Abstract
Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive neuromuscular disorders characterized by progressive irreversible muscle weakness and atrophy that affect both skeletal and cardiac muscles. DMD/BMD is caused by mutations in the Dystrophin gene on the X chromosome, leading to the absence of the essential muscle protein Dystrophin in DMD. In BMD, Dystrophin is partially functioning with a shorter protein product. Recent advances in molecular therapies for DMD require precise genetic diagnoses because most therapeutic strategies are mutation-specific. Hence, early diagnosis is crucial to allow appropriate planning for patient care and treatment. In this study, data from DMD/BMD patients who attended the Kuwait Medical Genetic Center during the last 20 years was retrieved from a Kuwait neuromuscular registry and analyzed. We combined multiplex PCR and multiplex ligation-dependent probe amplification (MLPA) with Sanger sequencing to detect Dystrophin gene mutations. A total of 35 different large rearrangements, 2 deletion-insertions (Indels) and 4 substitution mutations were identified in the 68 unrelated families. The deletion and duplication rates were 66.2% and 4.4%, respectively. The analyzed data from our registry revealed that 11 (16%) of the DMD families will benefit from newly introduced therapies (Ataluren and exon 51 skipping). At the time of submitting this paper, two cases have already enrolled in Ataluren (Tranlsarna™) therapy, and one case has been enrolled in exon 51 skipping therapy.
Highlights
Duchenne and Becker muscular dystrophies (DMD; MIM 310200/BMD; MIM 300376) are Xlinked recessive neuromuscular disorders
When the mutation causes a shift in the open reading frame (ORF) or generates a premature stop codon, non-functional protein is produced and the patient will suffer from DMD; in contrast, when the reading frame is maintained, a partially functional protein is produced and the patients will show the milder clinical symptoms associated with BMD [10,11]
We analyzed 68 DNA samples from unrelated patients diagnosed with DMD/ BMD based on clinical, biochemical and electrophysiological findings
Summary
Duchenne and Becker muscular dystrophies (DMD; MIM 310200/BMD; MIM 300376) are Xlinked recessive neuromuscular disorders. When the mutation causes a shift in the open reading frame (ORF) or generates a premature stop codon, non-functional protein is produced and the patient will suffer from DMD; in contrast, when the reading frame is maintained (inframe mutation), a partially functional protein is produced and the patients will show the milder clinical symptoms associated with BMD [10,11]. Frame-shift mutations will result in a DMD phenotype; mutations before exon 8 can present as BMD instead. This has been explained by the presence of alternative start sites in exon 8 that compensate for the earlier mutations. Frame-shifting mutations flanking exon 44 generally promote a disease course milder than typical DMD [14,15]. It is important to consider the specific mutations associated with DMD when diagnosing DMD patients
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