Medicine:Neurodegeneration with brain iron accumulation

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Short description: Group of neurodegenerative disorders with associated iron accumulation in the brain
Neurodegeneration with brain iron accumulation
Other namesNBIA

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.[4] Symptoms can include various movement disorders, neuropsychiatric issues, seizures, visual disturbances, and cognitive decline, usually in different combinations.[4] 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.[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 variant Gene 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
Fatty acid hydroxylase-associated neurodegeneration (FAHN)[11] 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[12] REPS1 autosomal recessive
NBIA8[12] 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)[13] are used to distinguish between the different forms of NBIA due to the accumulation of iron in different areas of the brain.[14] Patients typically fall into two different categories: (1) early onset, rapid progression or (2) late onset, slow progression.[14] 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.[15]

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.[16]

References

  1. ↑ Ward, Roberta J.; Chrichton, Robert R. (2019). "Chapter 4. Ironing out the Brain". in Sigel, Astrid; Freisinger, Eva; Sigel, Roland K. O. et al.. Essential Metals in Medicine:Therapeutic Use and Toxicity of Metal Ions in the Clinic. 19. Berlin: de Gruyter GmbH. 87–122. doi:10.1515/9783110527872-010. ISBN 978-3-11-052691-2. 
  2. ↑ "Gene co-expression networks shed light into diseases of brain iron accumulation". Neurobiology of Disease 87: 59–68. March 2016. doi:10.1016/j.nbd.2015.12.004. PMID 26707700. 
  3. ↑ "Clinical and genetic delineation of neurodegeneration with brain iron accumulation". Journal of Medical Genetics 46 (2): 73–80. February 2009. doi:10.1136/jmg.2008.061929. PMID 18981035. 
  4. ↑ 4.0 4.1 4.2 4.3 "Neurodegeneration with brain iron accumulation". Current Opinion in Neurology 25 (4): 499–506. August 2012. doi:10.1097/wco.0b013e3283550cac. PMID 22691760. 
  5. ↑ 5.0 5.1 5.2 5.3 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. PMID 34909266. 
  6. ↑ Neurodegeneration with Brain Iron Accumulation Disorders Overview. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle. 28 February 2013. https://www.ncbi.nlm.nih.gov/books/NBK121988/. 
  7. ↑ "Neurodegeneration with brain iron accumulation: diagnosis and management" (in en). Journal of Movement Disorders 8 (1): 1–13. January 2015. doi:10.14802/jmd.14034. PMID 25614780. 
  8. ↑ "Pantothenate Kinase-Associated Neurodegeneration". GeneReviews [Internet]. 2003. PMID 20301663. https://www.ncbi.nlm.nih.gov/books/NBK1490/. 
  9. ↑ "PLA2G6-Associated Neurodegeneration". GeneReviews [Internet]. 2008. PMID 20301718. https://www.ncbi.nlm.nih.gov/books/NBK1675/. 
  10. ↑ "Mitochondrial Membrane Protein-Associated Neurodegeneration". GeneReviews [Internet]. 2014. PMID 24575447. https://www.ncbi.nlm.nih.gov/books/NBK185329/. 
  11. ↑ "Fatty Acid Hydroxylase-Associated Neurodegeneration". GeneReviews [Internet]. 28 Jun 2011. PMID 21735565. https://www.ncbi.nlm.nih.gov/books/NBK56080/. 
  12. ↑ 12.0 12.1 "Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation". American Journal of Human Genetics 102 (2): 266–277. February 2018. doi:10.1016/j.ajhg.2018.01.003. PMID 29395073. 
  13. ↑ 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.
  14. ↑ 14.0 14.1 "Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations". American Journal of Neuroradiology 27 (6): 1230–3. 2006-06-01. PMID 16775270. PMC 2099458. https://www.ajnr.org/content/27/6/1230. 
  15. ↑ "Syndromes of neurodegeneration with brain iron accumulation". Seminars in Pediatric Neurology 19 (2): 57–66. June 2012. doi:10.1016/j.spen.2012.03.005. PMID 22704258. 
  16. ↑ 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. PMID 31202468. 

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