Neurodegeneration with Brain Iron Accumulation: Genetic Diversity and Pathophysiological Mechanisms

Annu Rev Genomics Hum Genet. 2015;16:257-79. doi: 10.1146/annurev-genom-090314-025011. Epub 2015 May 8.


Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive disorders with the common feature of excessive iron deposition in the brain. Over the last decade, advances in sequencing technologies have greatly facilitated rapid gene discovery, and several single-gene disorders are now included in this group. Identification of the genetic bases of the NBIA disorders has advanced our understanding of the disease processes caused by reduced coenzyme A synthesis, impaired lipid metabolism, mitochondrial dysfunction, and defective autophagy. The contribution of iron to disease pathophysiology remains uncertain, as does the identity of a putative final common pathway by which the iron accumulates. Ongoing elucidation of the pathogenesis of each NBIA disorder will have significant implications for the identification and design of novel therapies to treat patients with these disorders.

Keywords: BPAN; CoA metabolism; CoPAN; MPAN; NBIA; PKAN; PLAN; iron metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autophagy / genetics
  • Brain / metabolism*
  • Brain / physiopathology
  • Ceruloplasmin / deficiency
  • Ceruloplasmin / genetics
  • Ceruloplasmin / metabolism
  • Coenzyme A / biosynthesis
  • Genetic Variation*
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism
  • Humans
  • Iron / metabolism*
  • Iron Metabolism Disorders / genetics*
  • Iron Metabolism Disorders / metabolism
  • Iron Metabolism Disorders / physiopathology*
  • Lipid Metabolism / genetics
  • Mice
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neuroaxonal Dystrophies / genetics
  • Neuroaxonal Dystrophies / metabolism
  • Neuroaxonal Dystrophies / physiopathology
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / physiopathology
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism


  • C19orf12 protein, human
  • Mitochondrial Proteins
  • Iron
  • Ceruloplasmin
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • Coenzyme A

Supplementary concepts

  • Familial apoceruloplasmin deficiency
  • Kufor-Rakeb syndrome
  • Neuroferritinopathy