CONGENITAL MYOPATHIES (CNM): P.147Novel SPEG mutations in congenital myopathy without centralized nuclei

Abstract

Congenital myopathies are clinically and genetically heterogeneous disorders characterized by distinctive morphological abnormalities in skeletal muscle fibers. Several genes have already been linked to congenital myopathies. However, about half of the patients do not have a genetic diagnosis. Within the 'Myocapture' project, a French consortium with the aim to better characterize the genetic data of patients, we studied a patient with molecularly unexplained muscle weakness. At birth, the patient presented with hypotonia and poor sucking. Motor milestones were delayed and cognitive involvement was normal. Reduced myocardial contraction appeared at age 5 and normalized with treatment. At 9 years of age, the patient presented with proximal and distal muscle weakness and facial weakness without ptosis. Morphological studies of muscle biopsy revealed mild fiber size heterogeneity as main histological change. Biallelic truncating SPEG mutations were identified by exome sequencing. SPEG encodes the striated muscle preferentially expressed protein kinase, that interacts with myotubularin (MTM1), a protein mutated in X-linked centronuclear myopathy (CNM). Biallelic SPEG mutations were recently described as mutated in patients with CNM associated in most cases with dilated cardiomyopathy. Conversely, in our patient, muscle biopsy did not reveal internalized nuclei and our patient did not develop dilated cardiomyopathy. Overall, we describe two novel SPEG mutations in a patient with a mild myopathy characterized by muscle weakness and fiber size heterogeneity on muscle biopsy. This study expands the spectrum of diseases associated with mutations in SPEG, previously described in patients with CNM. Specific SPEG mutations can induce a severe CNM-like or, as described in our study, a rather moderate congenital myopathy without central nuclei.