Neurodegeneration with brain iron accumulation

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
Neurodegeneration with brain iron accumulation
Other namesNBIA
SpecialtyNeurology Edit this on Wikidata

Neurodegeneration with brain iron accumulation is a heterogenous group of inherited neurological disorders, 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] 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] The cause of NBIA disorders are a multitude of possible mutations in genes directly involved in iron metabolism, and/or impaired phospholipid, and/or ceramide metabolism, and/or lysosomal disorders, as well as mutations in genes with unknown functions.[4] Onset can occur at different ages, from early childhood to late adulthood.[4]


Overview of NBIA subtypes[5][6][7]
NBIA variant Gene Inheritance MRI diagnosis Symptoms
Pantothenate kinase-associated neurodegeneration (PKAN)[8] PANK2 autosomal recessive
PLA2G6-associated neurodegeneration (PLAN)[9] PLA2G6 autosomal recessive
Mitochondrial membrane protein-associated neurodegeneration (MPAN)[10] C19orf12 autosomal recessive
Beta-propeller protein-associated neurodegeneration (BPAN)[11] WDR45 X-linked dominant (mostly de novo mutations)
Fatty acid hydroxylase-associated neurodegeneration (FAHN)[12] FA2H autosomal recessive
Kufor–Rakeb syndrome ATP13A2 autosomal recessive
Neuroferritinopathy FTL autosomal dominant
Aceruloplasminemia CP autosomal recessive
Woodhouse–Sakati syndrome DCAF17 autosomal recessive
COASY protein-associated neurodegeneration (CoPAN) COASY autosomal recessive
NBIA7[13] REPS1 autosomal recessive
NBIA8[13] CRAT autosomal recessive

Other variants[edit]

There are a number of idiopathic NBIA variants for which details are still rare or missing. They all have in common that a disturbed iron metabolism causes havoc in the brain, especially the basal ganglia.[14]


DAT-Scans, TC(D)-Sonography, PET-Scans and in some cases Magnetic resonance imaging (MRI) (type of scans depending on the symptoms)[15] are used to distinguish between the different forms of NBIA due to the accumulation of iron in different areas of the brain.[16] Patients typically fall into two different categories: (1) early onset, rapid progression or (2) late onset, slow progression.[16] 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.[17]


An effective treatment has yet to be found. In many cases electrical stimulation of the globus pallidus has been shown to produce improvement of dystonia severity, however it has not been shown to delay neurodegeneration.[17][18] There is often overlap in the phenotypes of the symptoms both between different NBIA disorders and between NBIA and other disorders, leading to misdiagnoses.[18] Treatments typically treat or ameliorate the symptoms and do not address the accumulation of iron.[18] Psychopharmacology, such as with dopaminergic drugs, anticholinergics, tetrabenazine, is often used to treat the symptoms but does not improve the long term outcome of the patient.[18]


  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. (Guest editor) (eds.). Essential Metals in Medicine:Therapeutic Use and Toxicity of Metal Ions in the Clinic. Metal Ions in Life Sciences. 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. ^ a b c d 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. ^ "Einführung und Klinische Symptomatik". NBIA-Krankheitsbilder (in German). Friedrich Baur Institute, University Hospital Munich, Germany. Retrieved 2018-05-13.
  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. ^ a b 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. ^ Hogarth P. et al.: New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. In: Neurology. 2013 Jan 15;80(3):268-75. doi: 10.1212/WNL.0b013e31827e07be. Epub 2012 Dec 26.
  15. ^ 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.
  16. ^ a b 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.
  17. ^ a b 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.
  18. ^ a b c d Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP (January 2013). "Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)". primary. Current Neuropharmacology. 11 (1): 59–79. doi:10.2174/157015913804999469. PMC 3580793. PMID 23814539.

External links[edit]

External resources