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Epilepsy is a frequent manifestation of primary mitochondrial diseases (PMDs), affecting up to 40% of patients. Seizures in PMD are typically difficult to treat and often represent a poor prognostic feature. We aimed to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy using Delphi methodology. Twenty-four experts in mitochondrial medicine, pharmacology, and epilepsy management of adults and/or children from seven countries, who were members of five different European Reference Networks - known as the Mito InterERN Working Group - formed a Delphi panel, together with two patient organisation representatives. Delphi methodology was followed to allow the panelists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two survey rounds with predetermined levels of agreement. There was a high level of consensus regarding safety of 14 of 25 drugs reviewed, resulting in endorsement of NICE guidelines for seizure management, with some modifications. The experts caution against using sodium valproate in POLG disease, vigabatrin in patients with GABA transaminase deficiency and topiramate in patients at risk of renal tubular acidosis. We hope that these consensus recommendations will improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy. [ABSTRACT FROM AUTHOR]

Bovine tuberculosis (TBB) is a zoonotic disease distributed worldwide and is of great importance for public health and the livestock industry. Several experimental vaccines against this disease have been evaluated in recent years, yielding varying results. An example is the Bacillus Calmette-Guérin (BCG) vaccine, which has been used extensively in humans and tested in cattle showing mixed results related to protection (0-80%) against Mycobacterium bovis. In this study, we used the food-grade bacterium Lactococcus lactis as an expression system for production of mycobacterial protein Hsp65. For this purpose, the construction of a replicable plasmid in strain NZ9000 L. lactis (pVElepr) was conducted, which expressed the Mycobacterium leprae Hsp65 antigen, and was recognized by traded anti-Hsp65 antibodies. The strain NZ9000-pVElepr was applied to calves that were negative to tuberculin test and the immune response was monitored. The results showed that immune response was not significantly increased in calves with NZ9000-pVElepr with respect to control groups, and no injury was observed in any lung or lymph of the calves. Finally, this study suggest that the recombinant NZ9000 strain of L. lactis may protect against the development of M. bovis infection, although studies with longer exposure to this pathogen are necessary to conclude the matter. [ABSTRACT FROM AUTHOR]

Neuromuscular disorders (NMD) with neonatal or perinatal onset are usually severe. The establishment of a definite diagnosis relies on the combination of clinical examination, enzymatic tests, muscle morphology analyses, and genetic investigations, and is essential to provide a vital prognosis, propose adequate genetic counseling, consider treatment options, and include the patients into clinical trials for innovative therapies. However, the recent and rapid advancements of panel, exome, and genome sequencing questions the utility of invasive muscle biopsies and the contribution of histological and ultrastructural studies of muscle sections to the diagnosis process. Here, we explored the relevance of muscle biopsies collected at the Institute of Myology in Paris over a period of more than 50 years (1970-2021) in light of the evolution of Sanger and next-generation sequencing (NGS) technologies. Altogether, 82% of the biopsies showed typical structural myofiber anomalies highly suggestive of specific NMD classes (congenital myopathies, metabolic myopathies, lower motor neuron (LMN) and neuromuscular junction (NMJ) disorders, muscular dystrophies, inflammatory myopathies), while the remaining 18% showed no or only non-specific histological abnormalities. The diagnosis success rate differed among the NMD classes and changed over time following the identification of major disease genes like SMN1 or DMD , shifting the focus to direct gene sequencing and reducing the necessity of muscle biopsies. Ultrastructural investigations were of particular importance for the diagnosis of congenital myopathies and less relevant for the other NMD categories. Typical myofiber lesions found in congenital myopathies as intranuclear rods in ACTA1-related nemaline myopathy are barely discernible under the light microscope and solely detectable by electron microscopy (EM). This shows that the higher resolution of EM is not only a feature complementing light microscopy, but also a powerful diagnostic method. From our experience, morphological muscle biopsy examinations were frequently accurate and either pointed to a group of myopathies or to single genes. In conclusion, this retrospective study describes a unique collection of neonatal muscle biopsies and illustrates that the thorough analysis of muscle sections was of major diagnostic relevance in the past and still plays an important role nowadays - either by directing purposeful gene sequencing or by complementing clinical findings and biochemical analysis methods. [ABSTRACT FROM AUTHOR]

The article reports on the findings of the pilot study which examines the prevalence of Rhipicephalus sanguineus ticks on dogs on the border between Mexico and U.S. It describes the association between the detection of ticks and risk factors. The study has morphologically identified all of the ticks collected from dogs as Rhipicephalus sanguineus. Results of the study reveal 59.6% of ticks in dogs in the city, 46% in Culiacán, Sinaloa, and 20% in Cuernavaca, Morelos.

• Multiple myeloma (MM) and AL amyloidosis are two closely related conditions that can occur concurrently in some patients. • Amyloid myopathy is a rare manifestation of AL amyloidosis. It is characterized by muscle weakness that can be difficult to distinguish from the muscle weakness associated with other myopathies, including inflammatory myopathies. • For all unexplained myopathies in the adult age, it is suggested to perform a muscle biopsy and use routine Congo red staining to improve diagnostic accuracy of this rare disease. We present the case of a 79-year-old man with rapidly progressive myopathy as the initial manifestation of light chain amyloidosis associated with multiple myeloma. The patient experienced progressive lower limb weakness resulting in difficulty climbing stairs. Ancillary tests revealed slightly elevated serum creatine kinase levels. The electromyogram revealed a diffuse myogenic pattern while muscle MRI indicated fatty replacement of the quadriceps muscles. Muscle biopsy revealed the presence of amyloid deposits in the vessel walls. An elevated level of lambda (246 mg/L) light chain was detected. The bone marrow aspiration results were consistent with the diagnosis of multiple myeloma. In conclusion, even if amyloid myopathy is a rare condition, routine screening for amyloid deposits in muscle biopsy is crucial and should be performed systematically. In the present case, it enabled a rapid diagnosis and the beginning of treatment. [ABSTRACT FROM AUTHOR]

We describe two brothers who presented with different phenotypes and progression, sharing compound heterozygous mutations in the GMPPB gene. The index case, 34 years old, was referred to the muscle clinic for increased CK (>2.000), proximal weakness and calf hypertrophy. He is on therapy for myoclonic epilepsy following encephalitis in infancy and has mild cognitive and motor delay. Because of his symptoms, a muscle biopsy was performed: the immune-histochemistry showed a reduction in alpha dystroglycan labelling, with a secondary reduction of laminin alpha2 chain on western blot. Genes known to be associated to alpha-dystroglycanopathy have been excluded by direct sequencing (FKRP,POMT1, POMT2, POMGnT1,LARGE, FKTN). Two heterozygous variants in the GMPPB gene, a previously described mutation[c.860G>A (p.Arg287Gln)] and a novel variant [c.656T>C (p.Ile219Thr)]. The older brother, 36 years old, shares the same mutations having been shown to also have increased CK (2.832). He has global developmental delay presenting with speech and language difficulties, motor delay, impaired fine motor coordination and autistic spectrum disorder. He is not affected by weakness or fatigue, nor has weakness at physical examination. GMPPB catalyses the formation of GDP-mannose, required for O-mannosylation of alpha-dystroglycan. Mutations in this gene have been recently described in association to a spectrum of muscular dystrophy variants (Carss et al. AJHG, 2013), ranging from congenital to limb girdle muscular dystrophy, with additional symptoms as intellectual disability, epilepsy or brain structural anomalies. The family we describe highlights the clinical variability of these patients, with different presentation despite sharing the same mutations. Furthermore, it underlines the importance of testing CK in children presenting with global developmental delay: if the younger brother had not presented with a LGMD phenotype, the diagnosis in the older brother would have continued to be missed. [ABSTRACT FROM AUTHOR]

To describe the natural history of a Late-onset Pompe disease (LOPD) asymptomatic and untreated patient in order to gain insight to guide evidence-based patient care and therapeutic decisions. Clinical, radiological, and histopathological reevaluation of a LOPD asymptomatic and untreated patient 32 years after the initial diagnosis. A presymptomatic diagnosis of LOPD was made in a 2-year-old male patient with isolated elevation of CK levels, based on widespread left deltoid muscle glycogen deposits on biopsy and an enzymatic and genetic confirmation. The patient remains asymptomatic at 34 years old, despite not introducing enzyme replacement therapy (ERT). The clinical examination is normal, with stable functional outcomes (6-minutes' walk test > 600 m, 4 stairs climb test < 2 sec, MFM=100%) and normal supine vital capacity, despite moderate but steady progression of fatty degeneration of teres major, abdominal and adductor magnus muscles on MRI in the last 14 years. Interestingly, a new biopsy of the same muscle shows now an almost normal histological picture. Int the advent of neonatal screening, this case report advises against the systematic introduction of ERT in asymptomatic LOPD patients. Furthermore, muscle MRI seems to be the most sensitive method to detect the earliest signs of disease progression. The normality (or normalization) of the muscle biopsy performed in the same muscle years after the diagnosis advises against the prospective analysis of muscle glycogen accumulation in clinical trials. Finally, whether muscle glycogen deposits may spontaneously improve over time in mild cases needs further study. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a progressive, recessive neuromuscular disease characterized by significant reduction of SMN protein. This causes degeneration of lower motor neurons in the spinal cord and brainstem leading to weakness and muscle atrophy. Clinical severity is categorized in different subtypes (type 0-3), which is in turn influenced by residual SMN level. While the genetic basis of SMA is well described, the tissue-specific molecular pathways underlying SMA are still not fully understood and identification of marker proteins in human vulnerable tissue such as skeletal muscle is still lacking. To elucidate molecular markers in SMA-diseased muscle, we performed unbiased proteomics and transcriptomics on muscle biopsies derived from 3 SMA type 3 (walker) patients in addition to immunofluorescence including 5 additional cases and SMA myoblasts. Combined proteomic and transcriptomic studies unraveled FUS (a DNA/RNA-binding protein and aggregation marker) as a potential molecular marker increased in SMA muscle and SMA myoblasts. Results of our immunofluorescence studies showed increased FUS protein abundance in both accompanied by perimyonuclear disposition of the protein in a proportion of myofibres compared to the immunoreactivity obtained in control samples. To identify proteins that were associated with FUS we performed an interactome analysis, the results are pending. Our data classified FUS as a protein involved in SMA-based myopathology and support the concept of skeletal muscle as a primary tissue target of SMA. Further studies are crucial to define the role of mis-localized FUS in SMA muscle. [ABSTRACT FROM AUTHOR]

The ERN EURO-NMD registry is a registry of neuromuscular patients seen at EURO-NMD's expert centres, collecting data from these patients while focusing on their needs and experiences. The registry counts on the support of patient organizations that ensure that the registry is patient-centred and relevant. The registry has three levels of datasets. The first level is the European Commission-mandated data elements (EU-CDEs). The second level is the cross-neuromuscular data elements (NMD-CDEs). The third level is the disease-specific data elements (DS-DEs). These datasets capture clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data, and patient-reported outcomes. The data is recorded in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub allows for the exchange of GDPR-compliant information between different neuromuscular registries that follow the FAIR data stewardship principles. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. The EURO-NMD REgistry Hub is a platform where FAIR-enabled federated queries can be established between other existing or future datasets and the EURO-NMD registry, promoting the de-siloing of patient data on an unprecedented scale. In conclusion, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy (DM) is the most common genetic neuromuscular disease in adults. This complex, multisystemic disorder encompasses various clinical manifestations, including progressive muscle wasting and weakness, cataracts, and cardiac arrhythmias. The wide-ranging clinical spectrum of DM poses challenges in establishing accurate prognoses for patients and in forming homogeneous cohorts for clinical trials. To overcome some of these limitations, the French DM-Scope registry was established in France in 2005 with financial support from AFM-Téléthon. The goals of the registry are: i) to facilitate the rapid and secure identification of all potential patients, along with their clinical and genetic characteristics, to promote research, better delineate, and accelerate future clinical trials in DM; ii) to develop and enhance recommendations and standards of care for DM patients; and iii) to provide a precise description of the clinical course of the disease. To date, a total of 3828 patients have been enrolled in the registry, spanning 55 centers across France. In 2016, the French DM-Scope Registry transitioned into the iDM-Scope Registry through collaboration with Canadian teams. In 2023, the Canadian registry expanded to include the Outaouais and Eastern Ontario region. Since 2020, the registry has contributed to the establishment of a European project for rare neuromuscular diseases, known as the EURO-NMD Registry Hub. With data collected from neuromuscular expert physicians and/or patients, the registry serves as a valuable resource that requires further development and enhancement to accelerate the optimization of care for DM patients and translational research. [ABSTRACT FROM AUTHOR]

GNE myopathy (GNEM) is a rare autosomal recessive distal myopathy characterized by early adult-onset, slow to moderately progressive distal muscle weakness that preferentially affects the tibialis anterior muscle and that usually spares the quadriceps femoris. Muscle biopsy reveals presence of rimmed vacuoles (inclusion body myopathy 2) and fibrosis seen in scattered areas. The disease is caused by bi-allelic variants in the GNE gene encoding the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. The pathophysiology of GNE myopathy presumably involves aberrant protein sialylation. Thus far, the proteomic signature of GNE-mutant muscle has not been studied to determine a biochemical fingerprint serving as pathogenicity markers. Moreover, except myostatin, easy-accessible minimal-invasive biomarkers are still lacking for GNE myopathy. Exome sequencing was applied to identify the genetic cause of a myopathy present in three adolescents (all developed symptoms at approximately 15 years of age) of a consanguineous family from Afghanistan. In silico tools were applied to evaluate the pathogenicity of a candidate variant. Moreover, untargeted proteomics was performed to determine the proteinogenic signature of muscle biopsies derived from three additional unrelated GNEM patients with different grades of myopathology and immunostaining was completed to validate the findings and to define marker proteins of pathophysiological relevance. Additionally, proteomic profiling and ELISA were performed on serum derived from 24 GNE patients to identify novel minimal-invasive biomarkers. Genetic testing unveiled the novel homozygous p.(Val569Leu) missense variant in the 3 siblings. In silico studies confirmed a pathogenic effect of this amino acid substitution. Histological studies showed pathology including presence of vacuoles in quadriceps muscle derived from one of the patients carrying this variant. Muscle proteomics on three biopsies with other different GNEM genotypes unraveled 176 proteins (161 increased and 15 decreased) commonly affected in GNE patient-derived muscle. This defined catalogue of dysregulated proteins served to confirm the pathogenicity of the novel missense variant – in comparison to further missense variants with well-known pathogenicity – by immunostaining of paradigmatic proteins serving as tissue disease markers. Serum profiling enabled the definition of two proteins (serglycin and periostin) significantly decreased in patients. Pathophysiological relevance of altered periostin was confirmed by immunostaining on muscle biopsies showing increase in fibrotic scars. Our combined clinical, genetic and histology data extend the current genetic landscape of GNE myopathy by introducing a variant of early-onset and proximal muscle vulnerability. Muscle proteomics enabled a defined catalogue of tissue markers holding the potential to evaluate the pathogenicity of novel variants as exemplified on p.(Val569Leu) mutant muscle. Studies on serum derived from GNEM patients led to the identification of two novel blood biomarkers, serglycin and periostin, whereby an impact of periostin in fibrotic remodeling of muscle was demonstrated thus underlying the pathophysiological relevance. [ABSTRACT FROM AUTHOR]

TIA1/SQSTM1 myopathy is one of the few myopathies with a true digenic inheritance. Our goal was to define the phenotype presentation of the disease, genotype-phenotype correlations, and to study the prevalence of the TIA1 -N357S variant in distal myopathy. We describe four new adult male patients carrying the TIA1 -N357S and SQSTM1 -P392L variant and review the literature to include 20 additional cases. We reviewed the results of the distal myopathy gene panels of Pitié-Salpêtrière's hospital cohort for the TIA1 -N357S variant. Twenty-four patients (75% males) were included, with late-onset (52,6±10,1years), mainly asymmetric, distal ankle and hand finger extension weakness (75%), mild CK elevation (82.4%) and EMG myopathic changes. Two of the four French patients also had a sensorimotor axonal polyneuropathy and an additional one had neurogenic features in tibialis anterior biopsy. Most commonly, muscle histopathology showed rimmed vacuoles (44.4%), myofibrillar disorganization (16.7%) or both (38.9%), with P62/TDP43 aggregates. The TIA1 -N357S variant was present in all patients and the SQSTM1-P392L was the most frequent (68%) of the four reported SQSTM1 variants. The TIA1 -N357S variant was carried by 11/414=2.7% of distal myopathy patients and two had an alternative diagnosis (TTN and MYH7) with atypical phenotypes. TIA1/SQSTM1 myopathy has a homogenous and characteristic phenotype reinforcing the pathogenicity of its digenic variants. Furthermore, sensorimotor axonal polyneuropathy may be an additional feature of the disease. Finally, we confirm an increased burden of the TIA1 -N357S variant in distal myopathy patients which could act as a genetic modifier. [ABSTRACT FROM AUTHOR]

Colchicine and hydroxycloroquine are supposed to drive their toxic effect according to different pathogenic mechanisms that lead to autophagy impairment. The aim of this study is to investigate the role of human leukocyte antigen (HLA) class I molecules and membrane attack complex (MAC) in toxic autophagic vacuolar myopathies. Three patients presenting with neuromuscular symptoms were referred to the Neuromuscular Morphology Unit of the Myology Institute in Paris for open muscle biopsy. Muscle biopsy specimens obtained from each patient were studied using standard histoenzymatic techniques. Immunolabeling was performed to evaluate the expression of major histocompatibility complex class I and II (MHC-I, MCH-II), P62, LC3 and the complement component C5b9. Patients 1 and 2 were treated for 10 and 3 years with HCQ for Sjogren's disease and Lupus respectively. Patient 3 received colchicine for 7 days for suspected perycarditis. The main histological finding was the presence of a vacuolar autophagic myopathy without inflammation or necrosis. In all patients, immunolabeling with antibodies against MHC-I demonstrated generalised sarcolemmal and sarcoplasmic positivity. C5b9 showed either a punctate or a diffuse sarcolemmal positivity. Punctate cytoplasmic p62 and LC3 positivity was identified. Colchicine and HCG usually have immunomodulatory effects, so overexpression of the MCH-I remains incompletely understood but probably reflects the increased autophagic activity. The accumulation of autophagic substrates, including p62 and LC3, may be the consequence not only of an impairment of the degradation process but also of an enhanced transcription of the corresponding genes. Immunohistochemistry for MCH-I, C5b9, LC3 and p62 are useful markers for toxic autophagic vacuolar myopathies, yet further studies are needed to explore the molecular pathways involved. [ABSTRACT FROM AUTHOR]

X-linked myopathy with excessive autophagy (XMEA) linked to the VMA21 gene leads to autophagy failure with progressive vacuolation and atrophy of skeletal muscles. Current knowledge of this rare disease is limited. Our objective was to define the clinical, radiological and natural history of XMEA. We conducted a retrospective study collecting clinical, genetic, muscle imaging and biopsy data of XMEA patients followed in France and reviewed the literature for additional cases. Eighteen males had genetically confirmed VMA21 -linked XMEA in France, in 94.4% of patients due to splicing variants. Mean age at disease onset was 9.4±9.9 (range 1-40) years. In 14/18 patients (77.8%) onset occurred during childhood (<15 years), however in four patients the disease started in adulthood. Patients had anterior and medial compartment thigh muscle weakness, distal contractures (56.3%), elevated CK levels (1287.9±757.8 U/l) and autophagic vacuoles with sarcolemmal features on muscle histopathology. Muscle MRI (n=10) showed a characteristic pattern of lower limb muscle involvement. On follow-up, mean change of functional outcomes was 0.5±1.2 points for Brooke and 2.2±2.5 points for Vignos score, 7/16 patients (43.8%) needed a walking aid and 3/16 (18.8%) were wheelchair-bound. The variant c.164-7T>G was associated with a later onset of symptoms and milder phenotype. Respiratory insufficiency was common (57.1%) but cardiac involvement rare (12.5%). This is the largest study of XMEA disease. Patients show a variable age of onset, but a characteristic clinical, histopathological and muscle imaging presentation, guiding the diagnosis. Although slowly, motor disability progresses with time, and we show that respiratory insufficiency is a feature of the disease. Relevant genotype-phenotype correlations like the presence of the c.164-7T>G variant will help design future clinical trials. [ABSTRACT FROM AUTHOR]

MYH2 gene encodes the myosin heavy chain (MyHC)-IIA isoform expressed in muscle fast type 2A fibers. First described in 1998, the clinical and histological picture of MYH2 -related myopathy is still expanding. Our aim is to provide a case series of unreported patients and to summarize the main histopathological features and associated mutations. Five patients carrying MYH2 mutations were included. The histoenzymatic, immune and electron microscopy data were correlated with the clinical and genetic data. The age of disease onset ranged from childhood to 50 years old. The main clinical aspects were proximal limbs weakness, associated with ophthalmoparesis or ptosis in three cases. Two mutations were inherited in an autosomal dominant (AD) manner. All mutations had not been previously reported in literature except for heterozygous AD variant, c.5673+1G>C. Although the histopathological findings are heterogeneous, the most prevalent features were the predominance of type 1 fibres and the relative scarcity of type 2A fibres. Only one patient had marked disorganization of the intermyofibrillar network with a multi-core appearance. Our patients' histology reflects some of the previously described pathological changes and the individual variability of these changes. Type 1 fibre predominance associated with type 2 A fibre scarcity or atrophy were the most common findings. Rimmed vacuoles were absent in all cases, although they were once considered as a histological hallmark of AD- MYH2 myopathy. MyHC-IIa residual expression seems to influence the severity of the clinical phenotype regardless of the pattern of inheritance. MYH2 defect should be considered in the suspicion of congenital myopathy even in the absence of ocular involvement. Among the various histopathological patterns, the reduction or absence of type IIA fibres is the main diagnostic clue. [ABSTRACT FROM AUTHOR]

The heterogeneous disease progression in FSHD makes assessing treatment response in clinical trials challenging. Quantitative whole-body MRI has been recognized as a promising technique to address these challenges, but there are limited data from its use in natural history studies. The overall aim of the CTRN FSHD France study (NCT03458832) is to validate new outcome measures, define minimal clinically important change, and establish FSHD characteristics useful for determining clinical trial eligibility criteria. Up to 70 ambulatory FSHD1 patients with symptomatic limb weakness aged 18-75 will be included and followed for 24 months. In addition to whole-body MRI, the study will also assess muscle strength and function, as well as several patient-reported outcome measures. 68 patients successfully completed the baseline analysis, including MRI. The median (min, max) age was 50 (21, 75) years, with CSS 6 (1, 9) and 6 (2, 10) D4Z4-repeats. The muscle fat fraction (MFF) was 7% (1, 91), 21% (2, 96), 6% (1, 87), and 31% (2, 100) in the arms, legs, rotator cuffs, and torso, respectively. We have successfully implemented quantitative whole-body MRI in a natural history study of a FSHD cohort with baseline characteristics resembling what can be expected in clinical trials. Initial analysis of disease progression after 12 months is expected to be available this fall. [ABSTRACT FROM AUTHOR]

Valosin-containing protein (VCP) disease is an adult autosomal dominant multisystem proteinopathy (MSP) with a heterogeneous phenotype including myopathy, Paget's disease of bone, fronto temporal dementia, motor neuron disease and peripheral neuropathy. We describe the muscle biopsy features of 72 patients enrolled in the VCP International Multicentre Study. Muscle biopsies were retrospectively reviewed by experts in muscle pathology at each centre following the recommendation of the "Common Data Elements for Muscle Biopsy Reporting" publication. Experts entered relevant data into a database that was used for the overall biopsy analysis. Representative images from each biopsy were also collected. The mean age at muscle biopsy was 53.0 SD 11 years (SD, standard deviation) and the mean time between first symptom and biopsy was 7.0 SD 5.0 years. Fifty percent of the biopsies had a myopathic pattern while 29.2% showed combined myopathic and neurogenic changes. The most frequent findings were the presence of atrophic fibres, 98.6% (involving both fibre types in the 54.9%); myophagocytosis, 80.6%; rimmed vacuoles, 80.6%; areas of healthy tissue mixed with extensive areas of fat replacement, fibrosis and/or necrosis, 62.5%; fibre hypertrophy, 57.7% and fibre grouping, 23.6%. Only 16.7% of the samples showed focal endomysial inflammatory infiltrates. Protein aggregates were reported in 62.0% of the patients of which p-62 was identified in 54.4% and VCP in 29.5%. No significant differences were identified in the biopsy findings among the four most frequent mutations in the cohort and among the clinical phenotypes (myopathy, motor neuron, and others). This preliminary analysis confirms that muscle biopsies of patients with VCP-MSP depict a myopathic or mixed pattern with rimmed vacuoles, p-62 and VCP immunoreactive inclusions. The myopathologic findings in VCP-MSP are highly similar and consistent irrespective of the clinical phenotype. However, some biopsies might not show rimmed vacuoles, which increases the challenge in the diagnosis of VCP-MSP. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is defined as a rapid breakdown of muscle cells, leading to the release of its proteins and enzymes causing elevation of serum creatine kinase and myoglobinuria. The muscle biopsy is an important method of assessment of these patients, as it can point to the underlying cause of the process and aid in the investigation. A retrospective study was conducted at the Institute of Myology of the Pitié-Salpêtrière Hospital, between October 1, 1996 and October 1, 2022. The study included patients that underwent muscle biopsy and with clinical presentation compatible as Rhabdomyolysis. In total, 75 patients matched the criteria. The medical records were reviewed to collected demographic data, time from last episode of rhabdomyolysis to biopsy, CPK levels and muscle biopsy data. In the population studied, we have found that 84% (63) of the patients were male. The median age was 28.16 years. The median time between the presentation and biopsy was 11.15 months and the time was unknown in 18.6% (14). Muscle biopsy was normal in 26% (20). The most frequent alteration was increased lipid content in 45,3% (34), followed by nuclei internalization, present in 44% (33). Immunohistochemistry was performed in 54,6% (41) patients. Inflammatory markers were found in 9,7% (4) and absent Dysferline in 2,4% (1). Electron Microscopy was realized in 5.3% (4) patients and there was a moderate accumulation of lipids in two samples, and accumulation of glycogen in one patient. Genetic testing was performed in 22 cases, and it was diagnostic in 68.1% (15). A diagnosis of inflammatory myopathy was done in 6.6% (5). The most frequent genetic diagnostics were RIR1 variant. The muscle biopsy with histoenzymology and immunohistochemistry is an important tool for the analysis and diagnosis of patients presenting with rhabdomyolyses. Mutations in the gene RYR1 were the most common cause of rhabdomyolysis and should be systematically searched. [ABSTRACT FROM AUTHOR]

Data relevant to the diagnosis, care and treatment of patients with neuromuscular disorders are kept in different data systems and their joint (re)use is prevented by prevailing silo mentalities. The adoption of FAIR (Findable, Accessible, Interoperable and Reusable) data practices by all stakeholders who build, manage, and own these data systems, can overcome this. We present a proof-of-concept demonstrating how five different rare disease registries for neuromuscular disorders achieved a FAIR status and are interoperable. After a joint effort from a number of partners building the EURO-NMD registry hub for the European Reference Network on neuromuscular disorders, it is now possible to conduct the same queries related to neuromuscular diseases in multiple, independent registries simultaneously, without exposing sensitive patient details. Example queries include "How many patients are in the registry with a certain diagnosis, age range and gender?" or "What is the average time between the earliest onset of symptoms and a final diagnosis?". The registries that participated in this proof-of-concept are: CRAMP (Computer Registry of All Myopathies and Polyneuropathies, Netherlands), DDP (the patient-led Duchenne Data Platform), DM-Scope (National registry for Myotonic Dystrophies, France), SMArtCARE (Clinical registry for Spinal Muscular Atrophy, Germany), and the EURO-NMD registry. The solution is based on technology that connects web addresses to database queries and is available from: https://github.com/markwilkinson/Duchenne-daru. The next steps are to onboard other neuromuscular registries and to increase the number and sophistication of the publicly available queries, all reviewed for security by both technical and rare disease experts. The EURO-NMD registry received funding from the European Union under grant no. 947598. [ABSTRACT FROM AUTHOR]

Filamin-A-interacting protein 1 (FILIP1) is a structural protein that is involved in neuronal and muscle function and integrity and interacts with FLNa and FLNc. Pathogenic variants in filamin-encoding genes have been linked to neurological disorders (FLNA) and muscle diseases characterized by myofibrillar perturbations (FLNC), but human diseases associated with FILIP1 variants have not yet been described. Here, we report on five patients from four unrelated consanguineous families with homozygous FILIP1 variants (two nonsense and two missense). Functional studies indicated altered stability of the FILIP1 protein carrying the p.[Pro1133Leu] variant. Patients exhibit a broad spectrum of neurological symptoms including brain malformations, neurodevelopmental delay, muscle weakness and pathology, and dysmorphic features. Electron and immunofluorescence microscopy on the muscle biopsy derived from the patient harbouring the homozygous p.[Pro1133Leu] missense variant revealed core-like zones of myofibrillar disintegration, autophagic vacuoles and accumulation of FLNc. Proteomic studies on the fibroblasts derived from the same patient showed dysregulation of a variety of proteins including FLNc and alpha-B-crystallin, a finding (confirmed by immunofluorescence) which is in line with the manifestation of symptoms associated with the syndromic phenotype of FILIP1opathy. The combined findings of this study show that the loss of functional FILIP1 leads to a recessive disorder characterized by neurological and muscular manifestations as well as dysmorphic features accompanied by perturbed proteostasis and myopathology. [ABSTRACT FROM AUTHOR]

Skeletal muscle structure can differ depending on the specie or type of muscle. For example, deltoid, diaphragm, tibialis anterior and gastrocnemius muscles have different morphological features (Burdi et al, 2009; Rafael et al, 1994; Piñol-Jurado et al, 2018). In addition, several myopathies affect only a subset of skeletal muscles with no particular explanation (Jacques et al, 2019). Different types of histoenzymological techniques can be made on muscle biopsies, hematoxylin/eosin, modified gomori trichrome, adenosine triphosphatase to identify fiber types, or reduced NAD-tetrazolium reductase, cytochrome C oxidase and succinate dehydrogenase to evaluate enzymatic/mitochondria activity. Other techniques allow the detection of lipids, glycogen, fibrosis, satellite cells, vascularization etc... This large panel of assays identifies differences between muscles types or physiological and abnormal conditions. However, the knowledge to discern the differences between muscle types and pathological contexts remains restricted to a small subset of researchers and specialized physicians. We have thus created the Muscle Atlas containing more than 5 000 images of muscles from 85 different diseases, with different stainings. All data is fully anonymized and consent forms has been obtained from patients. Moreover, all human cases have a complete morphological and genetic characterization. From this, we developed a web application to digitize, format and explore multimodal patient data. It has a modular architecture, composed of four components to: (i) create a standard vocabulary for a domain (ii) digitize and format free-text data by mapping it to a set of standard terms, (iii) annotate images and perform image segmentation and (iv) generate an automatic visualization dashboard to provide insight on the data and perform automatic diagnosis suggestions. While the Muscle Atlas will foster research on skeletal muscle and facilitate physiopathological assessments, the platform will allow to digitize, format and explore patient data and process image and free-text data. As it relies on user-designed standard vocabulary, it is highly flexible to fit any domain of research and can be used as a patient registry for exploratory data analysis (EDA). The ultimate goal is to propose a diagnostic tool for neuromuscular diseases using images of biopsies, histopathological and clinical reports. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMSs) are heterogeneous genetic disorders that result from impaired signal transmission at the neuromuscular junction (NMJ). Congenital disorders of glycosylation (CDG) are a challenging group of diseases affecting different organs in particular the central nervous system and the skeletal muscle. Only recently CDG have been implicated in some forms of post-synaptic autosomal recessive CMS. The protein encoded by the DPAGT1 gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. Mutations in DPAGT1 were described in patients with CMS and tubular aggregates on muscle biopsy. We report a 16 year old young man, first child of a consanguineous family, who presented with walking difficultywith onset by the age of 3 year. The motor milestones were slightly delayed. There was speech difficulty which fluctuated during the day. On examination, he had generalized muscle weakness with proximal groups being more affected, excessive lordosis, waddling gait, and contractures of the Achilles tendons. There was no bulbar or extra-ocular muscle involvement. He had a mild intellectual disability with an IQ score of 50–55. Tensilon test was positive. Electromyography revealed decrementing response to repetitive nerve stimulation. He responded well to pyridostigmine, 3,4-diaminopyridine and salbutamol treatment. We carried out whole exome sequencing and identified a novel homozygous DPAGT1 mutation (c.509A>T). The non-synonymous change (p.Tyr170Phe) is predicted to be deleterious by in silico analysis and affects an aminoacid residue that is highly conserved across species. In conclusion we report a novel mutation on the DPAGT1 gene responsible for a form of “limb-girdle CMS”. Comparing with the previously reported cases this family has mental retardation as an unusual feature and a good response to a combined treatment with pyridostigmine and 3,4-diaminopyridine. [ABSTRACT FROM AUTHOR]

Myofibrillar myopathies (MFM) are a group of usually autosomal dominant inherited muscle disorders characterized by focal disintegration of myofibrils and by the formation of intramyoplasmic protein aggregates. Known diseases genes encode proteins that are located at or associated with the Z-disc. We extended our previous proteomic analysis in MFM to identify novel disease-relevant proteins that accumulate in aggregate areas and to search for subtype-specific proteomic profiles. We analyzed skeletal muscle samples from 72 MFM patients. Aggregate samples and intraindividual control samples (from normally looking muscle fibers) were collected from 10 μ m muscle sections by laser microdissection and analyzed by a label-free mass spectrometric approach for identification and relative quantification of proteins. We detected 4716 different proteins in the samples and 291 of these showed a statistically significant accumulation in aggregate samples with a ratio >1.5 compared to controls (mean ratio 4.5). Z-disc and Z-disc-associated proteins, especially desmin, filamin C and their binding partners, constituted the most abundant group of over-represented aggregate proteins followed by proteins involved in protein quality control and protein degradation, extracellular and sarcolemmal proteins, components of signaling pathways and proteins involved in actin dynamics and myofibrillar organization. Subgroup analysis revealed a characteristic basic pattern of aggregate composition but also significant differences regarding the accumulation ratio, order and proportion of individual proteins that enabled the definition of subtype-specific proteomic profiles. Our proteomic findings expand the knowledge about proteins and pathways that seem to be involved in the pathogenesis of MFM. The identification of specific proteomic profiles in different MFM subtypes can be useful in differential diagnosis of protein aggregation myopathies. [ABSTRACT FROM AUTHOR]