Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation is a heterogenous group of inherited neurodegenerative diseases, still under research, in which iron accumulates in the basal ganglia, either resulting in progressive dystonia, Parkinsonism, spasticity, optic atrophy, retinal degeneration, neuropsychiatric, or diverse neurologic abnormalities.[1] Some of the NBIA disorders have also been associated with several genes in synapse and lipid metabolism related pathways.[2] NBIA is not one disease but an entire group of disorders, characterized by an accumulation of brain iron, sometimes in the presence of axonal spheroids in the central nervous system.[3]

Neurodegeneration with brain iron accumulation
Other namesNBIA
SpecialtyNeurology 

Iron accumulation can occur anywhere in the brain, with accumulation typically occurring in globus pallidus, substantia nigra, pars reticula, striatum and cerebellar dentate nuclei.[4] Symptoms can include various movement disorders, neuropsychiatric issues, seizures, visual disturbances, and cognitive decline, usually in different combinations.[4] 10-15 genetic NBIA disorders have been identified involved in various cell processes: iron metabolism, coenzyme A biosynthesis, phospholipid metabolism, ceramide metabolism, lysosomal disorders, as well as mutations in genes with unknown functions.[5][4] Onset can occur at different ages, from early childhood to late adulthood.[4]

There are currently no curative treatments for any of the NBIA disorders, though several medications have been subject to clinical trial including the iron chelator deferiprone.[5]

Variants
Overview of monogenic NBIA disorders[5][6][7]
NBIA variantGeneInheritance
Pantothenate kinase-associated neurodegeneration (PKAN)[8]PANK2autosomal recessive
PLA2G6-associated neurodegeneration (PLAN)[9]PLA2G6autosomal recessive
Mitochondrial membrane protein-associated neurodegeneration (MPAN)[10]C19orf12autosomal recessive or dominant
Beta-propeller protein-associated neurodegeneration (BPAN)[11]WDR45X-linked dominant (mostly de novo'' mutations)
Fatty acid hydroxylase-associated neurodegeneration (FAHN)[12]FA2Hautosomal recessive
Kufor–Rakeb syndromeATP13A2autosomal recessive
NeuroferritinopathyFTLautosomal dominant
AceruloplasminemiaCPautosomal recessive
Woodhouse–Sakati syndromeDCAF17autosomal recessive
COASY protein-associated neurodegeneration (CoPAN)COASYautosomal recessive
NBIA7[13] REPS1 autosomal recessive
NBIA8[13] CRAT autosomal recessive

Diagnosis

DAT-Scans, TC(D)-Sonography, PET-Scans and in some cases Magnetic resonance imaging (MRI) (type of scans depending on the symptoms)[14] are used to distinguish between the different forms of NBIA due to the accumulation of iron in different areas of the brain.[15] Patients typically fall into two different categories: (1) early onset, rapid progression or (2) late onset, slow progression.[15] The first type is considered to be the classic presentation, while the second type is thought to be a more atypical presentation. Phenotypes of the different disorders appear to be dependent on age, i.e. amount of iron accumulation and cognitive abilities.[16]

Treatments

Effective disease-modifying treatments have not yet been found for any of the NBIA disorders.[5] Current treatment is supportive and focused on improving symptoms: Dystonia is a common debilitating symptom and can be managed with oral medications, and sometimes with deep-brain electrical stimulation, therapy support for walking, eating, and manual tasks is essential. Later, in many of the diseases, slowing and stopping of movement (known as parkinsonism) can become common. Removal of iron, using medications known as iron-chelators, has been tested in clinical trial but was not definitively shown to be effective.[17]

References
  1. Ward, Roberta J.; Chrichton, Robert R. (2019). "Chapter 4. Ironing out the Brain". In Sigel, Astrid; Freisinger, Eva; Sigel, Roland K. O.; Carver, Peggy L. (eds.). Essential Metals in Medicine:Therapeutic Use and Toxicity of Metal Ions in the Clinic. Metal Ions in Life Sciences. Vol. 19. Berlin: de Gruyter GmbH. pp. 87–122. doi:10.1515/9783110527872-010. ISBN 978-3-11-052691-2. PMID 30855105.
  2. Bettencourt C, Forabosco P, Wiethoff S, Heidari M, Johnstone DM, Botía JA, Collingwood JF, Hardy J, Milward EA, Ryten M, Houlden H (March 2016). "Gene co-expression networks shed light into diseases of brain iron accumulation". primary. Neurobiology of Disease. 87: 59–68. doi:10.1016/j.nbd.2015.12.004. PMC 4731015. PMID 26707700.
  3. Gregory A, Polster BJ, Hayflick SJ (February 2009). "Clinical and genetic delineation of neurodegeneration with brain iron accumulation". review. Journal of Medical Genetics. 46 (2): 73–80. doi:10.1136/jmg.2008.061929. PMC 2675558. PMID 18981035.
  4. Dusek P, Schneider SA (August 2012). "Neurodegeneration with brain iron accumulation". review. Current Opinion in Neurology. 25 (4): 499–506. doi:10.1097/wco.0b013e3283550cac. PMID 22691760.
  5. Spaull, Robert V. V.; Soo, Audrey K. S.; Hogarth, Penelope; Hayflick, Susan J.; Kurian, Manju A. (24 November 2021). "Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation". Tremor and Other Hyperkinetic Movements. 11 (1): 51. doi:10.5334/tohm.661.accessed 7 December 2021
  6. Gregory A, Hayflick S (28 February 2013). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). Neurodegeneration with Brain Iron Accumulation Disorders Overview. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. PMID 23447832.
  7. Hogarth P (January 2015). "Neurodegeneration with brain iron accumulation: diagnosis and management". Journal of Movement Disorders. 8 (1): 1–13. doi:10.14802/jmd.14034. PMC 4298713. PMID 25614780.
  8. Gregory A, Hayflick SJ (2003). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). "Pantothenate Kinase-Associated Neurodegeneration". GeneReviews [Internet]. PMID 20301663.
  9. Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ (2008). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). "PLA2G6-Associated Neurodegeneration". GeneReviews [Internet]. PMID 20301718.
  10. Gregory A, Hartig M, Prokisch H, Kmiec T, Hogarth P, Hayflick SJ (2014). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). "Mitochondrial Membrane Protein-Associated Neurodegeneration". GeneReviews [Internet]. PMID 24575447.
  11. Gregory A, Kurian MA, Haack T, Hayflick SJ, Hogarth P (16 Feb 2017). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). "Beta-Propeller Protein-Associated Neurodegeneration". GeneReviews [Internet]. PMID 28211668.
  12. Kruer MC, Gregory A, Hayflick SJ (28 Jun 2011). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). "Fatty Acid Hydroxylase-Associated Neurodegeneration". GeneReviews [Internet]. PMID 21735565.
  13. Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traoré M, et al. (February 2018). "Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation". primary. American Journal of Human Genetics. 102 (2): 266–277. doi:10.1016/j.ajhg.2018.01.003. PMC 5985451. PMID 29395073.
  14. Brüggemann N. et al.: Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype. Arch Neurol. 2010 Nov;67(11):1357-63. doi: 10.1001/archneurol.2010.281.
  15. Hayflick SJ, Hartman M, Coryell J, Gitschier J, Rowley H (2006-06-01). "Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations". primary. AJNR. American Journal of Neuroradiology. 27 (6): 1230–3. PMC 2099458. PMID 16775270.
  16. Schneider SA, Bhatia KP (June 2012). "Syndromes of neurodegeneration with brain iron accumulation". review. Seminars in Pediatric Neurology. 19 (2): 57–66. doi:10.1016/j.spen.2012.03.005. PMID 22704258.
  17. Klopstock, Thomas; Tricta, Fernando; Neumayr, Lynne; Karin, Ivan; Zorzi, Giovanna; et al. (July 2019). "Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study". The Lancet Neurology. 18 (7): 631–642. doi:10.1016/S1474-4422(19)30142-5.accessed 7 December 2021
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