Abstract
Cell trafficking alterations are a growing group of disorders and one of the largest categories of Inherited Metabolic Diseases. They have complex and variable clinical presentation. Regarding neurological manifestations they can present a wide repertoire of symptoms ranging from neurodevelopmental to neurodegnerative disorders. The study of monogenic cell trafficking diseases draws an scenario to understanding this complex group of disorders and to find new therapeutic avenues. Within their pathophysiology, alterations in autophagy outstand as a targetable mechanism of disease, ammended to be modulated through different strategies. In this work we have studied the pathophysiology of two cell trafficking disorders due to mutations in SYNJ1 and NBAS genes. Specifically, we have assesed the autophagic flux in primary fibroblast cultures of the patients and gender/age-matched controls and whether it could be address with a therapeutic purpose. The results have shaped autophagy as one of the hallmarks of the disease. Moreover, we tested in vitro the effect of spermidine, a natural polyamine that acts as an autopagy inductor. Due to the positive results, its efficacy was evaluated later on the patients as well, in a series of n-of-1 clinical trials, achieving improvement in some clinical aspects related to motricity and cognition. Defining autophagy alterations as a common feature in the pathophysiology of cell trafficking disorders is a great step towards their treatment, as it represents a potential actionable target for the personalized treatement of these disorders.