydration and mitochondrial cocktail therapy should be added to the patient until the diagnosis is clarified.

6-OHDA-Induced Changes in Colonic Segment Contractility in the Rat Model of Parkinson's Disease.

Gastrointestinal dysfunction is one of the most common non-motor symptoms in Parkinson's disease (PD). The exact mechanisms behind these symptoms are not clearly understood. Studies in the well-established 6-hydroxydopamine (6-OHDA) lesioned rats of PD have shown altered contractility in isolated circular and longitudinal smooth muscle strips of distal colon. Contractile changes in proximal colon and distal ileum are nevertheless poorly studied. Moreover, segments may serve as better tissue preparations to understand the interplay between circular and longitudinal smooth muscle. This study aimed to compare changes in contractility between isolated full-thickness distal colon muscle strips and segments, and extend the investigation to proximal colon and distal ileum in the 6-OHDA rat model. Spontaneous contractions and contractions induced by electrical field stimulation (EFS) and by the non-selective muscarinic agonist methacholine were investigated in strip and/or segment preparations of smooth muscle tissue from distal and proximal colon and distal ileum in an in vitro organ bath comparing 6-OHDA-lesioned rats with Sham-operated animals. Key Results. Our data showed increased contractility evoked by EFS and methacholine in segments, but not in circular and longitudinal tissue strips of distal colon after central 6-OHDA-induced dopamine denervation. Changes in proximal colon segments were also displayed in high K+ Krebs-induced contractility and spontaneous contractions. This study further confirms changes in smooth muscle contractility in distal colon and to some extent in proximal colon, but not in distal ileum in the 6-OHDA rat model of PD. However, the changes depended on tissue preparation.

Automatic Text-Mining Approach to Identify Molecular Target Candidates Associated with Metabolic Processes for Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary disease caused by abnormal expansion of unstable CTG repeats in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. This disease mainly affects skeletal muscle, resulting in myotonia, progressive distal muscle weakness, and atrophy, but also affects other tissues and systems, such as the heart and central nervous system. Despite some studies reporting therapeutic strategies for DM1, many issues remain unsolved, such as the contribution of metabolic and mitochondrial dysfunctions to DM1 pathogenesis. Therefore, it is crucial to identify molecular target candidates associated with metabolic processes for DM1. In this study, resorting to a bibliometric analysis, articles combining DM1, and metabolic/metabolism terms were identified and further analyzed using an unbiased strategy of automatic text mining with VOSviewer software. A list of candidate molecular targets for DM1 associated with metabolic/metabolism was generated and compared with genes previously associated with DM1 in the DisGeNET database. Furthermore, g:Profiler was used to perform a functional enrichment analysis using the Gene Ontology (GO) and REAC databases. Enriched signaling pathways were identified using integrated bioinformatics enrichment analyses. The results revealed that only 15 of the genes identified in the bibliometric analysis were previously associated with DM1 in the DisGeNET database. Of note, we identified 71 genes not previously associated with DM1, which are of particular interest and should be further explored. The functional enrichment analysis of these genes revealed that regulation of cellular metabolic and metabolic processes were the most associated biological processes. Additionally, a number of signaling pathways were found to be enriched, e.g., signaling by receptor tyrosine kinases, signaling by NRTK1 (TRKA), TRKA activation by NGF, PI3K-AKT activation, prolonged ERK activation events, and axon guidance. Overall, several valuable target candidates related to metabolic processes for DM1 were identified, such as NGF, NTRK1, RhoA, ROCK1, ROCK2, DAG, ACTA, ID1, ID2 MYOD, and MYOG. Therefore, our study strengthens the hypothesis that metabolic dysfunctions contribute to DM1 pathogenesis, and the exploitation of metabolic dysfunction targets is crucial for the development of future therapeutic interventions for DM1.

Thermal Stability of Contractile Proteins in Bat Wing Muscles Explains Differences in Temperature Dependence of Whole-Muscle Shortening Velocity.

AbstractMuscle contractile properties are dependent on temperature: cooler temperatures generally slow contractile rates. Contraction and relaxation are driven by underlying biochemical systems, which are inherently sensitive to temperature. Carollia perspicillata, a small Neotropical bat, experiences large temperature differentials among body regions, resulting in a steep gradient in temperature along the wing. Although the bats maintain high core body temperatures during flight, the wing muscles may operate at more than 10°C below body temperature. Partially compensating for these colder operating temperatures, distal wing muscles have lower temperature sensitivities in their contractile properties, including shortening velocity, relative to the proximal pectoralis. Shortening velocity is correlated with the activity of myosin ATPase, an enzyme that drives the cross-bridge cycle. We hypothesized that the thermal properties of myofibrillar ATPase from the pectoralis and forearm muscles of the bat wing would correlate with the temperature sensitivity of those muscles. Using myofibrillar ATPases from the proximal and distal muscles, we measured enzyme activity across a range of temperatures and enzyme thermal stability after heat incubation across a range of time points. We found that forearm muscle myofibrillar ATPase was significantly less thermally stable than pectoralis myofibrillar ATPase but that there was no significant difference in the acute temperature dependence of enzyme activity between the two muscles.

Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy.

Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis. Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis. Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ10 levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle. This report describes a new neurologic phenotype of COQ7-related primary CoQ10 deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ10 deficiency previously reported in the literature.

Large-gap peripheral nerve repair using xenogeneic transplants in rhesus macaques.

Surgical intervention is required to successfully treat severe, large-gap (≥4cm) peripheral nerve injuries. However, all existing treatments have shortcomings and an alternative to the use of autologous nerves is needed. Human and porcine nerves are physiologically similar, with comparable dimensions and architecture, presence and distribution of Schwann cells, and conserved features of the extracellular matrix (ECM). We report the repair of fully transected radial nerves in 10 Rhesus Macaques using viable, whole sciatic nerve from genetically engineered (GalT-KO), designated pathogen free (DPF) porcine donors. This resulted in the regeneration of the transected nerve, and importantly, recovery of wrist extension function, distal muscle reinnervation, and recovery of nerve conduction velocities and compound muscle action potentials similar to autologous controls. We also demonstrate the absence of immune rejection, systemic porcine cell migration, and detectable residual porcine material. Our preliminary findings support the safety and efficacy of viable porcine nerve transplants, suggest the interchangeable therapeutic use of cross-species cells, and highlight the broader clinical potential of xenotransplantation.

Hindlimb muscle spindles inform preparatory forelimb coordination prior to landing in toads.

Animals move across a wide range of surface conditions in real-world environments to acquire resources and avoid predation. To effectively navigate a variety of surfaces, animals rely on several mechanisms including intrinsic mechanical responses, spinal-level central pattern generators, and neural commands that require sensory feedback. Muscle spindle Ia afferents play a critical role in providing sensory feedback and informing motor control strategies across legged vertebrate locomotion, which is apparent in cases where this sensory input is compromised. Here, we tested the hypothesis that spindle Ia afferents from hindlimb muscles are important for coordinating forelimb landing behavior in the cane toad. We performed bilateral sciatic nerve reinnervations to ablate the stretch reflex from distal hindlimb muscles while allowing for motor neuron recovery. We found that toads significantly delayed the onset and reduced the activation duration of their elbow extensor muscle following spindle Ia afferent ablation in the hindlimbs. However, reinnervated toads achieved similar elbow extension at touchdown to that of their pre-surgery state. Our results suggest that while toads likely tuned the activation timing of forelimb muscles in response to losing Ia afferent sensation from the hindlimbs they were likely able to employ compensatory strategies that allowed them to continue landing effectively with reduced sensory information during take-off. These findings indicate muscle spindle Ia afferents may contribute to tuning complex movements involving multiple limbs.

Neurophysiological Evaluation of the Functional State of Muscular and Nervous Systems in High-Maneuvering Jet Fighters

The present study aimed to assess the function of muscular and nervous systems in high-maneuvering jet fighters with the chosen method of clinical neurophysiology, which methodologically has not yet been presented in detail. Fifteen pilots with the experience of more than 1700 flying hours at 7G overloading on average and fifteen healthy subjects for the comparison of health status declared to participate in this study. The dermatomal perception from C4 to S1 was examined using von Frey’s filaments tactile method. Surface electromyography (sEMG) recordings examined the activity of proximal and distal muscles in the upper and lower extremities, the transmission of motor nerve impulses peripherally was diagnosed by electroneurography (ENG), the efferent transmission from C5–C7 and L4–L5 spinal centers to muscles was entirely verified with recordings of motor-evoked potentials induced oververtebrally with the magnetic field (MEP). The pilots estimated more lumbosacral than cervical pain at about 2 on the 10-point visual analog scale (VAS). Sensory perception studies did not reveal abnormal symptoms in the C2–S1 dermatomes innervation. Clinical neurophysiology studies indicated, in general, the lack of pathology during sEMG tests in comparison to healthy subjects or even better muscle motor unit contractile properties in pilots, both in the upper and lower extremities. In pilots, the parameters of ENG and MEP examinations show a statistically significant sensitivity for detecting the slight changes and their consequences in the transmission of neural impulses within L4–L5 ventral root fibers. The research results enable specifying the algorithm of future preventing rehabilitative treatment in high-maneuvering jet fighters with an average flight experience of 2000 h and working conditions at 7G on average. This study, for the first time, describes the application of a set of diagnostic neurophysiological methods with the particular importance of MEPs in the clinical evaluation of the jet fighters’ health status.

A genotype–phenotype description in two Indian patients: Broadening the spectrum in VRK1‐related complex motor disorders

AbstractVRK1 (vaccinia‐related kinase 1) was initially reported to be associated with spinal muscular atrophy–pontocerebellar hypoplasia (SMA‐PCH). Congenital or infantile‐onset progressive sensory‐motor neuropathy with microcephaly, adult‐onset distal SMA, and adult‐onset motor neuron disease are the other phenotypes described recently with VRK1. Since VRK1‐related complex motor disorders other than PCH is rare, we aim to depict the diverse clinical phenotypes and the genotypes of two patients with VRK1 variants from India. Proband‐1 is a 7‐year‐old girl who presented with distal muscle weakness and wasting of upper and lower limbs with brisk deep tendon reflexes (DTR), mild intellectual disability, and behavioral problems. She had a homozygous c.1159 + 1G &gt; A pathogenic variant in VRK1, inherited from parents. Proband‐2 is a 25‐year‐old adopted male with sensory‐motor neuropathy and brisk DTR. He had a homozygous c.7C &gt; T (p.R3C) missense variant of uncertain significance in VRK1 predicted to be damaging by multiple computational tools.

Limb-Girdle Muscular Dystrophy in Brazilian children: Clinical, histological and molecular characterization.

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular disorders, involving autosomal recessive and dominant forms, that clinically are characterized by progressive muscular weakness of proximal predominance, generally starting in the pelvic girdle and, later, in the shoulder girdle, frequently associated with other clinical signs such as calf hypertrophy, joint retractions and skeletal deformities such as winging scapula and scoliosis. The distal muscles may be affected, but usually only late in the progression of the disease. Involvement of respiratory muscles and cardiac muscles is described in many forms of the disease. Different degrees of increase in the serum level of creatine kinase (CK) are observed and, sporadically, there is involvement of the central nervous system (CNS) and gastrointestinal tract . Autosomal recessive forms are far more common than autosomal dominant, particularly in children. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunohistochemical studies and the confirmatory toll is the molecular test . This retrospective study had the objective to investigate the frequency of different subtypes of limb-girdle muscular dystrophy in children from a population from a large public teaching hospital serving the country, describing the clinical and histological aspects of the different forms.

Parkinsonism may aggravate dysphagia in myotonic dystrophy type 1: two case reports.

Weakness of trunk muscles, fatigue and reduced mobility are features of myotonic dystrophy type 1 (DM1) and may also characterize patients with extrapyramidal disorders.Dysphagia is common in DM1 and parkinsonism and can be predominant compared to other symptom, often requiring surgical tratment. We describe two cases of patients with DM1 and parkinsonism who arrived at our Center for worsening dysphagia and who showed very similar and peculiar clinical features. The first patient presented initially at the outpatient clinic reporting a 7 year history of progressive difficulties in swallowing and movement slowness. Neurologic examination showed a general bradykinesia, plastic rigidity of upper limbs, diffuse hypotrophy and deep tendon reflexes weakness. MRI scan of brain and spine was unremarkable, but neurophysiological evaluation revealed diffuse myotonic discharges on distal limb muscles. Genetic testing confirmed DM1 diagnosis (CTG range E1).The second patient, presented with an initial diagnosis of parkinsonism due to a 10 years history of gait impairment, generalized weakness and dysphagia. Due to low back pain a neurophysiological study was performed after 5 years from diagnosis of parkinsonism detecting diffuse myotonic discharges and genetic testing confirmed diagnosis of DM1 (CTG range E2).Percutaneous endoscopic gastrostomy (PEG) was severe and burdensome for both patients.To date, only one case of molecularly confirmed DM1 along with parkinsonism has been described. We have described two cases of DM1 and parkinsonism in which swallowing function has been affected by a synergic effect triggered by both muscle condition and extrapyramidal disease.

Broader Estimates of Gastrocnemius Activity Generated a More Representative Cocontraction Index: A Study in Pediatric Population.

The electromyography (EMG) cocontraction index (CCI) given by the antagonistic/agonistic Root Mean Square (RMS) amplitude ratio of the same muscle is a qualified biomarker used for spastic cocontraction quantification and management in cerebral palsy children. However, this normative EMG ratio is likely subject to a potential source of errors with biased estimates when measuring the gastrocnemius plantar flexors activity. Due to the uneven distribution of electrical activity within the muscle volume, cocontraction levels can be misestimated, if EMGs are obtained from the sole traditional bipolar sensor location recommended by SENIAM. This preliminary study, on 10 healthy children (mean age 10 yr), investigated whether surface EMG detected proximally and distally via two pairs of bipolar electrodes, within the medial gastrocnemius (MG), provides a significant difference in CCI estimates during non-dynamic (isometric dorsiflexion) and dynamic (swing phases of gait) conditions. Gait cycles were extracted from Inertial Measurement Unit sensors. Medial gastrocnemius activity was greater distally than proximally during plantar flexion when it acts as an agonist (~24±18%) and it was greater proximally during dorsiflexion (~23±9%) when it is acting as an antagonist. As a direct consequence, CCI estimates from the conventional sensor location were significantly different (~36%) from the CCIs computed by considering broader MG regions. This difference arose in all subjects during isometric efforts and in two of 10 healthy children during the swing phase of gait who presented cocontraction patterns (p<0.05). EMG bipolar sampling encompassing proximal and distal gastrocnemius muscle regions may reduce bias in CCI computation and provide a more representative and accurate cocontraction index that is especially important for comparisons to the diseased state.