Becker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin... Show moreBecker muscular dystrophy (BMD) is the milder allelic variant of Duchenne muscular dystrophy, with higher dystrophin levels. To anticipate on results of interventions targeting dystrophin expression it is important to know the natural variation of dystrophin expression between different muscles and over time. Dystrophin was quantified using capillary Western immunoassay (Wes) in the anterior tibial (TA) muscle of 37 BMD patients. Variability was studied using two samples from the same TA biopsy site in nine patients, assessing nine longitudinal TA biopsies, and eight simultaneously obtained vastus lateralis (VL) muscle biopsies. Measurements were performed in duplicate with two primary antibodies. Baseline dystrophin levels were correlated to longitudinal muscle strength and functional outcomes. Results showed low technical variability and high precision for both antibodies. Dystrophin TA levels ranged from 4.8 to 97.7%, remained stable over a 3-5 year period, and did not correlate with changes in longitudinal muscle function. Dystrophin levels were comparable between TA and VL muscles. Intra-muscle biopsy variability was low (5.2% and 11.4% of the total variability of the two antibodies). These observations are relevant for the design of clinical trials targeting dystrophin production, and may urge the need for other biomarkers or surrogate endpoints. 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
