Abstract
The syndromes of neurodegeneration with brain iron accumulation (NBIA) encompass a group of invalidating and progressive rare diseases that share the abnormal accumulation of iron in the basal ganglia. The onset of NBIA disorders ranges from infancy to adulthood. Main clinical signs are related to extrapyramidal features (dystonia, parkinsonism and choreoathetosis), and neuropsychiatric abnormalities. Ten NBIA forms are widely accepted to be caused by mutations in the genes PANK2, PLA2G6, WDR45, C19ORF12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17. Nonetheless, many patients remain without a conclusive genetic diagnosis, which shows that there must be additional as yet undiscovered NBIA genes. In line with this, isolated cases of known monogenic disorders, and also, new genetic diseases, which present with abnormal brain iron phenotypes compatible with NBIA, have been described. Several pathways are involved in NBIA syndromes: iron and lipid metabolism, mitochondrial dynamics, and autophagy. However, many neurodegenerative conditions share features such as mitochondrial dysfunction and oxidative stress, given the bioenergetics requirements of neurons. This review aims to describe the existing link between the classical ten NBIA forms by examining their connection with mitochondrial impairment as well as oxidative stress and neuroinflammation.
Highlights
The neurodegeneration with brain iron accumulation (NBIA) syndromes are rare diseases with an estimated prevalence of 1–3/1,000,000, characterized by progressive hypo- and/or hyperkinetic movement disorders with abnormal deposits of iron in the brain, primarily in the basal ganglia
Among NBIA disorders, the most common form is caused by biallelic mutations in the pantothenate kinase 2 (PANK2) gene (Table 1), which are responsible for Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive (AR) disorder [24,25,26,27,28]
NBIA syndromes share the distinctive feature of iron overload in the brain and present a wide genetic heterogeneity with genes related to disparate pathways
Summary
The NBIA (neurodegeneration with brain iron accumulation) syndromes are rare diseases with an estimated prevalence of 1–3/1,000,000, characterized by progressive hypo- and/or hyperkinetic movement disorders with abnormal deposits of iron in the brain, primarily in the basal ganglia These complex multisystem disorders exhibit extrapyramidal dysfunction, mainly dystonia, parkinsonism, and choreoathetosis. Atypical forms have an onset at adolescence or early adulthood, and include dystonia-parkinsonism, cerebellar ataxia, eye movement abnormalities, cognitive decline, and psychiatric disturbances. Adult-onset form with cognitive decline, cerebellar ataxia, and craniofacial dyskinesia, besides of retinal degeneration, and even, diabetes caused by the accumulation of iron. KRS is characterized by juvenile parkinsonism, dystonia, eye movement abnormalities, autonomic dysfunction, dementia, and psychiatric features, Hypointensity in the basal ganglia/caudo-putamen. GM1-gangliosidosis type I (infantile form; 230500) type II (juvenile form; 230600) type III (adult form; 8230650) AR
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