Neurodegeneration with brain iron accumulation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.

Fig. 1

Patterns on T2-weighted brain magnetic resonance imaging. The image on the left is from a normal patient. The center image from a PANK2 mutation-positive patient shows hypointensity (thick arrow) with a central region of hyperintensity (thin arrow) in the medial globus pallidus (eye-of-the-tiger sign). The right image from a PANK2-negative patient with NBIA shows only a region of hypointensity (arrow) in the medial globus pallidus. Image reprinted with permission from the Massachusetts Medical Society (copyright 2003): Hayflick SJ, Westaway SK, Levinson B, Zhou B, A. JM, Ching KHL and Gitschier J. Genetic, clinical and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003; 348: 33-40

Fig. 2

Pantothenate forms the chemical core of coenzyme A (from Kyoto Encyclopedia of Genes and Genomes, http://www.genome.ad.jp/kegg/)