G.P.47: Severe congenital myopathy with central nuclei and novel RYR1 gene mutations

Abstract

Congenital myopathies with centrally placed nuclei are a heterogenous group of diseases and mutations in the genes associated with centronuclear or myotobular myoapthy and even myotonia dystrophica congenita have been all well described. Recently, there have been reports of <i>RYR1</i> gene mutations associated with congenital myopathy with central nuclei without cores. We report a 17year old wheelchair-bound girl who presented at birth with severe generalized weakness, ptosis, ophthalmoplegia and profound facial and bulbar weakness. All findings have lasted throughout her life requiring tracheostomy and life-long nocturnal ventilation (at 17years FVC is 39% of predicted, and FEV1 33%) as well as placement of G-tube. Her CK has been repeatedly normal, EMG was myopathic. Muscle biopsy at 4months of age showed 91.2% fiber type I predominance and centrally placed nuclei in 10–15% of muscle fibers. EM showed focal myofribrillary disarray. DNA analysis of <i>MTM1</i> and <i>DNM2</i> genes revealed no mutations but she was found to have two novel heterozygous mutations in <i>RYR1</i> gene: in exon 21 c2682G>A, and, in exon 66 c.9859C>T (p.Arg3287Cys). Severe myopathy with central nuclei and <i>RYR1</i> mutations without cores requiring life-long ventilatory support has been reported in four other cases. The findings will be compared with the current case with focus on respiratory therapy. Our case of severe congenital myopathy with central nuclei and novel mutations in <i>RYR1</i> gene emphasizes the genetic and phenotypic heterogeneity of congenital muscle diseases associated with central nuclei. Apart from genes associated with CNM and MTM (i.e. <i>DNM2, BIN1</i> and <i>MTM1</i>) one needs to search for mutations in <i>RYR1</i> gene as well.