Neurodegeneration with brain iron accumulation explained

Synonyms:NBIA

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]

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

there were no curative treatments for any of the NBIA disorders, though several medications have been subject to clinical trial including the iron chelator deferiprone.[4]

Variants

Overview of monogenic NBIA disorders[6] [7]
NBIA variant Inheritance
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 or dominant
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
ATP13A2 autosomal recessive
FTL autosomal dominant
CP autosomal recessive
DCAF17 autosomal recessive
COASY protein-associated neurodegeneration (CoPAN)COASY autosomal recessive
NBIA7[13] REPS1 autosomal recessive
NBIA8 CRAT autosomal recessive

Diagnosis

DaT scans, transcranial Doppler sonography (TCD), 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.[4] 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]

Notes and References

  1. Book: Ward . Roberta J. . Chrichton. Robert R. . Sigel. Astrid . Freisinger. Eva . Sigel. Roland K. O. . Carver. Peggy L. . Essential Metals in Medicine:Therapeutic Use and Toxicity of Metal Ions in the Clinic . Metal Ions in Life Sciences . 19 . de Gruyter GmbH. Berlin . 978-3-11-052691-2 . 30855105 . 87–122. Chapter 4. Ironing out the Brain . 10.1515/9783110527872-010 . 2019.
  2. Bettencourt C, Forabosco P, Wiethoff S, Heidari M, Johnstone DM, Botía JA, Collingwood JF, Hardy J, Milward EA, Ryten M, Houlden H . Gene co-expression networks shed light into diseases of brain iron accumulation . Neurobiology of Disease . 87 . 59–68 . 26707700 . 4731015 . primary . 10.1016/j.nbd.2015.12.004 . March 2016.
  3. Gregory A, Polster BJ, Hayflick SJ . Clinical and genetic delineation of neurodegeneration with brain iron accumulation . Journal of Medical Genetics . 46 . 2 . 73–80 . 18981035 . 2675558 . review . 10.1136/jmg.2008.061929 . February 2009.
  4. Spaull . Robert V. V. . Soo . Audrey K. S. . Hogarth . Penelope . Hayflick . Susan J. . Kurian . Manju A. . Towards Precision Therapies for Inherited Disorders of Neurodegeneration with Brain Iron Accumulation . Tremor and Other Hyperkinetic Movements . 11 . 1 . 51 . free . 10.5334/tohm.661 . 24 November 2021. 34909266 . 8641530 .
  5. Dusek P, Schneider SA . Neurodegeneration with brain iron accumulation . Current Opinion in Neurology . 25 . 4 . 499–506 . 22691760 . review . 10.1097/wco.0b013e3283550cac . August 2012.
  6. Book: Neurodegeneration with Brain Iron Accumulation Disorders Overview . Gregory A, Hayflick S . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . University of Washington, Seattle . GeneReviews [Internet] . Seattle (WA) . 23447832 . 28 February 2013 .
  7. Hogarth P . Neurodegeneration with brain iron accumulation: diagnosis and management . en . Journal of Movement Disorders . 8 . 1 . 1–13 . 25614780 . 4298713 . 10.14802/jmd.14034 . January 2015.
  8. Gregory A, Hayflick SJ . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . Pantothenate Kinase-Associated Neurodegeneration . GeneReviews [Internet] . 2003 . 20301663 .
  9. Gregory A, Kurian MA, Maher ER, Hogarth P, Hayflick SJ . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . PLA2G6-Associated Neurodegeneration . GeneReviews [Internet] . 2008 . 20301718 .
  10. Gregory A, Hartig M, Prokisch H, Kmiec T, Hogarth P, Hayflick SJ . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . 2014 . Mitochondrial Membrane Protein-Associated Neurodegeneration . GeneReviews [Internet] . 24575447 .
  11. Gregory A, Kurian MA, Haack T, Hayflick SJ, Hogarth P . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . Beta-Propeller Protein-Associated Neurodegeneration . GeneReviews [Internet] . 28211668 . 16 Feb 2017 .
  12. Kruer MC, Gregory A, Hayflick SJ . Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A . Fatty Acid Hydroxylase-Associated Neurodegeneration . GeneReviews [Internet] . 21735565 . 28 Jun 2011 .
  13. Drecourt A, Babdor J, Dussiot M, Petit F, Goudin N, Garfa-Traoré M, Habarou F, Bole-Feysot C, Nitschké P, Ottolenghi C, Metodiev MD, Serre V, Desguerre I, Boddaert N, Hermine O, Munnich A, Rötig A . 6 . Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation . American Journal of Human Genetics . 102 . 2 . 266–277 . 29395073 . 5985451 . primary . 10.1016/j.ajhg.2018.01.003 . February 2018.
  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 . Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations . . 27 . 6 . 1230–3 . 16775270 . 2099458 . primary . 2006-06-01 .
  16. Schneider SA, Bhatia KP . Syndromes of neurodegeneration with brain iron accumulation . Seminars in Pediatric Neurology . 19 . 2 . 57–66 . 22704258 . review . 10.1016/j.spen.2012.03.005 . June 2012.
  17. Klopstock . Thomas . Tricta . Fernando . Neumayr . Lynne . Karin . Ivan . Zorzi . Giovanna . Fradette . Caroline . Kmieć . Tomasz . Büchner . Boriana . Steele . Hannah E . Horvath . Rita . Chinnery . Patrick F . Basu . Anna . Küpper . Clemens . Neuhofer . Christiane . Kálmán . Bernadette . Dušek . Petr . Yapici . Zuhal . Wilson . Ian . Zhao . Feng . Zibordi . Federica . Nardocci . Nardo . Aguilar . Christine . Hayflick . Susan J . Spino . Michael . Blamire . Andrew M . Hogarth . Penelope . Vichinsky . Elliott . 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 . 5 . 10.1016/S1474-4422(19)30142-5 . July 2019. 31202468 . 186245765 .

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