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Introducción: La Distrofia Muscular de Duchenne (DMD) y la Atrofia Muscular Espinal (AME) son enfermedades neuromusculares genéticas poco comunes pero graves en la población pediátrica con alta carga de morbilidad y mortalidad. A pesar de avances en su comprensión y búsqueda de opciones terapéuticas dirigidas, persisten vacíos en la detección oportuna, caracterización, seguimiento de pacientes, búsqueda activa de portadores y en algunos países de Latinoamérica sin tamización neonatal. Objetivo: Caracterizar clínica, paraclínica, imagenológica y molecularmente pacientes con diagnóstico presuntivo y confirmado de distrofia muscular de Duchenne (DMD) y Atrofia Muscular Espinal (AME) atendidos en un centro pediátrico de referencia y excelencia del Suroccidente Colombiano. Materiales y Métodos: Estudio observacional de corte transversal en pacientes menores de 18 años con diagnósticos CIE-10 relacionados con DMD y AME. Los datos se exportaron a una matriz de Excel en Office 365 versión 2403, y luego a IBM SPSS versión 29 para realizar un análisis univariado, se emplearon medidas de tendencia central y dispersión para variables numéricas, considerando su distribución, y frecuencias absolutas y porcentajes para variables cualitativas. Resultados: Tras revisar 954 historias clínicas pertenecientes a un centro de atención pediátrica en el Suroccidente Colombiano entre los años 2015 - 2021, se identificaron 422 casos relacionados a Distrofia Muscular de Duchenne (DMD) y Atrofia Muscular Espinal (AME); excluyendo duplicados y registros no relacionados, de estos, se seleccionaron aleatoriamente 99 casos para un análisis exhaustivo utilizando OpenEpi versión 3.01, distribuidos en dos grupos: AME (n=23) y DMD (n=76). Los pacientes confirmados con Distrofia Muscular de Duchenne (DMD) mostraron un inicio de síntomas a los 54,5 ± 29,0 meses y un diagnóstico a los 98,8 ± 34,9 meses, siendo más común en varones con hipotonía y niveles elevados de creatin quinasa (CK), el 54,5% presentaba trastorno cognitivo y el 88.2% tenía antecedentes familiares, en la Atrofia Muscular Espinal (AME), el inicio de síntomas fue a los 28,9 ± 37,7 meses y el diagnóstico a los 37,9 ± 38,2 meses, siendo predominante en mujeres con arreflexia y fasciculaciones, no hubo registros de la función cognitiva en los pacientes confirmados, y el 21,7% tenía antecedentes familiares de AME, además de ligeras elevaciones de CK. En el grupo AME, 9 casos se confirmaron molecularmente y 3 se respaldaron con registros médicos; en contraste, en el grupo de DMD, 22 casos tuvieron confirmación molecular, pero 9 contaban con anotaciones en los registros médicos, aunque estos informes eran incompletos. Conclusiones: La sospecha y diagnóstico temprano de estas enfermedades neurodegenerativas progresivas que se caracterizan por altas tasas de morbilidad y mortalidad es fundamental para impactar en el abordaje holístico que deben recibir los pacientes. Dado al continuo avance en métodos diagnósticos y opciones terapéuticas innovadoras y dirigidas ( medicina de la hiperpersonalización ), se hace necesario crear registros y "big data" médicos- clínicos completos, que cuenten con todas las herramientas actuales disponibles (opciones diagnósticas multimodales) que faciliten el re-contacto de pacientes, seguimiento y poderles ofrecer una atención personalizada, de precisión, que mejore la calidad de vida de ellos, sus familias, contribuyendo en la generación de políticas públicas integradas y dirigidas. (provisto por Infomedic International)

Introduction: Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA) are rare but severe genetic neuromuscular diseases in the pediatric population with high burden of morbidity and mortality. Despite advances in their understanding and search for targeted therapeutic options, there are still gaps in timely detection, characterization, patient follow-up, active search for carriers and in some Latin American countries no neonatal screening. Objective: To characterize clinically, paraclinically, imaging and molecularly patients with presumptive and confirmed diagnosis of Duchenne muscular dystrophy (DMD) and Spinal Muscular Atrophy (SMA) attended in a pediatric center of reference and excellence in Southwestern Colombia. Materials and Methods: Observational cross-sectional study in patients under 18 years of age with ICD-10 diagnoses related to DMD and SMA. Data were exported to an Excel matrix in Office 365 version 2403, and then to IBM SPSS version 29 to perform a univariate analysis, measures of central tendency and dispersion were used for numerical variables, considering their distribution, and absolute frequencies and percentages for qualitative variables. Results: After reviewing 954 medical records belonging to a pediatric care center in Southwestern Colombia between 2015 - 2021, 422 cases related to Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA) were identified; excluding duplicates and unrelated records, from these, 99 cases were randomly selected for a comprehensive analysis using OpenEpi version 3.01, distributed in two groups: SMA (n=23) and DMD (n=76). Patients confirmed with Duchenne Muscular Dystrophy (DMD) showed symptom onset at 54.5 ± 29.0 months and diagnosis at 98.8 ± 34.9 months, being more common in males with hypotonia and elevated creatin kinase (CK) levels, 54.5% had cognitive impairment and 88. 2% had family history, in Spinal Muscular Atrophy (SMA), the onset of symptoms was at 28.9 ± 37.7 months and diagnosis at 37.9 ± 38.2 months, being predominant in females with areflexia and fasciculations, there were no records of cognitive function in confirmed patients, and 21.7% had family history of SMA, in addition to slight elevations of CK. In the SMA group, 9 cases were molecularly confirmed and 3 were supported by medical records; in contrast, in the DMD group, 22 cases had molecular confirmation, but 9 had annotations in medical records, although these reports were incomplete. Conclusions: Early suspicion and diagnosis of these progressive neurodegenerative diseases characterized by high morbidity and mortality rates is critical to impact the holistic approach patients should receive. Given the continuous advance in diagnostic methods and innovative and targeted therapeutic options (hyperpersonalization medicine), it is necessary to create complete medical-clinical registries and big data, which have all the current tools available (multimodal diagnostic options) to facilitate patient re-contact, follow-up and to be able to offer personalized, precision care that improves the quality of life of patients and their families, contributing to the generation of integrated and targeted public policies. (provided by Infomedic International)

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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.

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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.

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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.

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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.

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Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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Duchenne Muscular Dystrophy (DMD) is characterized by an initial increase in motor function followed by a plateau phase and then entering a phase of steady decline. However, motor evolution of DMD have not been evaluated in developing countries. Therefore, this study aims to evaluate the trajectory of motor function in a sample of Colombian children with DMD. We included 119 children with DMD aged 4.8-19.3 years (mean follow-up = 1.7 years). A linear mixed model was used with age as the time scale and adjusted for covariates using a stepwise regression. Participants showed a progressive decline in motor skills from the age of 5 years with a decrease in speed around the age of 11 years (p < 0.001). After age 11, the decline in motor function was observed to continue until age 20 but at a slower rate (ßAge = -9.64. and ßAge2 = 0.18, p < 0.001 for both). Educational inclusion, glucocorticoid treatment and the number of mutated exons were shown to be associated with the motor performance. These findings may indicate that the evolution of DMD maintains similar patterns between high income countries and the Colombian population. They allow us to adapt and develop treatments that impact the population with DMD in Colombia, based in international evidence.

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BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked lethal genetic disorder for which there is no effective treatment. Previous studies have shown that stem cell transplantation into mdx mice can promote muscle regeneration and improve muscle function, however, the specific molecular mechanisms remain unclear. DMD suffers varying degrees of hypoxic damage during disease progression. This study aimed to investigate whether induced pluripotent stem cells (iPSCs) have protective effects against hypoxia-induced skeletal muscle injury. RESULTS: In this study, we co-cultured iPSCs with C2C12 myoblasts using a Transwell nested system and placed them in a DG250 anaerobic workstation for oxygen deprivation for 24 h. We found that iPSCs reduced the levels of lactate dehydrogenase and reactive oxygen species and downregulated the mRNA and protein levels of BAX/BCL2 and LC3II/LC3I in hypoxia-induced C2C12 myoblasts. Meanwhile, iPSCs decreased the mRNA and protein levels of atrogin-1 and MuRF-1 and increased myotube width. Furthermore, iPSCs downregulated the phosphorylation of AMPKα and ULK1 in C2C12 myotubes exposed to hypoxic damage. CONCLUSIONS: Our study showed that iPSCs enhanced the resistance of C2C12 myoblasts to hypoxia and inhibited apoptosis and autophagy in the presence of oxidative stress. Further, iPSCs improved hypoxia-induced autophagy and atrophy of C2C12 myotubes through the AMPK/ULK1 pathway. This study may provide a new theoretical basis for the treatment of muscular dystrophy in stem cells.

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BACKGROUND: The economic burden of rare diseases on health systems is still not widely measured, with the generation of accurate information about the costs with medical care for subjects with rare diseases being crucial when defining health policies. Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy, with new technologies recently being studied for its management. Information about the costs related to the disease in Latin America is scarce, and the objective of this study is to evaluate the annual hospital, home care and transportation costs per patient with DMD treatment in Brazil. RESULTS: Data from 27 patients were included, the median annual cost per patient was R$ 17,121 (IQR R$ 6,786; 25,621). Home care expenditures accounted for 92% of the total costs, followed by hospital costs (6%) and transportation costs (2%). Medications and loss of family, and patient's productivity are among the most representative consumption items. When disease worsening due to loss of the ability to walk was incorporated to the analysis, it was shown that wheelchair users account for an incremental cost of 23% compared with non-wheelchair users. CONCLUSIONS: This is an original study in Latin America to measure DMD costs using the micro-costing technique. Generating accurate information about costs is crucial to provide health managers with information that could help establish more sustainable policies when deciding upon rare diseases in emerging countries.

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A Distrofia Muscular de Duchenne (DMD) é uma doença neuromuscular progressiva recessiva causada por mutações genéticas ligadas ao cromossomo X. Além do enfraquecimento muscular progressivo, a condição é associada a alterações neuropsicológicas. O objetivo deste estudo foi realizar uma revisão sistematizada da temática, para investigar os aspectos cognitivos e comportamentais associados à DMD pela literatura, nos últimos dez anos (2011-2021). Realizou-se uma revisão integrativa da literatura, com o propósito de sintetizar e analisar o conhecimento sobre o tema no campo científico, sendo efetuada busca nas bases de dados e motores de busca Science Direct, SciELO, PubMed e BVS. Após consideração dos critérios de inclusão e exclusão, foram selecionados 29 artigos para análise. Os resultados endossaram que alterações cognitivas e do neurodesenvolvimento, bem como de problemas comportamentais parecem ser mais prováveis na DMD, em comparação com a população geral. Verificou-se escassez de estudos empíricos brasileiros e a necessidade de avaliar e intervir nos âmbitos neuropsicológico e psicossocial, de forma precoce, contínua e multidisciplinar, no intuito de atender às necessidades desse grupo.

Duchenne Muscular Dystrophy (DMD) is a recessive progressive neuromuscular disease caused by X-linked genetic mutations. In addition to progressive muscle weakness, the condition is associated with neuropsychological alterations. The aim of this study was to perform a systematic review about the theme, to investigate the cognitive and behavioral aspects associated with DMD in the literature, over the last ten years (2011-2021). An integrative literature review was carried out, with the purpose of synthesizing and analyzing the knowledge on the subject in the scientific field, with a search in the databases and search engines Science Direct, SciELO, PubMed and BVS. After considering the inclusion and exclusion criteria, 29 articles were selected for analysis. The results endorsed that cognitive and neurodevelopmental alterations and behavioral problems seem to be more likely in DMD, when compared to the general population. There was a lack of brazilian empirical studies and the need to assess and intervene in the neuropsychological and psychosocial spheres was observed, in an early, continuous and multidisciplinary way, in order to meet the needs of this group.

La distrofia muscular de Duchenne (DMD) es una enfermedad neuromuscular progresiva recesiva causada por mutaciones genéticas ligadas al cromosoma X. Además de la debilidad muscular progresiva, la afección se asocia con cambios neuropsicológicos. El objetivo de este estudio fue realizar una revisión sistemática del tema, para investigar los aspectos cognitivos y conductuales asociados a la DMD en la literatura, en los últimos diez años (2011-2021). Se realizó una revisión integradora de la literatura, con el propósito de sintetizar y analizar el conocimiento sobre el tema en el campo científico, mediante una búsqueda en las bases de datos y motores de búsqueda Science Direct, SciELO, PubMed y BVS. Después de considerar los criterios de inclusión y exclusión, se seleccionaron 29 artículos para su análisis. Los resultados respaldaron que alteraciones cognitivas y del neurodesarrollo, así como problemas del comportamiento parecen ser más probables en la DMD en comparación con la población general. Se observó la escasez de estudios empíricos brasileños, así como la necesidad de evaluar e intervenir en los ámbitos neuropsicológico y psicosocial, de forma precoz, continua y multidisciplinar, para atender las necesidades de esta población.

Assuntos

RESUMO

Oxidative stress (OS) plays an essential role in the pathophysiology of Duchenne muscular dystrophy (DMD). However, the actors that regulate OS need to be better studied. We aimed to evaluate whether NFE2-like bZIP transcription factor 2 (Nrf2), glutathione, malondialdehyde (MDA), and protein carbonyl concentrations change according to the disease severity in DMD patients. Moreover, we assessed whether OS correlated with muscle injury, clinical characteristics, physical activity, and antioxidant food consumption (AFC). A total of 28 DMD patients participated in this study. OS markers, metabolic indicators, and enzymatic markers of muscle injury were measured in circulation. Muscle injury was measured with clinical scales, and physical activity and AFC were evaluated with questionnaires. Nrf2 concentration was lower (p ≤ 0.01), and malondialdehyde concentration was higher (p < 0.05) in non-ambulatory patients than in ambulatory patients. Nrf2 correlated with age (rho = -0.387), Vignos scale (rho = -0.328), GMFCS scale (rho = -0.399), and Brooke scale scores (rho = -0.371) (p < 0.05). MDA correlated with Vignos (rho = 0.317) and Brooke scale scores (rho = 0.414) (p ≤ 0.05). In conclusion, DMD patients with the worst muscle function had more significant oxidative damage and lower antioxidant function than DMD patients with better muscle function.

RESUMO

Abstract Objective: To analyze the underlying components of reduced maximal static inspiratory (MIP) and expiratory (MEP) pressures in subjects with Duchenne muscular dystrophy. Methods: Forty-three subjects were assessed based on routine pulmonary function tests. MIP and MEP were measured the subjects performed maximal expirations and inspirations using a snorkel mouthpiece. Lung volumes were measured us ing the helium dilution technique. Results: The mean age was 13 years (range, 7-20 years). Median total lung capacity (TLC) and residual volume (RV) were 78.0 (49.0-94.0) and 27.0 (19.7-30.1) of the predicted values re spectively. The RV/TLC relationship was 35.3% (28.1-47.7). Thirty-five subjects had a TLC below the lower limit of normal, while 31 had an RV/TLC ratio above the upper limit of normal. The median (IQR) MIP and MEP values were -53.0 (-65.5 to -41.8) and 58.0 (41.5-74.8) cmH2O respectively. MIP and MEP in percent of the predicted values (predicted TLC and RV) were 42.6 (33.3-50.8) and 33.7 (23.9-44.5). MIP in percent of the RV reached for Group A (7-11 years old) was higher (p 0.025) while MEP in percent of the TLC reached for Group B (12-16 years) and C (17-20 years) were higher too (0.031). Conclusions: In subjects with Duchenne muscular dystrophy, the intrinsic weakness of respiratory muscles and mechanical disadvantage lead to inadequate maximal static pressure generation. Maximal static pressures should be interpreted cautiously as they overestimate respiratory muscle weakness when compared to predicted values obtained at TLC and RV. Our results provide additional data supporting absolute values use rather than predicted values.

Resumen Objetivo: Analizar los componentes subyacentes de las presiones inspiratorias (MIP) y espiratorias (MEP) es táticas máximas reducidas en sujetos con distrofia de Duchenne (DMD). Métodos: Se evaluaron 43 pacientes mediante pruebas de función pulmonar rutinarias. MIP y MEP fueron medidas a inspiración y espiración máximas. Los volúmenes pulmonares se midieron mediante dilución de helio. Resultados: Edad media 13 años (rango 7-20 años). La capacidad pulmonar total (TLC) y el volumen residual (RV) fueron 78.0% (49.0-94.0) y 27.0% (19.7- 30.1) de los valores predichos. El RV/TLC fue de 35.3% (28.1-47.7). Treinta y cinco sujetos tenían una TLC por debajo del límite inferior de normalidad, 31 tenían una RV/TLC por encima del límite superior de la normalidad. MIP y MEP fueron -53.0 (-65.5 a -41.8) y 58.0 (41.5-74.8) cmH2O, mientras que en % de los predichos (TLC y RV predichos) fueron 42.6 (33.3-50.8) y 33.7 (23.9-44.5). MIP en % del RV alcanzado (Grupo A 7-11 años) fue mayor (p 0.025), y MEP en % de la TLC alcanzada Grupo B (12-16 años) y C (17-20 años), también fue mayor (0.031). Conclusiones: En sujetos con DMD, debilidad intrínseca de los músculos respiratorios y desventaja mecánica conducen a generación de presión estática máxima inadecuada. Las mismas deben interpretarse con cautela, ya que sobrestiman la debilidad de los músculos respiratorios si se las compara con las tablas de valores predichos obtenidos a TLC y RV. Nuestros resultados proporcionan datos adicionales que respaldan la utilización de valores absolutos en lugar de los predichos.

RESUMO

OBJECTIVE: To analyze the underlying components of reduced maximal static inspiratory (MIP) and expiratory (MEP) pressures in subjects with Duchenne muscular dystrophy. METHODS: Forty-three subjects were assessed based on routine pulmonary function tests. MIP and MEP were measured the subjects performed maximal expirations and inspirations using a snorkel mouthpiece. Lung volumes were measured using the helium dilution technique. RESULTS: The mean age was 13 years (range, 7-20 years). Median total lung capacity (TLC) and residual volume (RV) were 78.0 (49.0-94.0) and 27.0 (19.7-30.1) of the predicted values respectively. The RV/TLC relationship was 35.3% (28.1-47.7). Thirty-five subjects had a TLC below the lower limit of normal, while 31 had an RV/TLC ratio above the upper limit of normal. The median (IQR) MIP and MEP values were -53.0 (-65.5 to -41.8) and 58.0 (41.5-74.8) cmH2O respectively. MIP and MEP in percent of the predicted values (predicted TLC and RV) were 42.6 (33.3-50.8) and 33.7 (23.9-44.5). MIP in percent of the RV reached for Group A (7-11 years old) was higher (p 0.025) while MEP in percent of the TLC reached for Group B (12-16 years) and C (17-20 years) were higher too (0.031). CONCLUSIONS: In subjects with Duchenne muscular dystrophy, the intrinsic weakness of respiratory muscles and mechanical disadvantage lead to inadequate maximal static pressure generation. Maximal static pressures should be interpreted cautiously as they overestimate respiratory muscle weakness when compared to predicted values obtained at TLC and RV. Our results provide additional data supporting absolute values use rather than predicted values.

OBJETIVO: Analizar los componentes subyacentes de las presiones inspiratorias (MIP) y espiratorias (MEP) estáticas máximas reducidas en sujetos con distrofia de Duchenne (DMD). Métodos: Se evaluaron 43 pacientes mediante pruebas de función pulmonar rutinarias. MIP y MEP fueron medidas a inspiración y espiración máximas. Los volúmenes pulmonares se midieron mediante dilución de helio. RESULTADOS: Edad media 13 años (rango 7-20 años). La capacidad pulmonar total (TLC) y el volumen residual (RV) fueron 78.0% (49.0-94.0) y 27.0% (19.7- 30.1) de los valores predichos. El RV/TLC fue de 35.3% (28.1-47.7). Treinta y cinco sujetos tenían una TLC por debajo del límite inferior de normalidad, 31 tenían una RV/TLC por encima del límite superior de la normalidad. MIP y MEP fueron -53.0 (-65.5 a -41.8) y 58.0 (41.5-74.8) cmH2O, mientras que en % de los predichos (TLC y RV predichos) fueron 42.6 (33.3-50.8) y 33.7 (23.9-44.5). MIP en % del RV alcanzado (Grupo A 7-11 años) fue mayor (p 0.025), y MEP en % de la TLC alcanzada Grupo B (12-16 años) y C (17-20 años), también fue mayor (0.031). CONCLUSIONES: En sujetos con DMD, debilidad intrínseca de los músculos respiratorios y desventaja mecánica conducen a generación de presión estática máxima inadecuada. Las mismas deben interpretarse con cautela, ya que sobrestiman la debilidad de los músculos respiratorios si se las compara con las tablas de valores predichos obtenidos a TLC y RV. Nuestros resultados proporcionan datos adicionales que respaldan la utilización de valores absolutos en lugar de los predichos.

Assuntos