On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation

Clin Genet. 2018 Apr;93(4):731-740. doi: 10.1111/cge.13057. Epub 2017 Sep 25.

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited heterogeneous neurodegenerative rare disorders. These patients present with dystonia, spasticity, parkinsonism and neuropsychiatric disturbances, along with brain magnetic resonance imaging (MRI) evidence of iron accumulation. In sum, they are devastating disorders and to date, there is no specific treatment. Ten NBIA genes are accepted: PANK2, PLA2G6, C19orf12, COASY, FA2H, ATP13A2, WDR45, FTL, CP, and DCAF17; and nonetheless, a relevant percentage of patients remain without genetic diagnosis, suggesting that other novel NBIA genes remain to be discovered. Overlapping complex clinical pictures render an accurate differential diagnosis difficult. Little is known about the pathophysiology of NBIAs. The reported NBIA genes take part in a variety of pathways: CoA synthesis, lipid and iron metabolism, autophagy, and membrane remodeling. The next-generation sequencing revolution has achieved relevant advances in genetics of Mendelian diseases and provide new genes for NBIAs, which are investigated according to 2 main strategies: genes involved in disorders with similar phenotype and genes that play a role in a pathway of interest. To achieve an effective therapy for NBIA patients, a better understanding of the biological process underlying disease is crucial, moving toward a new age of precision medicine.

Keywords: NBIA genes; interactome; movement disorders; neurodegeneration with brain iron accumulation.

Publication types

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

MeSH terms

  • Brain / diagnostic imaging*
  • Brain / physiopathology
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Iron / metabolism*
  • Lipid Metabolism / genetics
  • Magnetic Resonance Imaging
  • Neurodegenerative Diseases / diagnosis
  • Neurodegenerative Diseases / diagnostic imaging
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / physiopathology
  • Pantothenate Kinase-Associated Neurodegeneration / diagnosis
  • Pantothenate Kinase-Associated Neurodegeneration / diagnostic imaging
  • Pantothenate Kinase-Associated Neurodegeneration / genetics*
  • Pantothenate Kinase-Associated Neurodegeneration / physiopathology

Substances

  • Iron