Konjenital Myopatilerde Klinik, Histopatolojik ve Genetik Değerlendirme

Abstract

Congenital myopathies are a group of inherited muscle disorders presenting in childhood and mainly diagnosed by muscle biopsy. Nemaline myopathy, centronuclear myopathy, core myopathy and congenital fiber type disproportion consist the most common forms. A clinical and genetic overlap is frequently seen in different forms of congenital myopathies as well as similar histopathologic features may be seen in different clinical presentations and genetic mutations. Thus, an integrated approach is essential to reach a diagnosis and develop appropriate therapies. The aim of this study is to make clinical and histopathological assessment and identify causative genes and proteins of congenital myopathy patients in our hospital. We have reviewed the patients diagnosed with congenital myopathy between 2003-2013. Clinical information was obtained from medical records. Patients who were able to come to hospital were re-examined and their last clinical status was annotated. Muscle biopsies were reevaluated and reclassified according to most recent literature data. In collaboration with Boston Children’s Hospital Genetics/Genomics department, we have studied the DNA samples to look for known congenital myopathy genes from the patients whose clinical picture and histopathological features are evidently typical. For the patients who did not have such features, their samples were sent for whole exome sequencing in order to identify new causative genes. In the case of exploring an unknown gene, we have planned functional studies to look for any genotype-phenotype correlation. There were 90 non-related cases, whose age of biopsy ranged from 6 days to 17 years. Mean age was different in each congenital myopathy subgroup. There was no significiant difference between males and females. Consanguinity was present in %58 of patients. Histopathological classification yielded 30 patients of nemaline myopathy, 11 with core myopathy, 14 with centronuclear myopathy and 5 with congenital fiber type disproportion. In 30 patients, muscle biopsy showed features suggestive for congenital myopathy but not sufficient to classify into a single subgroup. DNA samples from 43 patients were analysed. Some analyses were culminated with clear results. The genes that were recently shown to cause congenital myopathy (e.g. KLHL40, TTN, SPEG) were identified as well as other known congenital myopathy genes (e.g. RYR1, SEPN1, TPM3, ACTA1). This study is the largest systematic review of the congenital myopathies in Turkey. Genetic studies are explicitly gaining dominancy in these diseases, which help us to identify new genes, elaborate new pathogenetic mechanisms and design new therapeutic approaches. However, it is not always feasible to access genetic tests and to get insufficient data is not rare. In this case, identifying certain clinical phenotypes along with histopathological (and/or genetic) data could obtain substantial information about the prognosis of the disease and therapeutic interventions.