Background Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic... Show moreBackground Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment. Methods and Findings We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in theTNFRSF10Agene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N= 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results. Conclusion We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker. Show less
In this thesis research is presented about the progressive muscle diseases Duchenne and Becker muscular dystrophy, two hereditary muscle diseases caused by a mutation in the gene coding for... Show moreIn this thesis research is presented about the progressive muscle diseases Duchenne and Becker muscular dystrophy, two hereditary muscle diseases caused by a mutation in the gene coding for dystrophin, a protein involved in muscle membrane stability. The first part describes the disease course of both diseases. It evaluates the effect of developments in care of Duchenne patients, improving age at wheelchair dependence and survival. Data are presented about the relatively mild disease course of selected Becker patients with a mutation that would be the result of exon skipping in a Duchenne patient, illustrating the possible result of this therapeutic approach. The second part of this thesis focusses on research into factors involved in disease variability. Data are presented regarding the role of dystrophin quantity in disease severity in Becker patients, showing no linear relationship. Expression of several dystrophin associated proteins is shown not to influence disease course either. Contrarily, a single nucleotide polymorphism in the LTBP4 gene involved in fibrosis and muscle regeneration is shown to influence disease severity. Lastly, a disease severity scale for Becker patients is presented in this thesis, enabling a better comparison of individual patients for the purpose of scientific research. Show less
Dystrophinopathies include the well known Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). This thesis is a collection of several clinical and genetic studies on... Show moreDystrophinopathies include the well known Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). This thesis is a collection of several clinical and genetic studies on dystrophinopathies with implications for genetic counselling of patients and their families and for future therapy (e.g. personalized medicine) of patients suffering from this group of chronic progressive muscle diseases. The following recommendations are made: - Testing for dystrophinopathies in newborn boys on a voluntary basis should start as soon as possible in the Netherlands. This will reduce the chance of the birth of subsequent affected boys in the family and will also help in early introduction of possible therapy when this becomes available. - Parents should be given the choice of having their daughters tested prenatally, if foetal DNA is available. They should also be encouraged to have their daughters tested, even before adulthood. This will not only considerably reduce the incidence of DMD but will also ease the burden for the parents who have to inform their daughter of their future risks. - Genetic counsellors should have a more active approach to cascade screening and informing the patients and their families of their risks and possibilities. Show less
