Recent Insights into Genotype-Phenotype Relationships in Patients with Rett Syndrome Using a Fine Grain Scale

Mutations in MECP2 gene cause Rett Syndrome (RTT), a neurodevelopmental disorder affecting around 1 in 10,000 female births. The clinical picture of RTT appears quite heterogeneous for each single feature. Mutations in MECP2 gene have been associated with the onset of RTT. The most known gene function consists of transcriptional repression of specific target genes, mainly by the binding of its methyl binding domain (MBD) to methylated CpG nucleotides and recruiting co-repressors and histone deacetylase binding to DNA by its Transcription Repressor Domain (TRD). This study aimed to evaluate a cohort of 114 Rett Syndrome (RTT) patients with a scale measuring in details the different kinds of impairments produced by the syndrome. The sample included relatively large subsets of the most frequent mutations so that genotype-phenotype correlations could be tested. Results revealed that frequent missense mutations showed a specific profile in different areas of impairment. The R306C mutation, considered as producing mild impairment, was associated to a moderate phenotype in which the behavioural characteristics were mainly affected. A notable difference emerged by comparing mutations truncating the protein before and after the Nuclear Localization Signal; it concerned prevalently the motor-functional and autonomy skills of the patients, affecting the management of everyday activities.