Classification and molecular pathogenesis of NBIA syndromes

Brain iron accumulation is the hallmark of a group of seriously invalidating and progressive rare diseases collectively denominated Neurodegeneration with Brain Iron Accumulation (NBIA), characterized by movement disorder, painful dystonia, parkinsonism, mental disability and early death. Currently there is no established therapy available to slow down or reverse the progression of these conditions. Several genes have been identified as responsible for NBIA but only two encode for proteins playing a direct role in iron metabolism. The other genes encode for proteins either with various functions in lipid metabolism, lysosomal activity and autophagic processes or with still unknown roles. The different NBIA subtypes have been classified and denominated on the basis of the mutated genes and, despite genetic heterogeneity, some of them code for proteins, which share or converge on common metabolic pathways. In the last ten years, the implementation of genetic screening based on Whole Exome Sequencing has greatly accelerated gene discovery, nevertheless our knowledge of the pathogenic mechanisms underlying the NBIA syndromes is still largely incomplete.