Rett Sendromlu Hastaların Klinik ve Moleküler Değerlendirmesi ve Genotip-Fenotip Korelasyonunun Araştırılması

Abstract

ABSTRACT Zengin Akkuş, Pınar, Clinical and Molecular Aspects of Rett Syndrome and Evaluation of Genotype-Phenotype Correlation, Hacettepe University, Faculty of Medicine, Thesis in Pediatrics. Ankara, 2015. Rett syndrome is a neurodevelopmental disorder characterized by early neurological regression following a seemingly normal early development, which is seen almost exclusively in females. Acquired fine and gross motor functions, language and communication skills are lost, with coexisting autonomic dysfunction and seizures. Rett syndrome occurs due to mutations in MECP2 gene and is a clinical diagnosis, however, molecular testing is supportive. In this study, 16 patients who were clinically diagnosed with Rett syndrome and had MECP2 mutations have been evaluated. Median age of the patients was 6.5 years (2.5-22 years). Following the onset of regression leading to hospital admission, median ages of clinical evaluation by a physician, a pediatric neurologist and a geneticist were 1.5, 1.5 and 3 years, respectively. Median age of onset was 1.5 years and median age at clinical diagnosis was 2.5 years. The difference indicated a clinical diagnostic delay of median 1 year and was statistically significant (p<0.05). In three patients, there was no diagnostic delay. Clinical diagnostic delay may be related to variability in presentation of initial findings and clinical course in patients, as well as time spent during testing for differential diagnosis. According to consensus criteria regulated in 2002 and revised in 2010, seven and two patients did not match main criteria, respectively. In MBD region missense mutations R106W (3), R133C (1), R152R (1) and T158M (1); in interdomain region nonsense mutation R168X (3); in TRD region nonsense mutations R255X (1) and R270X (1) and missense mutations R306C (1) and 808delG (1); at C terminal non-stop mutation X487R (1), frameshift mutation 1164delA (1) and exon 3-4 deletion (1) were detected. Pineda score for clinical severity was 6-23 (median 11) in the whole group, 9-15 (median 10.5) in MBD group, 10-17 (median 12) in interdomain group, 10-23 (median 12.5) in TRD group, 6 and 11 in C terminal group and 8 in exon 3-4 deletion, the difference being statistically insignificant (p>0.05). Establishment of genotype phenotype correlation would require a larger patient group. Keywords: Rett syndrome, MECP2 , genotype-phenotype correlation