Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Prosensa Therapeutics B.V., Leiden, The Netherlands.
J Neurol Neurosurg Psychiatry. 2014 Jul;85(7):747-53. doi: 10.1136/jnnp-2013-306350. Epub 2013 Nov 29.
Becker muscular dystrophy (BMD) is characterised by broad clinical variability. Ongoing studies exploring dystrophin restoration in Duchenne muscular dystrophy ask for better understanding of the relation between dystrophin levels and disease severity. We studied this relation in BMD patients with varying mutations, including a large subset with an exon 45-47 deletion.
Dystrophin was quantified by western blot analyses in a fresh muscle biopsy of the anterior tibial muscle. Disease severity was assessed using quantitative muscle strength measurements and functional disability scoring. MRI of the leg was performed in a subgroup to detect fatty infiltration.
33 BMD patients participated. No linear relation was found between dystrophin levels (range 3%-78%) and muscle strength or age at different disease milestones, in both the whole group and the subgroup of exon 45-47 deleted patients. However, patients with less than 10% dystrophin all showed a severe disease course. No relation was found between disease severity and age when analysing the whole group. By contrast, in the exon 45-47 deleted subgroup, muscle strength and levels of fatty infiltration were significantly correlated with patients' age.
Our study shows that dystrophin levels appear not to be a major determinant of disease severity in BMD, as long as it is above approximately 10%. A significant relation between age and disease course was only found in the exon 45-47 deletion subgroup. This suggests that at higher dystrophin levels, the disease course depends more on the mutation site than on the amount of the dystrophin protein produced.
贝克型肌营养不良症（BMD）的临床表现具有广泛的变异性。目前正在进行的研究探索杜氏肌营养不良症中肌营养不良蛋白的恢复情况，这需要更好地了解肌营养不良蛋白水平与疾病严重程度之间的关系。我们研究了具有不同突变的 BMD 患者的这种关系，包括一大亚组具有外显子 45-47 缺失的患者。
通过Western blot 分析在前胫骨肌的新鲜肌肉活检中定量肌营养不良蛋白。使用定量肌肉力量测量和功能障碍评分评估疾病严重程度。在亚组中进行腿部 MRI 以检测脂肪浸润。
33 名 BMD 患者参与了研究。在整个组和外显子 45-47 缺失的患者亚组中，均未发现肌营养不良蛋白水平（范围 3％-78％）与肌肉力量或不同疾病里程碑处的年龄之间存在线性关系。然而，肌营养不良蛋白水平低于 10％的患者均表现出严重的疾病过程。当分析整个组时，未发现疾病严重程度与年龄之间存在关系。相比之下，在外显子 45-47 缺失的亚组中，肌肉力量和脂肪浸润的水平与患者的年龄显著相关。
我们的研究表明，只要肌营养不良蛋白水平高于约 10％，肌营养不良蛋白水平似乎不是 BMD 疾病严重程度的主要决定因素。仅在外显子 45-47 缺失的亚组中发现了年龄与疾病过程之间的显著关系。这表明，在较高的肌营养不良蛋白水平下，疾病过程更多地取决于突变部位，而不是产生的肌营养不良蛋白的量。
