Iron Dysregulation in Neurodegeneration with Brain Iron Accumulation (NBIA): Links between Mutations Occurring in BPAN, PKAN, MPAN and PLAN Types and Iron Metabolism.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurodegenerative disorders characterized by excessive iron deposition in the central nervous system. The disease typically manifests in early childhood with progressive dystonia, muscle rigidity, spasticity, ataxia, as well as personality changes (such as nervousness, aggression, and learning difficulties) and psychiatric symptoms (including disorientation, confusion, seizures, and dementia). The most common forms - BPAN, PKAN, MPAN, and PLAN-are associated with mutations in the WDR45, PANK2, C19orf12, and PLA2G6 genes, respectively, leading to disruptions in mitochondrial functions, autophagy, and coenzyme A metabolism. These abnormalities result in oxidative stress and neurodegeneration; however, the connection between the observed mutations and iron accumulation in the central nervous system remains unclear. There is ongoing debate as to whether iron accumulation is a primary pathological factor or a secondary consequence of cellular dysfunction. Unfortunately, despite numerous therapeutic attempts, including the use of iron chelators, treatment efficacy remains very limited. Therefore, the aim of this review was to present the latest findings on the relationship between WDR45, PANK2, C19orf12, and PLA2G6 mutations and iron metabolism disorders. The data presented may help explain the previously undescribed roles of these mutations in the excessive iron accumulation observed in the nervous system of patients with NBIA, while also highlighting the complexity of NBIA pathogenesis. A better understanding of these mechanisms may contribute to the development of new, more effective therapeutic strategies, which are greatly needed by patients.