Mutation spectrum analysis of Duchenne/Becker muscular dystrophy in 68 families in Kuwait: The era of personalized medicine

PLoS One. 2018 May 30;13(5):e0197205. doi: 10.1371/journal.pone.0197205. eCollection 2018.

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.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • DNA Mutational Analysis
  • Dystrophin / genetics*
  • Exons
  • Family
  • Female
  • Gene Expression
  • Genetic Therapy / methods
  • Humans
  • INDEL Mutation*
  • Kuwait
  • Male
  • Multiplex Polymerase Chain Reaction
  • Muscular Dystrophy, Duchenne / genetics*
  • Muscular Dystrophy, Duchenne / metabolism
  • Muscular Dystrophy, Duchenne / pathology
  • Muscular Dystrophy, Duchenne / therapy
  • Mutation, Missense*
  • Oxadiazoles / therapeutic use
  • Precision Medicine
  • Sequence Deletion*

Substances

  • DMD protein, human
  • Dystrophin
  • Oxadiazoles
  • ataluren

Grants and funding

The author(s) received no specific funding for this work.