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

• Published in: Clinical genetics Vol. 93; no. 4; pp. 731 - 740
• Main Authors: Tello, C., Darling, A., Lupo, V., Pérez‐Dueñas, B., Espinós, C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2018
• Subjects: Autophagy; Basal ganglia; Central nervous system diseases; Differential diagnosis; Dystonia; Genetic screening; interactome; Iron; Lipid metabolism; Magnetic resonance imaging; Mental disorders; Movement disorders; NBIA genes; Neurodegeneration; neurodegeneration with brain iron accumulation; Neuroimaging; NMR; Nuclear magnetic resonance; Phagocytosis; Phenotypes; Precision medicine; Spasticity; neurodegeneration with brain iron accumulation; interactome; movement disorders; NBIA genes
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.13057

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.