Effect of arginine, glycine + serine concentrations, and guanidinoacetic acid supplementation in vegetable-based diets for chickens.

The study investigated guanidinoacetic acid (GAA) supplementation with varying dietary digestible arginine (Arg) and glycine+serine (Gly+Ser) concentrations in the starter phase, exploring respective carry-over effects on growth performance, blood chemistry, incidence of pectoral myopathies and proximate composition in broilers. A total of 2,800 one-day-old male broiler chicks were distributed in a central composite design with 2 factors and double experimental mesh, represented by supplementation or omission of 0.6 g per kg of GAA, with a central point represented by 107% of Arg and 147% of Gly+Ser, 4 factorial points (combinations of Arg/Gly+Ser concentrations: 96.4/132.5%; 117.6/132.5%; 96.4/161.5%, and 117.6/132.5%), and 4 axial points (combinations of axial points estimated for Arg and Gly+Ser, with the central points of 92/147%; 122/147%; 107/126.5, and 107/167.5%), totaling 18 treatments, 4 repetitions to factorial and axial points, 24 replicates to the central point, and 25 birds per pen. Feed conversion ratio (FCR) from d 1 to 10 had a linear response (P = 0.009) for the decreasing Arg content and a quadratic response (P = 0.047) for Gly+Ser concentrations. Broilers supplemented GAA had lower FCR compared with nonsupplemented groups from d 1 to 10 (P = 0.048) and d 1 to 42 (P = 0.026). Aspartate aminotransferase (AST) exhibited increasing and decreasing linear effects as a function of Arg (P = 0.008) and Gly+Ser (P = 0.020) concentrations, respectively. Guanidinoacetic acid decreased serum AST (P = 0.028). Guanidinoacetic acid reduced moderate + severe (P = 0.039) and mild (P = 0.015) Wooden Breast scores. The occurrence of normal White Striping increased (P = 0.002), while severe score was reduced (P = 0.029) with GAA supplementation. In conclusion, increased digestible Arg:Lys and 14% and 6% above the recommendations (107% and 147%), respectively, provided improved FCR during the starter phase. Dietary GAA supplementation (0.6 g per kg) improved FCR, reduced severity of breast myopathies and appears to have reduced muscle damage in broilers fed plant-based diets.

Heart Disease in Mothers of Children with Duchenne Muscular Dystrophy.

Female carriers of Duchenne Muscular Dystrophy (DMD) carry a heterozygous pathogenic variant in the dystrophin gene and can transmit pathogenic variants to their offspring. DMD is an X-linked recessive disease that affects up to 19.8 in every 100,000 male births. Those carriers with symptoms can be referred to as women with dystrophinopathy. Even among asymptomatic carriers, cardiac involvement can be verified in between 2.5% and 75% through echocardiography. The most commonly affected wall of the left ventricle is the inferolateral, with myocardial fibrosis detected by cardiac nuclear resonance. Therefore, screening is recommended for these women carriers due to the risk of cardiomyopathy. There is a lack of longitudinal studies on the evolution of these carriers. In this article, data on clinical presentation, cardiac assessment for female patients with dystrophinopathy and DMD carriers, and approaches for these patients are discussed.

Clinical and molecular characterization of limb-girdle muscular dystrophy 2G/R7 in a large cohort of Brazilian patients.

Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

Oculopharyngeal Muscular Dystrophy: A Case Report From Puerto Rico.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset inherited skeletal myopathy. The diagnosis is based on a clinical presentation of blepharoptosis, dysphagia, and a positive family history of the disease in patients past 40 years of age. A 57-year-old male patient presented with ptosis without lid crease, adult-onset dysphagia, and bilateral pseudophakia. The patient underwent ptosis repair of upper eyelids via frontalis slings with silicone rods. His mother was subsequently found to have ptosis, dry eyes, and anorexia due to dysphagia, thus suggesting a probable family history. Based on the comprehensive ophthalmic evaluation, and based on his ptosis, dysphagia, and family history, the patient was diagnosed with OPMD.

Short-term treatment with Uncaria tomentosa aggravates the injury phenotype in mdx mice

INTRODUCTION: Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) or UT is a medicinal plant with antiviral, antimutagenic, anti-inflammatory and antioxidant properties. Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene; this deficiency leads to sarcolemma instability, inflammation, muscle degeneration and fibrosis. OBJECTIVE: Considering the importance of inflammation to dystrophy progression and the anti-inflammatory activity of UT, in the present study we evaluated whether oral administration of UT extract would ameliorate dystrophy in the mdx mice, a DMD model. METHODS: Eight-week-old male mdx mice were submitted to 200 mg/kg body weight daily UT oral administration for 6 weeks. General histopathology was analysed, and muscle tumor necrosis factor α, transforming growth factor-ß, myostatin and osteopontin transcript levels were assessed. The ability of mice to sustain limb tension to oppose their gravitational force was measured. Data were analysed with the unpaired Student's t-test. RESULTS: Morphologically, both untreated and UT-treated animals exhibited internalised nuclei, increased endomysial connective tissue and variations in muscle fibre diameters. Body weight and muscle strength were significantly reduced in the UT-treated animals. Blood creatine kinase was higher in UT-treated compared to untreated animals. In tibialis anterior, myostatin, transcript was more highly expressed in the UT-treated while in the diaphragm muscle, transforming growth factor-ß transcripts were less expressed in the UT-treated. CONCLUSION: While previous studies identified anti-inflammatory, antiproliferative and anticarcinogenic UT effects, the extract indicates worsening of dystrophic muscles phenotype after short-term treatment in mdx mice.

Genetic profile of Brazilian patients with LAMA2-related dystrophies.

LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.

Expression of Dystrophin Dp71 Splice Variants Is Temporally Regulated During Rodent Brain Development.

Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.

Effects of a Ketogenic Diet on the Assessment of Biochemical and Clinical Parameters in Duchenne Muscular Dystrophy: A Preclinical Investigation.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive skeletal muscle degeneration and systemic effects, including the central nervous system (CNS). This study aimed to assess the impact of a 14-day ketogenic diet (DCet) on biochemical and clinical parameters in a DMD mouse model. Young adult mice (50 days old) were fed DCet, while control groups received a standard diet. On the 14th day, memory and behavior tests were conducted, followed by biochemical evaluations of oxidative stress, inflammatory biomarkers, body weight, feed intake, and brain-derived neurotrophic factor (BDNF) levels. mdx + DCet mice showed reduced mass (0.2 g ± 2.49) and improved memory retention (p < 0.05) compared to controls. Oxidative damage in muscle tissue and CNS decreased, along with a significant cytokine level reduction (p <0.05). The protocol led to an increase in hippocampal BDNF and mitochondrial respiratory complex activity in muscle tissue and the central nervous system (CNS), while also decreasing creatine kinase activity only in the striatum. Overall, a 14-day DCet showed protective effects by improving spatial learning and memory through reductions in oxidative stress and immune response, as well as increases in BDNF levels, consistent with our study's findings.

Quantitative ultrasonography reveals skeletal muscle abnormalities in carriers of DMD pathogenic variants.

INTRODUCTION/AIMS: Carriers of DMD pathogenic variants may become symptomatic and develop muscle-related manifestations. Despite that, few studies have attempted to characterize changes in the muscles of these carriers using imaging tools, particularly muscle ultrasound (MUS). The aim of this study was to compare lower limb MUS findings in carriers of DMD pathogenic variants (cDMD) vs healthy controls. METHODS: Twenty-eight women (15 cDMD and 13 controls) underwent clinical evaluation and MUS. We collected information about muscle-related symptoms and assessed muscle strength. MUS was performed by a single physician (blind to the genetic status of subjects). The following muscles were assessed: rectus femoris, sartorius, tibialis anterior, and medial gastrocnemius. For each site, we computed data on muscle thickness, cross-sectional area, sound attenuation index, and elastography. Between-group comparisons were assessed using nonparametric tests and p-values <.05 were deemed significant. RESULTS: None of the subjects had objective muscle weakness, but exercise intolerance/fatigue was reported by four cDMDs and only one control. Regarding MUS, sound attenuation indices were significantly higher among carriers for all muscles tested. Longitudinal and axial deep echo intensities for the rectus femoris and tibialis anterior were also higher in the cDMD group compared with controls. No significant between-group differences were noted for elastography values, muscle area, or mean echo intensities. DISCUSSION: cDMD have skeletal muscle abnormalities that can be detected using quantitative MUS. Further studies are needed to determine whether such abnormalities are related to muscle symptoms in these patients.

Co-Occurrence of Myotonic Dystrophy Type 1 and Limb-Girdle Muscular Dystrophy Type 2B: A Case Report.

Introduction: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease whose pattern of weakness is predominantly distal. Limb-girdle muscular dystrophy type 2B/R2-dysferlin-related (LGMD2B/R2) is another neuromuscular disease, which presents an autosomal recessive inheritance and is marked by proximal muscle weakness. Even if uncommon, comorbid inherited pathologies must be considered in cases of atypical presentations, especially in those with family history of consanguinity. Case Presentation: Herein, we report the unique case of a patient diagnosed with both DM1 and LGMD2B/R2: a 38-year-old woman in follow-up of DM1 in a neuromuscular disease service presenting prominent proximal weakness. The patient's parents were consanguineous, and creatine kinase levels were elevated. A multi-gene panel test was performed and revealed the diagnosis of LGMD2B/R2. Conclusion: Genetic diseases with atypical presentations should raise the possibility of a second disorder, prompting an appropriate investigation. Overlooking a second diagnosis can implicate in not offering adequate genetic counseling, support, or specific treatment.

Empowerment of genetic information by women at-risk of being carriers of Duchenne and Becker muscular dystrophies.

The emergence of therapies acting on specific molecular targets for Duchenne and Becker muscular dystrophies (DBMD) led to expanded access of diagnostic DMD analysis. However, it is unclear how much of these advances have also improved healthcare and access to genetic testing for women at-risk of being carriers. This study evaluates the process of genetic counseling and empowerment of genetic information by women from DBMD families. We carried out a cross-sectional study between February and June 2022 in Brazil. The online survey with items regarding sociodemographic data; family history; access to health services; reproductive decisions; and the Genomic Outcome Scale was answered by 123 women recruited from a rare diseases reference service and a nationwide patient advocacy group. Genetic counseling was reported by 77/123 (62.6%) of women and 53.7% reported having performed genetic analysis of DMD. Although the majority knew about the risks for carriers of developing heart disease and muscle weakness, only 35% of potential carriers have had cardiac studies performed at least once in their lives. Country region, type of kinship, number of affected males in the family, age, notion of genetic risk, education level, and participation in advocacy groups were the main factors associated with adequate healthcare access to women and empowerment of genetic information. Education to health professionals and policies to expand access to carrier genetic testing, whether public policies or regulation of pharmaceutical companies' diagnostic programs, is paramount to improve the care of families with DBMD in Brazil.

Duchenne and Becker muscular dystrophy: Cellular mechanisms, image analysis, and computational models: A review.

The muscle is the principal tissue that is capable to transform potential energy into kinetic energy. This process is due to the transformation of chemical energy into mechanical energy to enhance the movements and all the daily activities. However, muscular tissues can be affected by some pathologies associated with genetic alterations that affect the expression of proteins. As the muscle is a highly organized structure in which most of the signaling pathways and proteins are related to one another, pathologies may overlap. Duchenne muscular dystrophy (DMD) is one of the most severe muscle pathologies triggering degeneration and muscle necrosis. Several mathematical models have been developed to predict muscle response to different scenarios and pathologies. The aim of this review is to describe DMD and Becker muscular dystrophy in terms of cellular behavior and molecular disorders and to present an overview of the computational models implemented to understand muscle behavior with the aim of improving regenerative therapy.

Perfil clínica y electromiográfico de las distrofias musculares en República Dominicana / Clinical and electromyographic profile of muscular dystrophies in the Dominican Republic

Introducción: Las distrofias musculares son trastornos miogénicos hereditarios caracterizados por una atrofia muscular progresiva y una debilidad de distribución y gravedad variable. La población de Republica Dominicana es fruto de una mezcla de etnias, haciéndola portadora de una herencia cromosómica y ADN diverso, siendo susceptibles a poder presentar cualquier desorden de carácter hereditario. Material y métodos: Con una muestra de 17 pacientes obtenidos entre septiembre 2019- marzo 2020, se realizó un estudio retrospectivo, descriptivo y transversal, en el cual se hizo una revisión de los expedientes de la clínica de miopatías en la consulta de neurología pediátrica del Hospital Infantil Doctor Robert Reid Cabral, para describir el perfil clínico de los pacientes con distrofia muscular y los hallazgos de electromiografía en los casos que la misma. Resultados: se encontró que la distribución de la edad correspondió a 5-9 años en un 53%, siendo el sexo masculino, el más frecuente. En el 70.59% presentaron antecedentes familiares de distrofia muscular. Los principales motivos de consulta fueron cansancio y caídas frecuentes. Conclusión: En los hallazgos de electromiografía, el porcentaje de pacientes que presentó esta prueba con alteraciones fue de 88.24% y sin alteraciones el 11.76%. Esto nos demuestra, la gran utilidad de dicho estudio en el diagnóstico de las distrofias musculares en países donde no se cuenta con estudio molecular, siendo una de las pruebas esenciales en el abordaje diagnóstico de los pacientes con sospecha clínica de dichas patologías.

Introduction: Muscular dystrophies are hereditary myogenic disorders characterized by progressive muscular atrophy and weakness of variable distribution and severity. The population of the Dominican Republic is the result of a mixture of ethnic groups, making it the bearer of a diverse chromosomal inheritance and DNA, being susceptible to presenting any hereditary disorder. Methods: With a sample of 17 patients obtained between September 2019-March 2020, a retrospective, descriptive and cross-sectional study, in which a review of the files of the myopathies clinic was made in the pediatric neurology consultation of the Children's Hospital Doctor Robert Reid Cabral, to describe the clinical profile of patients with muscular dystrophy and the electromyography findings in the cases with the same. Results: The age distribution corresponded to 5-9 years; 53%, being the masculines, the most frequent sex. In 70.59%, there was a family history of muscular dystrophy. The main reasons for consultation were fatigue and frequent falls. Conclusion: In the electromyography findings, the percentage of patients who presented this test with alterations was 88.24% and 11.76% without alterations. This result shows us the great utility of said study in the workup of muscular dystrophies in countries with no availabilities for molecular studies, being one of the essential tests in the diagnostic approach of patients with clinical suspicion of said pathologies.

Gene-based therapies for neuromuscular disorders / Terapias gênicas nas doenças neuromusculares

Abstract Neuromuscular diseases (NMD) include a broad group of medical conditions with both acquired and genetic causes. In recent years, important advances have been made in the treatment of genetically caused NMD, and most of these advances are due to the implementation of therapies aimed at gene regulation. Among these therapies, gene replacement, small interfering RNA (siRNA), and antisense antinucleotides are the most promising approaches. More importantly, some of these therapies have already gained regulatory approval or are in the final stages of approval. The review focuses on motor neuron diseases, neuropathies, and Duchenne muscular dystrophy, summarizing the most recent developments in gene-based therapies for these conditions.

Resumo Doenças neuromusculares (DNM) compõem um grupo amplo de doenças de causa tanto adquiridas quanto genéticas. Nos últimos anos, importantes avanços ocorreram quanto ao tratamento das DNM de causa genética e grande parte desses avanços se deve à implementação de terapias voltadas para a modificação gênica. Dentre essas terapias, destacam-se as terapias de reposição gênica, uso de RNA de interferência, uso de antinucleotídeos antisense, entre outras. E, mais importante, algumas dessas terapias já se tornaram realidade na prática médica e já foram aprovadas, ou estão a poucos passos da aprovação, por órgãos governamentais regulatórios. Esta revisão aborda aspectos mais recentes quanto ao uso das terapias genéticas avançadas para algumas das formas mais comuns de DNM, em especial para doenças do neurônio motor (esclerose lateral amiotrófica e atrofia muscular espinhal), neuropatias e distrofia muscular de Duchenne.

Ankle-foot orthosis in patients with Duchenne muscular dystrophy: a retrospective study / Órtese tornozelo-pé em pacientes com distrofia muscular de Duchenne: um estudo retrospectivo

Abstract Introduction: Duchenne muscular dystrophy (DMD) is a recessive genetic disease linked to the X chromosome, leading to progressive muscle tissue loss. Initially, there is difficulty getting up from the floor and an increased frequency of falls. Maintaining ambulation as long as possible is essential, and the use of ankle-foot orthosis (AFO) has been investigated as an ally in this process. Objective: To verify the prescription and use of an AFO for ambulant boys with DMD. Methods: Information was collected using the medical records of 181 patients with DMD from the Neuropediatric Service of the Instituto de Puericultura e Pediatria Martagão Gesteira of the Universidade Federal do Rio de Janeiro. Variables used were: age at the first medical appointment, age at first symptoms, age at loss of independent gait, time between the first symptoms and loss of gait, prescription of orthosis, time of use, and surgical intervention in the lower limbs. Results: The orthosis was prescribed for 63.5% of patients and used by 38.1%. The range of orthosis time was 2 to 4 years (62.3%). The night sleep period was the most prescribed for orthosis use, with 67.2%. Patients who used the orthosis for a longer time were older at gait loss. However, the children who arrived earlier for the first appointment had a higher frequency of orthosis prescriptions and later loss of gait. Conclusion: The use of AFO can help maintain ambulation for longer in boys with DMD.

Resumo Introdução: A distrofia muscular de Duchenne (DMD) é uma doença genética recessiva ligada ao cromossomo X, que cursa com a perda progressiva do tecido muscular. Inicialmente, observa-se dificuldade para levantar do chão e aumento dafrequência de quedas. A manutenção da deambulação pelo maior tempo possível é importante e o uso de órtese tornozelo-pé (OTP) tem sido investigado como aliado nesse processo. Objetivo: Verificar a prescrição e uso de OTP para meninos deambulantes com DMD. Métodos: As informações foram coletadas dos prontuários de 181 pacientes com DMD do Serviço de Neuropediatria do Instituto de Puericultura e Pediatria Martagão Gesteira, da Universidade Federal do Rio de Janeiro. As variáveis utilizadas foram: idade na primeira consulta, idade aos primeiros sintomas, idade na perda da marcha independente, tempo entre os primeiros sintomas e a perda da marcha, prescrição de órtese, tempo de uso e intervenção cirúrgica nos membros inferiores. Resultados: A órtese foi prescrita para 63,5% dos pacientes e utilizada por 38,1%. A variação do tempo de uso foi de 2 a 4 anos (62,3%). O período noturno foi o mais prescrito para uso da órtese, com 67,2%. Os pacientes que a usaram por mais tempo apresentaram maiores idades na perda da marcha. Crianças que chegaram mais precocemente à primeira consulta tiveram maior frequência de prescrição de órtese e perda da marcha mais tardiamente. Conclusão: O uso de OTP pode ajudar a manter a deambulação por mais tempo em meninos com DMD.

Alterações Eletrocardiográficas e do Sistema Nervoso Autônomo com a Mudança de Postura em Crianças e Adolescentes com Distrofia Muscular de Duchenne / Electrocardiographic and Autonomic Nervous System Changes after Changes in the Posture of Children and Adolescents with Duchenne Muscular Dystrophy

Resumo Fundamento: Distrofia Muscular de Duchenne (DMD) é uma doença neuromuscular hereditária rara. O acometimento cardíaco inicial pode ser assintomático. Portanto, a avaliação por métodos não invasivos pode auxiliar sua abordagem. Objetivos: Analisar o eletrocardiograma (ECG) e a variabilidade da frequência cardíaca (VFC) do grupo com DMD, e comparar com a do grupo controle pareado por idade. Métodos: Estudo prospectivo com 27 pacientes masculinos com DMD (idade de 11,9 anos) que foram submetidos à avaliação clínica, ECG, ecocardiograma e Holter. ECG (aumento de 200%) foi avaliado por dois observadores independentes. VFC foi feita no domínio do tempo (24 h) e da frequência na posição supina e sentada. O grupo saudável foi de nove pacientes (11,0 anos). Um valor de p < 0,05 foi considerado estatisticamente significante. Resultados: A média da fração de ejeção (FE) foi de 60% (34 a 71%). O coeficiente de Kappa para as medidas do ECG variou de 0,64 a 1,00. Foram verificados aumento da relação R/S em V1 em 25,9%, onda Q patológica em 29,6% e QRS fragmentado em 22,2% em regiões inferior/lateral alta, este com correlação negativa com FE (p = 0,006). Houve baixa VFC, sem influência de nenhuma variável, inclusive tratamento. Com a mudança da posição, houve aumento da FC (p = 0,004), porém não houve alteração da VFC. A relação LF/HF foi de 2,7 na DMD e de 0,7 no controle (p = 0,002). Conclusões: Nos participantes com DMD, as ondas R proeminentes em V1 e alterações nas regiões inferior/lateral alta ocorreram em quase 30% dos casos. Houve menor tônus vagal sem influência das variáveis idade, fração de ejeção, dispersão do QT e tratamento. Apesar do aumento da FC, não houve resposta adequada da VFC com a mudança de posição.

Abstract Background: Duchenne Muscular Dystrophy (DMD) is a rare inherited neuromuscular disease. At first, cardiac involvement may be asymptomatic. Therefore, assessing patients using non-invasive methods can help detect any changes. Objectives: Analyze the electrocardiogram (ECG) test and heart rate variability (HRV) of the DMD group and compare the information with that of the age-matched control group. Methods: A prospective study with 27 male patients with DMD (11.9 years old), who underwent clinical evaluation, ECG, echocardiogram, and Holter monitoring. ECG (200% increase) was assessed by two independent observers. HRV was measured over time (24 h) and in the frequency domain, in the supine and sitting positions. The healthy group consisted of nine patients (11.0 years old). A value of p < 0.05 was considered statistically significant. Results: The mean ejection fraction (EF) was 60% (34 to 71%). The Kappa coefficient for ECG measurements ranged from 0.64 to 1.00. An increase in the R/S ratio in V1 was observed in 25.9% of the subjects, pathological Q wave in 29.6%, and fragmented QRS in 22.2% in inferior/high lateral regions, with a negative correlation with EF (p = 0.006). There was low HRV, without the influence of any variable, including treatment. With the change in position, there was an increase in HR (p = 0.004), but there was no change in HRV. The LF/HF ratio was 2.7 in the DMD group and 0.7 in the control group (p = 0.002). Conclusions: In DMD subjects, prominent R waves in V1 and changes in the inferior/high lateral regions occurred in almost 30% of the cases. Lower vagal tone was observed without the influence of the variables age, ejection fraction, QT dispersion, and treatment. Despite the increase in HR, there was no adequate HRV response to the change in position.

Uso de Electromiografía de Alta Densidad en las Distrofias Musculares: una Mirada Actual / Use of high-density electromyography in muscular dystrophies: a current look

Introducción. Las distrofias musculares son trastornos genéticamente heredados que causan la degeneración progresiva de las fibras musculares. La electromiografía, especialmente la de alta densidad, se ha convertido en una herramienta valiosa para el diagnóstico y el estudio de la función muscular de trastornos neuromusculares. Objetivo. Describir y discutir el uso actual de esta técnica en las distrofias musculares. Métodos. Se realizó un Scoping Review sobre el uso de electromiografía de alta densidad en personas con distrofia muscular. Se buscó en PubMed, ScienceDirect, Scopus, Web of Science y Biblioteca Cochrane Plus, usando palabras clave en inglés y español. Se consideraron estudios desde 2015 a la fecha. Se identificaron tres artículos que cumplían con los criterios establecidos. Resultados. Los estudios se centraron en aplicaciones clínicas y de bioingeniería para personas con distrofia muscular de Duchenne y distrofia facioescapulohumeral. Los resultados sugieren que variables como la fatiga, la activación temporo-espacial y la dimensionalidad en gestos motores están determinados por la degeneración de las fibras musculares, el reemplazo por tejido fibrótico, los cambios adaptativos y la debilidad muscular progresiva característica de este grupo de condiciones. Se resalta la utilidad de la electromiografía de alta densidad en la evaluación y el manejo de la distrofia muscular. Conclusiones. El uso de esta técnica en estos trastornos neuromusculares sigue en aumento, pero se hace necesario explorar más aristas para ampliar su uso como herramienta en el estudio y en el desarrollo de intervenciones terapéuticas en esta condición por parte de profesionales de la salud.

Background. Muscular dystrophies are genetically inherited disorders that cause progressive degeneration of muscle fibers. Electromyography, especially high-density electromyography, has become a valuable tool for the diagnosis and study of muscle function in neuromuscular disorders, so the objective of this study is to describe and discuss the current use of this technique in muscular dystrophies. Methods. A Scoping Review was carried out on the use of high density electromyography in people with muscular dystrophy. PubMed, ScienceDirect, Scopus, Web of Science, and Cochrane Plus Library were searched using keywords in English and Spanish. Studies from 2015 to date were considered. Three articles were identified that met the established criteria. Results. The studies focused on clinical and bioengineering applications for people with Duchenne muscular dystrophy and facioscapulohumeral dystrophy. The results suggest that variables such as fatigue, temporal-spatial activation and dimensionality in motor gestures are determined by the degeneration of muscle fibers, replacement by fibrotic tissue, adaptive changes and progressive muscle weakness characteristic of this group of conditions. The usefulness of high-density electromyography in the evaluation and management of muscular dystrophy is highlighted. Conclusions. The use of this technique in these neuromuscular disorders continues to increase, but it is necessary to explore more aspects to expand its use as a tool in the management of this condition.

Higher Prevalence of Nonsense Pathogenic DMD Variants in a Single-Center Cohort from Brazil: A Genetic Profile Study That May Guide the Choice of Disease-Modifying Treatments.

Dystrophinopathies are muscle diseases caused by pathogenic variants in DMD, the largest gene described in humans, representing a spectrum of diseases ranging from asymptomatic creatine phosphokinase elevation to severe Duchenne muscular dystrophy (DMD). Several therapeutic strategies are currently in use or under development, each targeting different pathogenic variants. However, little is known about the genetic profiles of northeast Brazilian patients with dystrophinopathies. We describe the spectrum of pathogenic DMD variants in a single center in northeast Brazil. This is an observational, cross-sectional study carried out through molecular-genetic analysis of male patients diagnosed with dystrophinopathies using Multiplex Ligation-dependent Probe Amplification (MLPA) followed by Next-Generation Sequencing (NGS)-based strategies. A total of 94 male patients were evaluated. Deletions (43.6%) and duplications (10.6%) were the most recurring patterns of pathogenic variants. However, small variants were present in 47.1% of patients, most of them nonsense variants (27.6%). This is the largest South American single-center case series of dystrophinopathies to date. We found a higher frequency of treatment-amenable nonsense single-nucleotide variants than most previous studies. These findings may have implications for diagnostic strategies in less-known populations, as a higher frequency of nonsense variants may mean a higher possibility of treating patients with disease-modifying drugs.

Novel Radiological Brain Anomalies in a Patient with Congenital Muscular Dystrophy due to FKRP Mexican Founder Mutation c.1387A > G: Review of the Literature.

Mutations in the FKRP gene result in phenotypes with severe forms of congenital muscular dystrophies (CMD) and limb-girdle muscular dystrophies. We present a Mexican patient with a pathogenic homozygous mutation in the FKRP gene (c.1387A > G, p.Asn463Asp) and CMD with radiological brain anomalies as disseminated hyperintensity lesions and discrete generalized cortical atrophy. These findings have not been reported to the best of our knowledge in other patients with the same mutation. The mutation c.1387A > G, p.Asn463Asp in the FKRP gene has been described to have a founder effect in central Mexico, since all the patients described to date are of Hispanic origin. Therefore, we emphasize studying mutations in the FKRP gene in Hispanic pediatric patients with clinical suspicion of CMD. Clinical and molecular diagnosis of specific CMD subtypes is needed to help clarify the prognosis, management, and genetic counseling to the patient and families.