Genetically Misdiagnosed Duchenne: Confirmation of a Becker Muscle Dystrophy with Proof of an In-Frame Mutation with Deletion of Three Additional Exons on mRNA Level Based on Experimental cDNA Analysis

Case Study: We present an extraordinary case of an 11-year-old boy with a genetically confirmed diagnosis of Duchenne muscular dystrophy (DMD). Phenotype and course of the disease were so mild that the original diagnosis was put into question. The boy presented in summer 2008 with high levels of creatine phosphokinase between 5,000 and 15,000 U/L that were determined because of the reported pain in the knees. At this time, only fine motoric deficits were reported by the parents, statomotoric development was normal. For further diagnostic work-up, MLPA analysis of the dystrophin gene was performed and showed a hemizygote deletion of exons 12 to 29. The identified deletion results in a frame shift mutation that is clinically associated with the course of a Duchenne DMD. From this time, the boy was seen regularly in our neuromuscular outpatient clinic. In April 2013, at the age of 10 years, he was still able to run long distances and climbing stairs without any problems. Gowers' sign was still negative, the boy reported only calf pain under efforts and fatigue. Clinical examination showed only decent lumbar hyperlordosis and minimally reduced proximal muscle strength. After consultation with our department of genetics under the clinically suspected course of a Becker muscular dystrophy (BMD), we performed an experimental cDNA analysis. After RNA isolation and cDNA synthesis of the region of exons 7 to 31, the DMD transcript was amplified with PCR technique and afterward sequenced. The already with MLPA confirmed deletion of exons 12 to 29 on DNA level results in a transcript with a deletion of three more exons from 9 to 29. This additive deletion, identified on cDNA level, results in an in-frame deletion of the dystrophin gene compatible with the clinically suspected phenotype of BMD.

Keywords: Duchenne muscular dystrophy, DMD, BMD, Becker muscular dystrophy.