RESUMO
Individuals with Duchenne Muscular Dystrophy (DMD) have an impairment of cardiac autonomic function categorized by parasympathetic reduction and sympathetic predominance. The objective of this study was to assess the cardiac autonomic modulation of individuals with DMD undergoing therapy with Prednisone/Prednisolone and Deflazacort and compare with individuals with DMD without the use of these medications and a typically developed control group. Methods: A cross-sectional study was completed, wherein 40 boys were evaluated. The four treatment groups were: Deflazacort; Prednisone/Prednisolone; no corticoid use; and typical development. Heart Rate Variability (HRV) was investigated via linear indices (Time Domain and Frequency Domain) and non-linear indices Results: The results of this study revealed that individuals with DMD undertaking pharmacotherapies with Prednisolone demonstrated HRV comparable to the Control Typically Developed (CTD) group. In contrast, individuals with DMD undergoing pharmacotherapies with Deflazacort achieved lower HRV, akin to individuals with DMD without any medications, as demonstrated in the metrics: RMSSD; LF (n.u.), HF (n.u.), LF/HF; SD1, α1, and α1/α2, and a significant effect for SD1/SD2; %DET and Ratio; Shannon Entropy, 0 V%, 2 LV% and 2 ULV%. Conclusions: Corticosteroids have the potential to affect the cardiac autonomic modulation in adolescents with DMD. The use of Prednisone/Prednisolone appears to promote improved responses in terms of sympathovagal activity as opposed to Deflazacort.
RESUMO
Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (â¼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.
RESUMO
The Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by the absence of dystrophin protein, causing severe myopathy from increases of oxidative stress. Injuries of intestinal muscle can compromise the myenteric plexus. This study aimed to evaluate the disorders occurred in the muscular layer and in the acetylcholinesterase myenteric neurons (ACHE-r) of ileum of mdx mice, and the effects of supplementation with ascorbic acid (AA) in both components. 30 male mice C57BL/10, and 30 male mice C57BL/10Mdx were separated according to the age and treatment (n=10/group): 30-days-old control group (C30); 30-days-old dystrophic group (D30); 60-days-old control group (C60); 60-days-old dystrophic group (D60); 60-days-old control group supplemented with AA (CS60); and 60-days-old dystrophic group supplemented with AA (DS60). The animals were euthanized and the ileum was collected and processed. Semi-serial sections were stained by Masson's trichrome, and acetylcholinesterase histochemical technique in whole-mounts preparations to identify the myenteric neurons. The muscular layer thickness and the area of smooth muscle of ileum were lower in dystrophic groups, especially in D30 group. The DS60 group showed the muscular layer thickness similar to C60. The density of ACHE-r neurons of myenteric plexus of ileum was lower in D30 animals; however, it was similar in animals of 60-days-old without treatment (C60 and D60) and, higher in DS60. The cell body profile area of ACHE-r neurons was similar in C30-D30 and C60-D60; however, it was higher in DS60. DMD caused damage to the ileum's musculature and myenteric plexus, and the AA prevented the ACHE-r neuronal loss.
Assuntos
Acetilcolinesterase/metabolismo , Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Íleo/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Contagem de Células , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Tamanho Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Citoplasma/patologia , Modelos Animais de Doenças , Íleo/enzimologia , Íleo/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Liso/metabolismo , Músculo Liso/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patologia , Plexo Mientérico/efeitos dos fármacos , Plexo Mientérico/enzimologia , Plexo Mientérico/patologia , Neurônios/enzimologia , Neurônios/patologia , Tamanho do ÓrgãoRESUMO
A distrofia muscular de Duchenne (DMD) em humanos é uma alteração neuromuscular hereditária, de caráter recessivo, ligada ao cromossomo X e causada pela ausência ou disfunção da distrofina. Clinicamente, caracteriza-se por grave alteração na musculatura esquelética, resultando em morte precoce do indivíduo acometido. Em cães da raça Golden Retriever, a mutação que leva à distrofia muscular ocorre espontaneamente e a extensa homologia entre a patogênese da DMD e da distrofia muscular do Golden Retriever permite qualificar o cão como o principal substituto de humanos nos testes clínicos de novas terapias. O miocárdio deficiente em distrofina é mais vulnerável à sobrecarga de pressão e os pacientes com DMD podem desenvolver cardiomiopatia dilatada, hipertensão arterial e o eletrocardiograma pode se apresentar distintamente anormal. No presente estudo, foram avaliados exames eletrocardiográficos de 38 cães da raça Golden Retriever clinicamente sadios (20 animais de até 12 meses de idade e 18 animais entre 12 e 36 meses de idade), com a finalidade de se obter parâmetros para a padronização do eletrocardiograma nessa referida raça, o que futuramente poderá servir de referência na identificação de cães portadores ou afetados pela distrofia muscular. Os valores eletrocardiográficos obtidos encontraram-se dentro dos valores de normalidade e referência para as diferentes raças de cães; e as variáveis peso e idade alteraram significativamente a freqüência cardíaca e a amplitude do complexo QRS.
The Duchenne's muscular dystrophy (DMD) in humans is a X-linked neuromuscular disease, of recessive character, caused either by the absence or dysfunction of the dystrophin. Clinically, it is characterized by severe alteration in the skeletal musculature, resulting in precocious death. In Golden Retriever dogs, the mutation that takes to the muscular dystrophy happens spontaneously and the extensive homology among the pathogenesis of DMD and of Golden Retriever muscular dystrophy allows to qualify the dog as the main substitute of humans in the clinical tests of new therapies. The deficient myocardium in distrofin is more vulnerable to the pressure overload and the patients with DMD can develop dilated cardiomyopathy, arterial hypertension and the electrocardiogram can come distinctly abnormal. In the present study, 38 healthy Golden Retriever dogs were evaluated by electrocardiographic exam with the purpose to obtain parameters for the standardization of the electrocardiogram in the referred breed, what hereafter can serve as reference in the identification of bearer or affected dogs. Electrocardiographic values obtained were within normal values and reference for the various breeds of dogs, and the variables weight and age significantly altered heart rate and amplitude of the QRS complex.
Assuntos
Cães , Eletrocardiografia/métodos , Eletrocardiografia/veterinária , Padrões de Referência/estatística & dados numéricosRESUMO
A distrofia muscular de Duchenne (DMD) em humanos é uma alteração neuromuscular hereditária, de caráter recessivo, ligada ao cromossomo X e causada pela ausência ou disfunção da distrofina. Clinicamente, caracteriza-se por grave alteração na musculatura esquelética, resultando em morte precoce do indivíduo acometido. Em cães da raça Golden Retriever, a mutação que leva à distrofia muscular ocorre espontaneamente e a extensa homologia entre a patogênese da DMD e da distrofia muscular do Golden Retriever permite qualificar o cão como o principal substituto de humanos nos testes clínicos de novas terapias. O miocárdio deficiente em distrofina é mais vulnerável à sobrecarga de pressão e os pacientes com DMD podem desenvolver cardiomiopatia dilatada, hipertensão arterial e o eletrocardiograma pode se apresentar distintamente anormal. No presente estudo, foram avaliados exames eletrocardiográficos de 38 cães da raça Golden Retriever clinicamente sadios (20 animais de até 12 meses de idade e 18 animais entre 12 e 36 meses de idade), com a finalidade de se obter parâmetros para a padronização do eletrocardiograma nessa referida raça, o que futuramente poderá servir de referência na identificação de cães portadores ou afetados pela distrofia muscular. Os valores eletrocardiográficos obtidos encontraram-se dentro dos valores de normalidade e referência para as diferentes raças de cães; e as variáveis peso e idade alteraram significativamente a freqüência cardíaca e a amplitude do complexo QRS.(AU)
The Duchenne's muscular dystrophy (DMD) in humans is a X-linked neuromuscular disease, of recessive character, caused either by the absence or dysfunction of the dystrophin. Clinically, it is characterized by severe alteration in the skeletal musculature, resulting in precocious death. In Golden Retriever dogs, the mutation that takes to the muscular dystrophy happens spontaneously and the extensive homology among the pathogenesis of DMD and of Golden Retriever muscular dystrophy allows to qualify the dog as the main substitute of humans in the clinical tests of new therapies. The deficient myocardium in distrofin is more vulnerable to the pressure overload and the patients with DMD can develop dilated cardiomyopathy, arterial hypertension and the electrocardiogram can come distinctly abnormal. In the present study, 38 healthy Golden Retriever dogs were evaluated by electrocardiographic exam with the purpose to obtain parameters for the standardization of the electrocardiogram in the referred breed, what hereafter can serve as reference in the identification of bearer or affected dogs. Electrocardiographic values obtained were within normal values and reference for the various breeds of dogs, and the variables weight and age significantly altered heart rate and amplitude of the QRS complex.(AU)
Assuntos
Cães , Eletrocardiografia/métodos , Eletrocardiografia/veterinária , Padrões de Referência/estatística & dados numéricosRESUMO
The Duchenne's muscular dystrophy (DMD) in humans is a recessive X-linked neuromuscular disease, caused either by the absence or dysfunction of the dystrophin. Clinically it is characterized by severe alteration in the skeletal musculature, resulting in precocious death of the affected patient. In Golden Retriever dogs, the mutation that determines the muscular dystrophy occurs spontaneously and the extensive homology among the pathogenesis of DMD and of Golden Retriever muscular dystrophy allows to qualify the dog as the main substitute of humans in the clinical tests of new therapies. The deficient myocardium in dystrophin is more vulnerable to the pressure overload, and the patients with DMD can develop dilated cardiomyopathy as well as arterial hypertension; in echocardiography, diastolic function abnormalities are verified and systolic inadequacy can be observed in some old patients. In the present study, 41 healthy Golden Retriever dogs were evaluated by echocardiographic exam with the purpose to obtain parameters for the standardization of these cardiovascular characteristics in the refered breed, what hereafter can be used as reference in the identification of bearer or affected dogs by muscular dystrophy.
A distrofia muscular de Duchenne (DMD) em humanos é uma alteração neuromuscular hereditária, de caráter recessivo, ligada ao cromossomo X e causada pela ausência ou disfunção da distrofina. Clinicamente, caracteriza-se por severa alteração na musculatura esquelética, resultando em morte precoce do indivíduo acometido. Em cães da raça Golden Retriever, a mutação que leva à distrofia muscular ocorre espontaneamente e a extensa homologia entre a patogênese da DMD e da distrofia muscular do Golden Retriever permite qualificar o cão como principal substituto de humanos nos testes clínicos de novas terapias. O miocárdio deficiente em distrofina é mais vulnerável à sobrecarga de pressão e os pacientes com DMD podem desenvolver cardiomiopatia dilatada e hipertensão arterial; à ecocardiografia, verificam-se anormalidades na função diastólica, além de insuficiência sistólica em alguns pacientes mais velhos. No presente estudo, 41 cães da raça Golden Retriever, clinicamente sadios, foram submetidos ao exame ecocardiográfico com a finalidade de se obterem os citados parâmetros na referida raça, o que futuramente poderá servir de referência na identificação de cães portadores ou afetados pela distrofia muscular.
RESUMO
The Duchenne's muscular dystrophy (DMD) in humans is a recessive X-linked neuromuscular disease, caused either by the absence or dysfunction of the dystrophin. Clinically it is characterized by severe alteration in the skeletal musculature, resulting in precocious death of the affected patient. In Golden Retriever dogs, the mutation that determines the muscular dystrophy occurs spontaneously and the extensive homology among the pathogenesis of DMD and of Golden Retriever muscular dystrophy allows to qualify the dog as the main substitute of humans in the clinical tests of new therapies. The deficient myocardium in dystrophin is more vulnerable to the pressure overload, and the patients with DMD can develop dilated cardiomyopathy as well as arterial hypertension; in echocardiography, diastolic function abnormalities are verified and systolic inadequacy can be observed in some old patients. In the present study, 41 healthy Golden Retriever dogs were evaluated by echocardiographic exam with the purpose to obtain parameters for the standardization of these cardiovascular characteristics in the refered breed, what hereafter can be used as reference in the identification of bearer or affected dogs by muscular dystrophy.
A distrofia muscular de Duchenne (DMD) em humanos é uma alteração neuromuscular hereditária, de caráter recessivo, ligada ao cromossomo X e causada pela ausência ou disfunção da distrofina. Clinicamente, caracteriza-se por severa alteração na musculatura esquelética, resultando em morte precoce do indivíduo acometido. Em cães da raça Golden Retriever, a mutação que leva à distrofia muscular ocorre espontaneamente e a extensa homologia entre a patogênese da DMD e da distrofia muscular do Golden Retriever permite qualificar o cão como principal substituto de humanos nos testes clínicos de novas terapias. O miocárdio deficiente em distrofina é mais vulnerável à sobrecarga de pressão e os pacientes com DMD podem desenvolver cardiomiopatia dilatada e hipertensão arterial; à ecocardiografia, verificam-se anormalidades na função diastólica, além de insuficiência sistólica em alguns pacientes mais velhos. No presente estudo, 41 cães da raça Golden Retriever, clinicamente sadios, foram submetidos ao exame ecocardiográfico com a finalidade de se obterem os citados parâmetros na referida raça, o que futuramente poderá servir de referência na identificação de cães portadores ou afetados pela distrofia muscular.