[SP6-3D-8] Nonsense mutation dystrophinopathy: The shift in the diagnostic paradigm in the era of mutation-specific treatments
About 15% of Duchenne muscular dystrophy (DMD) is caused by nonsense mutations. We report clinical and genetic characteristics of 40 patients (39 boys, and one manifesting 38-year-old female carrier) with nonsense mutated-DMD. Age at diagnosis was 4.1 years (3 months-11.2 years). Presentations were incidentally detected high serum creatine kinase level (n= 17, 42.5%), difficulty in climbing stairs/frequent falls (n=14, 35%), delay in gross-motor milestones (n= 9, 22.5%), learning disability (n=14), and attention deficient hyperactivity disorder (n=5). Sixteen patients had a family history of DMD. Multiplex PCR study of the most commonly deleted exons were negative (n=21), and muscle biopsy was consistent with dystrophinopathy (n= 22). Multiplex ligation-dependent probe amplification (MLPA) was performed in 33 patients followed by direct sequencing of all exons at the genomic level revealed nonsense mutations. Mean age at multiplex-PCR, MLPA, and exome sequencing were 4.4 years, 6.8 years, and 7.2 years respectively. Currently, nine non-ambulatory patients are older than 10 years, and six patients are younger than 5 years of age. Twenty patients (80%) are receiving steroid therapy, and 23 (58%) are on Translarna (PTC-124) treatment for a mean period of 11 months (1-18 month). Advances in the field and availability of different genetic tests resulted in a shift in the molecular diagnosis of patients. In our center, a stepwise approach includes MLPA followed by muscle biopsy and direct sequencing of all exons at the genomic level. A dynamic approach for molecular diagnosis provides opportunity for genetic counseling and disease-modifying therapies.