No abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, many patients with clinical and radiologic features of NBIA have not had a clearly identifiable molecular cause. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6. In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia-parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome and together they implicate new cellular pathways in the pathogenesis of these disorders.