Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

External validation of the 2017 ACR/EULAR classification criteria for inflammatory myopathies in a Mexican cohort: Role of autoantibodies in the diagnosis and classification of patients with inflammatory myopathies / Validación externa de los criterios de clasificación de la ACR/EULAR de 2017 para miopatías inflamatorias en una cohorte mexicana. Papel de los anticuerpos en el diagnóstico y la clasificación de pacientes con miopatías inflamatorias

Objective: This retrospective study aimed to perform the first external validation of the ACR/EULAR classification criteria for inflammatory myopathy (IIM) in a Mexican dynamic cohort where the patients were evaluated with clinical and laboratory values. As secondary objectives, we presented the clinical characteristics of the patients and included antibodies other than anti Jo1 to evaluate their impact on our population. Methodology: This study included 70 patients with IIM and 70 patients with differential diagnoses of IIM, according to the absolute score of the classification criteria. We obtained sensitivity and specificity in the modality without biopsy, and as an exploratory analysis, we added other antibodies from the myositis extended panel. We analyzed the area under the curve (AUC) of three models: score without antibodies, with anti Jo1 and with any antibody. Results: The ACR/EULAR criteria showed increased specificity and at least similar sensitivity to that of the original cohort (85% sensitivity and 92% specificity), with a cohort point of >55%. When we classified patients into definite, probable, possible, and no IIM categories, by adding the extended myopathy panel, 6 of the 10 patients initially classified as “no IIM” changed their classification to “Probable IIM” and 4 to “Definite IIM”; of the 16 patients classified as “probable IIM,” 15 changed their classification to “Definite IIM.” Conclusion: Considering the limitations of this study, we concluded that the 2017 EULAR/ACR criteria for IIM classification are sensitive and specific for classifying patients with IIM in the Mexican population. Additionally, the addition of antibodies other than anti-Jo1 may improve performance in certain populations.(AU)

Objetivo: Este estudio retrospectivo tuvo como objetivo realizar la primera validación externa de los criterios de clasificación ACR/EULAR para miopatía inflamatoria (MII) en una cohorte dinámica de pacientes mexicanos que fueron evaluados en consulta y con muestras de laboratorio. Como objetivos secundarios presentamos las características clínicas de los pacientes e incluimos anticuerpos distintos al anti-Jo1 para evaluar su impacto en nuestra población. Metodología: Este estudio incluyó a 70 pacientes con MII y 70 pacientes con diagnóstico diferencial de MII, según la puntuación absoluta de los criterios de clasificación. Obtuvimos la sensibilidad y la especificidad en la modalidad sin biopsia, y como análisis exploratorio añadimos otros anticuerpos del panel extendido de miositis. Analizamos el área bajo la curva (AUC) de tres modelos: puntuación sin anticuerpos, con anti-Jo1 y con cualquier otro anticuerpo. Resultados: Los criterios ACR/EULAR mostraron una mayor especificidad y una sensibilidad, al menos similar a la de la cohorte original (85% de sensibilidad y 92% de especificidad), con un punto de cohorte de >55%. Cuando clasificamos a los pacientes en las categorías de definitiva, probable, posible y sin MII, al agregar el panel ampliado de miopatía, 6 de los 10 pacientes clasificados inicialmente como «Sin MII» cambiaron su clasificación a «Probable MII» y 4 a «MII Definitiva»; de los 16 pacientes clasificados como «Probable MII», 15 cambiaron su clasificación a «MII Definitiva». Conclusión: Considerando las limitaciones de este estudio, concluimos que los criterios de 2017 de la EULAR/ACR para la clasificación de la MII son sensibles y específicos para clasificar a los pacientes con MII en la población mexicana. Además, la adición de anticuerpos que no sean anti-Jo1 puede mejorar la estadificación en ciertas poblaciones.(AU)

Wooden breast myopathy on broiler breast fillets affects quality and consumer preference.

INTRODUCTION: The emergence of myopathies such as wooden breast in the poultry industry generally associated with the fast development of the breast muscle of broilers has provided changes in the morphological structure of muscle tissues, as well as problems of meat qualitative attributes. The aim of this study was to evaluate physical, chemical, qualitative, and sensorial attributes of broiler fillets associated with severity levels of wooden breast (WB) myopathy in a poultry slaughterhouse. MATERIALS AND METHODS: Three hundred fillets in a poultry slaughterhouse were classified into three severity levels: normal (100 samples), moderate (100 samples), and severe (100 samples). RESULTS: After identification, classification, and description of changes, fillets with a severe WB level presented higher levels of red (a*), yellow (b*), and final pH. The lowest shear force and the highest myofibrillar fragmentation index were observed in fillets with a severe level when compared with normal fillets. The collagen content increased according to severity level. Tasters better evidenced the characteristic taste of chicken meat when tasting fillets with a severe WB level when compared with normal and moderate fillets. The succulence and preference of the Brazilian testers increased according to the severity level of the myopathy. CONCLUSION: In general, fillets with moderate and severe WB myopathy were affected not only in appearance but also in qualitative, physical, chemical, and sensory characteristics.

[Non-inflammatory muscle pain]. / Nichtentzündliche Muskelschmerzen.

Muscle pain as a common symptom in daily practice frequently occurs as a non-specific accompanying symptom in multiple internal and neurological diseases. Primarily inflammatory or autoimmune muscular diseases are causing muscle pain. However, a number of non-inflammatory causes of pain can also be considered for differential diagnosis. These are presented in this article. In principle, a distinction must be made between focal and diffuse muscle pain. As an invasive diagnostic procedure, a muscle biopsy should only be performed as the last step in the diagnostic alogorithm. If diffuse muscle pain is only associated with slight muscle weakness or is completely absent, there is usually a primary rheumatic cause. Statins (HMG-CoA reductase inhibitors) can lead to rhabdomyolysis, muscle fiber atrophy and muscle necrosis by damaging the muscle fiber membrane. Myotonias are autosomal dominant or autosomal recessive inherited disorders of muscle function. The genetic defect leads to pronounced muscle stiffness. The cause of metabolic myopathies can be disorders of the carbohydrate, fat or purine metabolism. Fibromyalgia syndrome (FMS) is a non-inflammatory disease and, according to the current knowledge, recognized as the result of an exposure to physical, biological and psychosocial factors (biopsychological disease model). To help diagnosing FMS, pain regions and core symptoms (fatigue, sleep disturbances) can be detected using questionnaires (Widespread Pain Index [WPI] and Symptom Severity Scale [SSS]).

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies.

BACKGROUND: Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies. OBJECTIVE: To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants. METHODS: We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort. RESULTS: We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified. CONCLUSIONS: We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.

The MLG-R muscle injury classification for hamstrings. Examples and guidelines for its use / Clasificación de lesiones musculares MLG-R para los isquiotibiales. Ejemplos y directrices de uso

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18F-FDG PET/CT versus conventional investigations for cancer screening in autoimmune inflammatory myopathy in the era of novel myopathy classifications.

BACKGROUND: To compare the performance of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) and conventional tests for cancer screening in autoimmune inflammatory myopathy (AIM) patients. PATIENTS AND METHODS: We carried out a retrospective cohort study of AIM patients from one academic center in Montreal, Canada, classified using myositis-specific antibodies, who underwent F-FDG PET/CT between April 2005 and February 2018 and were followed up on average 3.5±2.4 years. Patients were excluded if follow-up was insufficient, AIM diagnosis was indeterminate, and/or malignancy was diagnosed before an F-FDG PET/CT scan. Demographic/clinical data, F-FDG PET/CT results, and available conventional screening tests results were retrieved from electronic and paper medical records. RESULTS: 100 F-FDG PET/CT studies in 63 unique patients [31/63 dermatomyositis (DM), 25/63 overlap myositis, 1/63 inclusion body myositis, 1/63 polymyositis, 1/63 orbital myositis and 4/63 unspecified myositis] were evaluated. Three patients, all classified as DM, were diagnosed with cancer during follow-up with conventional cancer screening tests: breast cancer detected by mammography; squamous cell carcinoma of the skin detected by physical examination; and multiple myeloma detected by blood work. F-FDG PET/CT did not detect any malignancy and led to more additional biopsies than conventional screening (8 vs. 5). CONCLUSION: F-FDG PET/CT does not appear to be useful in cancer screening for AIM patients compared with conventional screening and carries potential harms associated with follow-up investigations. The risk of cancer in AIM differs by myositis-specific antibodies-defined subsets and cancer screening is likely to be indicated only in high-risk patients, particularly DM. These results, replicated in larger, multicentered studies, may carry significant consequences for optimal management of AIM and health resource utilization.

Common Running Injuries: Evaluation and Management.

Running is a common form of exercise but predisposes athletes to several running-related injuries. Most running injuries are due to overuse and respond to conservative treatment. Tendinopathies in the patellar, Achilles, and hamstring tendons are common, and are primarily treated with eccentric exercise. Iliotibial band syndrome and patellofemoral pain syndrome are less common than patellar tendinopathy and are treated by strengthening exercises for the core and legs in addition to flexibility exercises. Acute hamstring strains and medial tibial stress syndrome require a period of relative rest, followed by stretching and graded return to activity. Tibial stress fractures require an extended period of relative rest, followed by a more gradual return to activity. Early mobilization improves recovery from ankle sprains, and exercise therapy and functional bracing while running for six to 12 months prevents reinjury. Plantar fasciopathy (plantar fasciitis) can be significantly improved with stretching, heel raises, and orthoses that provide arch support.

History and current difficulties in classifying inherited myopathies and muscular dystrophies.

The wide spectrum of hereditary muscular disorders leads to unavoidable difficulties in their classification, even for specialists. For this reason, new proposals are required that would ultimately replace our current rather complex classifications by a simpler structure. Our proposal will be limited to dystrophic and non-dystrophic myopathies (excluding metabolic disorders, mitochondriopathies, and channelopathies) for which similar proposals would also be relevant. Various genes (encoding structural proteins associated with the sarcolemma, nuclear membrane proteins, and proteins involved in myofiber metabolism have now been sequenced and mutations ascribed to specific forms of inherited muscular disorders. Based on our observations and our recent proposals in other neurogenetic conditions and informal discussions with specialists of neuromuscular disorders, the prerequisite for a simple and sound classification for inherited muscular disorders should encompass the clinical and pathological phenotypes (described in a simple and clear manner), the mode of inheritance, and the mutated gene. We think that the denomination of the different subtypes could be simplified considerably, although any new proposal of classification of muscular disorders will need to be discussed in the neurological and genetic communities.

Muscle Injuries in Sports: A New Evidence-Informed and Expert Consensus-Based Classification with Clinical Application.

Muscle injuries are among the most common injuries in sport and continue to be a major concern because of training and competition time loss, challenging decision making regarding treatment and return to sport, and a relatively high recurrence rate. An adequate classification of muscle injury is essential for a full understanding of the injury and to optimize its management and return-to-play process. The ongoing failure to establish a classification system with broad acceptance has resulted from factors such as limited clinical applicability, and the inclusion of subjective findings and ambiguous terminology. The purpose of this article was to describe a classification system for muscle injuries with easy clinical application, adequate grouping of injuries with similar functional impairment, and potential prognostic value. This evidence-informed and expert consensus-based classification system for muscle injuries is based on a four-letter initialism system: MLG-R, respectively referring to the mechanism of injury (M), location of injury (L), grading of severity (G), and number of muscle re-injuries (R). The goal of the classification is to enhance communication between healthcare and sports-related professionals and facilitate rehabilitation and return-to-play decision making.

Coding in Muscle Disease.

Accurate coding is critically important for clinical practice and research. Ongoing changes to diagnostic and billing codes require the clinician to stay abreast of coding updates. Payment for health care services, data sets for health services research, and reporting for medical quality improvement all require accurate administrative coding. This article provides an overview of administrative coding for patients with muscle disease and includes a case-based review of diagnostic and Evaluation and Management (E/M) coding principles in patients with myopathy. Procedural coding for electrodiagnostic studies and neuromuscular ultrasound is also reviewed.

Classification of involuntary movements in dogs: Tremors and twitches.

This review focuses on important new findings in the field of involuntary movements (IM) in dogs and illustrates the importance of developing a clear classification tool for diagnosing tremor and twitches. Developments over the last decade have changed our understanding of IM and highlight several caveats in the current tremor classification. Given the ambiguous association between tremor phenomenology and tremor aetiology, a more cautious definition of tremors based on clinical assessment is required. An algorithm for the characterisation of tremors is presented herein. The classification of tremors is based on the distinction between tremors that occur at rest and tremors that are action-related; tremors associated with action are divided into postural or kinetic. Controversial issues are outlined and thus reflect the open questions that are yet to be answered from an evidence base of peer-reviewed published literature. Peripheral nerve hyper-excitability (PNH; cramps and twitches) may manifest as fasciculations, myokymia, neuromyotonia, cramps, tetany and tetanus. It is anticipated that as we learn more about the aetiology and pathogenesis of IMs, future revisions to the classification will be needed. It is therefore the intent of this work to stimulate discussions and thus contribute to the development of IM research.

The diagnostic value of biexponential apparent diffusion coefficients in myopathy.

To investigate the performance of a biexponential signal decay model using DWI in myopathies and to differentiate Polymyositis (PM)/Dermatomyositis (DM), Glycogen Storage Diseases (GSDs) and Muscular Dystrophies (MDs) utilizing diffusion-weighted imaging. 11 healthy volunteers (control group) and 46 patients with myopathy were enrolled in the retrospective study. 27 of 46 patients had PM/DM, 7 patients GSDs and 12 patients MDs. After conventional MR sequences, diffusion weighted imaging with a b-factor ranging from 0 to 1200 s/mm(2) was performed on both thighs. The intra-muscular signal-to-noise ratios (SNRs) on multiple-b DWI images were measured for 7 different muscles and compared among the different groups. The median T2 signal intensity and biexponential apparent diffusion coefficients (ADC), including standard ADC, fast ADC, and slow ADC values, were compared among the different groups. The intra-muscular SNRs were statistically significantly different depending on the b value, and also found among the 4 groups (p < 0.05). The median T2 signal intensity of the normal muscles in control group was statistically significantly lower than that of edematous muscles in the PM/DM, GSDs and MDs groups (p = 0.000), while there were no statistically significant differences among the PM/DM, GSDs, and MDs groups (p > 0.05). The median standard ADC value of the edematous muscles in GSDs was statistically significantly lower than that of normal muscles in the control group (p = 0.000) and the median ADC value of the edematous muscles in PM/DM patients was statistically significantly greater than that of the GSDs (p = 0.000) and MDs groups (p = 0.005). The median slow ADC value of the edematous muscles in MDs patients and PM/DM patients was statistically significantly greater than that of GSDs patients (p < 0.05). Intra-muscular SNR decay curves and biexponential ADC parameters are useful in distinguishing among PM/DM, GSDs, and MDs.

Axial myopathy: an overlooked feature of muscle diseases.

Classically, myopathies are categorized according to limb or cranial nerve muscle affection, but with the growing use of magnetic resonance imaging it has become evident that many well-known myopathies have significant involvement of the axial musculature. New disease entities with selective axial muscle involvement have also been described recently, but overall the axial myopathy is unexplored. We performed a PubMed search using the search terms 'myopathy', 'paraspinal', 'axial' and 'erector'. Axial myopathy was defined as involvement of paraspinal musculature. We found evidence of axial musculature involvement in the majority of myopathies in which paraspinal musculature was examined. Even in diseases named after a certain pattern of non-axial muscle affection, such as facioscapulohumeral and limb girdle muscular dystrophies, affection of the axial musculature was often severe and early, compared to other muscle groups. Very sparse literature evaluating the validity of clinical assessment methods, electromyography, muscle biopsy and magnetic resonance imaging was identified and reference material is generally missing. This article provides an overview of the present knowledge on axial myopathy with the aim to increase awareness and spur interest among clinicians and researchers in the field.

Myotonic Disorders and Channelopathies.

Myotonic dystrophies and channelopathies are rare but important causes of muscle diseases which may present with myotonia, episodic attacks of weakness, fixed muscle weakness, and atrophy or their combination. Here, the authors provide an overview of these disorders and describe their clinical and pathophysiological features, diagnostic methods, and management.

British athletics muscle injury classification: a reliability study for a new grading system.

AIM: To implement and validate the newly proposed British athletics muscle injury classification in the assessment of hamstring injuries in track and field athletes and to analyse the nature and frequency of the discrepancies. MATERIALS AND METHODS: This was a retrospective study analysing hamstring injuries in elite British athletes using the proposed classification system. Classification of 65 hamstring injuries in 45 high-level athletes by two radiologists at two time points 4 months apart to determine interrater variability, intrarater variability, and feasibility of the classification system was undertaken. RESULTS: Interrater Kappa values of 0.80 (95% confidence interval [CI]: 0.67-0.92; p<0.0001) for Round 1 and 0.88 (95% CI: 0.76-1.00; p<0.0001) for Round 2 of the review were observed. Percentages of agreement were 85% for Round 1 and 91% for Round 2. The intrarater Kappa value for the two reviewers were 0.76 (95% CI: 0.63-0.88; p<0.0001) and 0.65 (95% CI: 0.53-0.76; p<0.0001) and the average was 0.71 suggesting substantial overall agreement. The percentages of agreement were 82% and 72%, respectively. CONCLUSIONS: This classification system is straightforward to use and produces both reproducible and consistent results based on interrater and intrarater Kappa values with at least substantial agreement in all groups. Further work is ongoing to investigate whether individual grades within this classification system provide prognostic information and could guide clinical management.