CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.236Congenital fiber type disproportion with mutations in tropomyosin 3 (TPM3) gene presenting as respiratory failure

Abstract

Congenital fiber type disproportion(CFTD) is a rare subtype of congenital myopathy. CFTD is clinically heterogenous and histologically marked by hypotrophy of type I fibers compared with type 2 fibers. CFTD has been related with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. Particularly, TPM3 mutation was identified to the most frequent cause of CFTD and was also detected in cap myopathy and nemaline myopathy. We report autosomal dominant TPM3 missense mutations with CFTD in a family over two-generations. The two patients, the brother and sister, experienced first symptoms of muscle weakness in infancy with delayed motor milestones and followed a slowly progressive course. They presented generalized muscular hypotrophy, neck flexor muscle and distal limb muscle weakness, elongated face, retrognathia, high arched palate and scoliosis. Respiratory function became critical in two patients despite relatively good limb strength. The brother presented in respiratory arrest during sleep. The sister did not complain of difficulty on walking and climbing stairs but presented in respiratory failure needing ventilator. The finding of electromyography was compatible with myopathy and muscle biopsy showed type 1 fiber atrophy with predominance in the absence of other notable pathological findings such as nemaline rods and cap structures. TPM3 missense mutation c.502C>T (p.R168C) in exon 5 was identified by a target NGS. We confirmed CFTD caused by TPM3 mutation in this family. CFTD patients with mutation in TPM3 have been previously reported that many patients required nocturnal noninvasive ventilatory support despite remaining ambulant and several patients of these abruptly presented in respiratory failure. All patients in our family also showed sudden respiratory failure with relatively spared limb weakness. Therefore, it is clinically important for monitoring respiratory function regularly in CFTD patients with TPM3 mutation.