Purpose of review: After the recent discovery of the major genetic defect in neurodegeneration with brain iron accumulation (NBIA, formerly Hallervorden-Spatz syndrome), this heterogeneous group of disorders can now be differentiated by clinical, radiographic, and molecular features.

Recent findings: Disease caused by mutations in the gene encoding pantothenate kinase 2 (PANK2) is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric defects in adults, in concert with a specific pattern on MRI of the brain. This virtually pathognomonic radiographic abnormality, called the eye-of-the-tiger sign, comprises hyperintensities within a hypointense medial globus pallidus on T2-weighted images. This disorder is called pantothenate kinase-associated neurodegeneration (PKAN) and accounts for most patients diagnosed with NBIA. Pantothenate kinase is essential to coenzyme A biosynthesis, and PANK2 is targeted to mitochondria, a feature that distinguishes it from the three other human pantothenate kinase homologs. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing enzyme substrates, which may chelate iron and lead to the cardinal disease feature of basal ganglia iron accumulation.

Summary: Recent insight into the biochemical basis of PKAN has led to novel ideas for rational therapies. Investigations are under way to enable testing of promising compounds, first in animal models of disease and then in human patients. Identification of the genetic basis for the major form of NBIA has allowed more accurate clinical delineation of the specific diseases that compose this group, a new molecular diagnostic test for PKAN, and hypotheses for treatment of this neurodegenerative disorder.