Omics analyses combined with neurodevelopmental assessment in Pitt-Hopkins syndrome patients to search for indicators of efficacy of new therapeutics

Pitt-Hopkins syndrome (PTHS) is a multisystemic disorder with severe intellectual disability, high risk of autism and many additional signs, including epilepsy, altered intestinal motility and breathing regulation, unstable gait and ophthalmological anomalies. It is caused by alterations in one copy of the TCF4 gene. The disease mechanism is haploinsufficiency. What prompted us to plan the present research is the evidence that some possibilities of treatment for PTHS already exists, in vivo, through IGF-1, for which a multicenter clinical trial is planned, and that gene therapy approaches aimed at increasing the activity of the normal copy of the gene are already being tested in vitro. Any new therapy is expected not to reverse the whole clinical phenotype, but to improve communication, social, motor and cognitive skills, to reduce anxiety and behavioral problems. A series of PTHS with a variable clinical presentation will be analyzed by an accurate clinical evaluation, combined with molecular analyses aimed to investigate how TCF4 mutations can alter the expression and function of many other genes. The clinical evaluation, and any molecular indicator of the disease, defining candidate biomarkers, will be tested after the administration of IGF-1, that will be part of a future research. The main purpose of the present project is to look for indicators of clinical presentation and of efficacy of new therapeutics. The same clinical and molecular indicators could be proposed as a tool to test the efficacy of any new future treatment.