Neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) describes a heterogeneous group of inherited rare clinical and genetic entities. Clinical core symptoms comprise a combination of early-onset dystonia, pyramidal and extrapyramidal signs with ataxia, cognitive decline, behavioral abnormalities, and retinal and axonal neuropathy variably accompanying these core features. Increased nonphysiologic, nonaging-associated brain iron, most pronounced in the basal ganglia, is often termed the unifying characteristic of these clinically variable disorders, though occurrence and extent can be fluctuating or even absent. Neuropathologically, NBIA disorders usually are associated with widespread axonal spheroids and local iron accumulation in the basal ganglia. Postmortem, Lewy body, TDP-43, or tau pathology has been observed. Genetics have fostered ongoing progress in elucidating underlying pathophysiologic mechanisms of NBIA disorders. Ten associated genes have been established, with many more being suggested as new technologies and data emerge. Clinically, certain symptom combinations can suggest a specific genetic defect. Genetic tests, combined with postmortem neuropathology, usually make for the final disease confirmation. Despite these advances, treatment to date remains mainly symptomatic. This chapter reviews the established genetic defects leading to different NBIA subtypes, highlights phenotypic presentations to direct genetic testing, and briefly discusses the scarce available treatment options and upcoming challenges and future hopes of the field.