Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-669899f699-2mbcq Total loading time: 0 Render date: 2025-04-24T23:26:17.890Z Has data issue: false hasContentIssue false

Chapter 16 - Syndromes of Neurodegeneration with Brain Iron Accumulation

from Section II - A Metabolism-Based Approach to Movement Disorders and Inherited Metabolic Disorders

Published online by Cambridge University Press:  24 September 2020

By
Susanne A. Schneider ,
Carmen Espinós  and
Belén Pérez-Dueñas
Edited by
Darius Ebrahimi-Fakhari  and
Phillip L. Pearl
Darius Ebrahimi-Fakhari
Affiliation:
Harvard Medical School
Phillip L. Pearl
Affiliation:
Harvard Medical School
Get access

Summary

The syndromes of neurodegeneration with brain iron accumulation (NBIA) are a group of disorders defined by progressive hypo- and/or hyperkinetic movement disorders and excessive iron deposition in the brain [1]. Iron predominantly accumulates in (and around) the basal ganglia, mainly the globus pallidus, and can be detected as hypointensity on T2-weighted images due to shortening effects on relaxation time. Brain pathology demonstrates degeneration of neurons and astrocytes. Eosinophilic, roundish swellings containing degenerate organelles (i.e. spheroid bodies) are also common in many subtypes of NBIA. Several genes associated with NBIA disorders have been identified (including PANK2, PLA2G6, WDR45, C19orf12, FA2H, ATP13A2, COASY, FTL1, CP, and DCAF17).

Type
Chapter
Information
Movement Disorders and Inherited Metabolic Disorders
Recognition, Understanding, Improving Outcomes
 , pp. 215 - 229
Publisher: Cambridge University Press
Print publication year: 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Schneider, SA, Bhatia, KP. Syndromes of neurodegeneration with brain iron accumulation. Semin Pediatr Neurol. 2012;19(2):57–66.Google Scholar
Hayflick, SJ, Westaway, SK, Levinson, B, et al. Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med. 2003;348(1):33–40.CrossRefGoogle ScholarPubMed
Hayflick, SJ. Neurodegeneration with brain iron accumulation: From genes to pathogenesis. Semin Pediatr Neurol. 2006;13(3):182–5.CrossRefGoogle ScholarPubMed
Egan, RA, Weleber, RG, Hogarth, P, et al. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden–Spatz syndrome). Am J Ophthalmol. 2005;140(2):267–74.Google Scholar
Yoon, WT, Lee, WY, Shin, HY, Lee, ST, Ki, CS. Novel PANK2 gene mutations in Korean patient with pantothenate kinase-associated neurodegeneration presenting unilateral dystonic tremor. Mov Disord. 2010;25(2):245–7.Google Scholar
Aggarwal, A, Schneider, SA, Houlden, H, et al. Indian-subcontinent NBIA: Unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord. 2010;25(10):1424–31.CrossRefGoogle ScholarPubMed
Chung, SJ, Lee, JH, Lee, MC, Yoo, HW, Kim, GH. Focal hand dystonia in a patient with PANK2 mutation. Mov Disord. 2008;23(3):466–8.Google Scholar
Vasconcelos, OM, Harter, DH, Duffy, C, et al. Adult Hallervorden–Spatz syndrome simulating amyotrophic lateral sclerosis. Muscle Nerve. 2003;28(1):118–22.Google Scholar
Antonini, A, Goldwurm, S, Benti, R, et al. Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration. Mov Disord. 2006;21(3):417–8.Google Scholar
Seo, JH, Song, SK, Lee, PH. A novel PANK2 mutation in a patient with atypical pantothenate-kinase-associated neurodegeneration presenting with adult-onset parkinsonism. J Clin Neurol. 2009;5(4):192–4.Google Scholar
Diaz, N. Late onset atypical pantothenate-kinase-associated neurodegeneration. Case Rep Neurol Med. 2013;2013:860201.Google Scholar
Kurian, MA, Morgan, NV, MacPherson, L, et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008;70(18):1623–9.CrossRefGoogle ScholarPubMed
Morgan, NV, Westaway, SK, Morton, JE, et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38(7):752–4.Google ScholarPubMed
Paisan-Ruiz, C, Li, A, Schneider, SA, et al. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia–parkinsonism cases with PLA2G6 mutations. Neurobiol Aging. 2012;33(4):814–23.Google Scholar
Gregory, A, Westaway, SK, Holm, IE, et al. Neurodegeneration associated with genetic defects in phospholipase A(2). Neurology. 2008;71(18):1402–9.CrossRefGoogle ScholarPubMed
Riku, Y, Ikeuchi, T, Yoshino, H, Mimuro, M, Mano, K, Goto, Y, et al. Extensive aggregation of alpha-synuclein and tau in juvenile-onset neuroaxonal dystrophy: An autopsied individual with a novel mutation in the PLA2G6 gene-splicing site. Acta Neuropathol Commun. 2013;1:12.Google Scholar
Hayflick, SJ, Kruer, MC, Gregory, A, et al. Beta-propeller protein-associated neurodegeneration: A new X-linked dominant disorder with brain iron accumulation. Brain. 2013;136(Pt 6):1708–17.Google Scholar
Saitsu, H, Nishimura, T, Muramatsu, K, et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. 2013;45(4):445–9, 9e1.Google Scholar
Verhoeven, WM, Egger, JI, Koolen, DA, et al. Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: Novel mutations and neuropsychiatric phenotype in three adult patients. Parkinsonism Relat Disord. 2013;20(3):332–6.Google Scholar
Skowronska, M, Kmiec, T, Jurkiewicz, E, et al. Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12. Parkinsonism Relat Disord. 2017;39:71–6.Google Scholar
Dezfouli, MA, Alavi, A, Rohani, M, Rezvani, M, Nekuie, T, Klotzle, B, et al. PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. Mov Disord. 2013;28(2):228–32.Google Scholar
Goldman, JG, Eichenseer, SR, Berry-Kravis, E, et al. Clinical features of neurodegeneration with brain iron accumulation due to a C19orf12 gene mutation. Mov Disord. 2013;28(10):1462–3.Google Scholar
Hogarth, P, Gregory, A, Kruer, MC, et al. New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013;80(3):268–75.Google Scholar
Schulte, EC, Claussen, MC, Jochim, A, et al. Mitochondrial membrane protein associated neurodegenration: A novel variant of neurodegeneration with brain iron accumulation. Mov Disord. 2013;28(2):224–7.Google Scholar
Panteghini, C, Zorzi, G, Venco, P, et al. C19orf12 and FA2H mutations are rare in Italian patients with neurodegeneration with brain iron accumulation. Semin Pediatr Neurol. 2012;19(2):75–81.Google Scholar
Schottmann, G, Stenzel, W, Lutzkendorf, S, Schuelke, M, Knierim, E. A novel frameshift mutation of C19ORF12 causes NBIA4 with cerebellar atrophy and manifests with severe peripheral motor axonal neuropathy. Clin Genet. 2013;85(3):290–2.Google Scholar
Kruer, MC, Salih, MA, Mooney, C, et al. C19orf12 mutation leads to a pallido-pyramidal syndrome. Gene. 2014;537(2):352–6.Google Scholar
Kruer, MC, Paisan-Ruiz, C, Boddaert, N, et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010;68(5):611–8.Google Scholar
Schneider, SA, Paisan-Ruiz, C, Quinn, NP, et al. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Mov Disord. 2010;25(8):979–84.CrossRefGoogle ScholarPubMed
Bruggemann, N, Hagenah, J, Reetz, K, et al. Recessively inherited parkinsonism: Effect of ATP13A2 mutations on the clinical and neuroimaging phenotype. Arch Neurol. 2010;67(11):1357–63.Google Scholar
Behrens, MI, Bruggemann, N, Chana, P, et al. Clinical spectrum of Kufor–Rakeb syndrome in the Chilean kindred with ATP13A2 mutations. Mov Disord. 2010;25(12):1929–37.Google Scholar
Dusi, S, Valletta, L, Haack, TBet al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2014;94(1):11–22.CrossRefGoogle ScholarPubMed
Vroegindeweij, LH, van der Beek, EH, Boon, AJ, et al. Aceruloplasminemia presents as type 1 diabetes in non-obese adults: A detailed case series. Diabet Med. 2015;32(8):993–1000.Google Scholar
Bohlega, SA, Alkuraya, FS. Woodhouse–Sakati Syndrome. 1993.Google Scholar
Horvath, R, Lewis-Smith, D, Douroudis, K, et al. SCP2 mutations and neurodegeneration with brain iron accumulation. Neurology. 2015;85(21):1909–11.Google Scholar
Ferdinandusse, S, Kostopoulos, P, Denis, S, et al. Mutations in the gene encoding peroxisomal sterol carrier protein x (SCPx) cause leukencephalopathy with dystonia and motor neuropathy. Am J Hum Genet. 2006;78(6):1046–52.Google Scholar
Jaberi, E, Rohani, M, Shahidi, GA, et al. Identification of mutation in GTPBP2 in patients of a family with neurodegeneration accompanied by iron deposition in the brain. Neurobiol Aging. 2016;38:216 e11-8.CrossRefGoogle ScholarPubMed
Darling, A, Tello, C, Marti, MJ, et al. Clinical rating scale for pantothenate kinase-associated neurodegeneration: A pilot study. Mov Disord. 2017;32(11):1620–30.Google Scholar
Greblikas, F, Escolar, M, Klopstock, T, et al. The FOsmetpantotenate Replacement Therapy (FORT) Pivotal Trial: Utilization of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration (abstract 25). Mov Disord. 2018;33(Suppl 2):S11-2.Google Scholar
Amaral, LL, Gaddikeri, S, Chapman, PR, et al. Neurodegeneration with brain iron accumulation: Clinicoradiological approach to diagnosis. J Neuroimaging. 2015;25(4):539–51.Google Scholar
Delgado, RF, Sanchez, PR, Speckter, H, et al. Missense PANK2 mutation without “eye of the tiger” sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN). J Magn Reson Imaging. 2012;35(4):788–94.Google Scholar
Schenck, JF, Zimmerman, EA. High-field magnetic resonance imaging of brain iron: Birth of a biomarker? NMR Biomed. 2004;17(7):433–45.Google Scholar
Stankiewicz, J, Panter, SS, Neema, M, et al. Iron in chronic brain disorders: Imaging and neurotherapeutic implications. Neurotherapeutics. 2007;4(3):371–86.Google Scholar
Fermin-Delgado, R, Roa-Sanchez, P, Speckter, H, et al. Involvement of globus pallidus and midbrain nuclei in pantothenate kinase-associated neurodegeneration: Measurement of T2 and T2* time. Clin Neuroradiol. 2013;23(1):11–5.Google Scholar
Chiapparini, L, Savoiardo, M, D’Arrigo, Set al. The “eye-of-the-tiger” sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration. Neuropediatrics. 2011;42(4):159–62.Google Scholar
Grandas, F, Fernandez-Carballal, C, Guzman-de-Villoria, J, Ampuero, I. Treatment of a dystonic storm with pallidal stimulation in a patient with PANK2 mutation. Mov Disord. 2011;26(5):921–2.Google Scholar
Awasthi, R, Gupta, RK, Trivedi, R, et al. Diffusion tensor MR imaging in children with pantothenate kinase-associated neurodegeneration with brain iron accumulation and their siblings. AJNR Am J Neuroradiol. 2010;31(3):442–7.Google Scholar
Haack, TB, Hogarth, P, Gregory, A, Prokisch, H, Hayflick, SJ. BPAN: The only X-linked dominant NBIA disorder. Int Rev Neurobiol. 2013;110:85–90.Google Scholar
Schneider, SA, Neurodegenerations with brain iron accumulation. Parkinsonism Relat Disord. 2016;22:S21–5.Google Scholar
Schneider, SA, Bhatia, KP, Hardy, J. Complicated recessive dystonia parkinsonism syndromes. Mov Disord. 2009;24(4):490–9.Google Scholar
Kell, DB. Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples. Arch Toxicol. 2010;84(11):825–89.CrossRefGoogle ScholarPubMed
Di Meo, I, Tiranti, V. Classification and molecular pathogenesis of NBIA syndromes. Eur J Paediatr Neurol. 2018;22(2):272–84.CrossRefGoogle ScholarPubMed
Tello, C, Darling, A, Lupo, V, Perez-Duenas, B, Espinos, C. On the complexity of clinical and molecular bases of neurodegeneration with brain iron accumulation. Clin Genet. 2018;93(4):731–40.Google Scholar
Svingen, L, Goheen, M, Godfrey, R, et al. Late diagnosis and atypical brain imaging of Aicardi–Goutières syndrome: Are we failing to diagnose Aicardi–Goutières syndrome-2? Dev Med Child Neurol. 2017;59(12):1307–11.Google Scholar
Sferra, A, Baillat, G, Rizza, T, et al. TBCE Mutations cause early-onset progressive encephalopathy with distal spinal muscular atrophy. Am J Hum Genet. 2016;99(4):974–83.Google Scholar
Gautschi, M, Merlini, L, Calza, AM, et al. Late diagnosis of fucosidosis in a child with progressive fixed dystonia, bilateral pallidal lesions and red spots on the skin. Eur J Paediatr Neurol. 2014;18(4):516–9.Google Scholar
Zoons, E, de Koning, TJ, Abeling, NG, Tijssen, MA. Neurodegeneration with brain iron accumulation on MRI: An adult case of alpha-mannosidosis. JIMD Rep. 2012;4:99–102.Google Scholar
Roubertie, A, Hieu, N, Roux, CJ, et al. AP4 deficiency: A novel form of neurodegeneration with brain iron accumulation? Neurol Genet. 2018;4(1):e217.Google Scholar
Dard, R, Meyniel, C, Touitou, V, et al. Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation. Eur J Med Genet. 2017;60(12):639–42.Google Scholar
Vill, K, Muller-Felber, W, Alhaddad, B, et al. A homozygous splice variant in AP4S1 mimicking neurodegeneration with brain iron accumulation. Mov Disord. 2017;32(5):797–9.Google Scholar
Herebian, D, Alhaddad, B, Seibt, A, et al. Coexisting variants in OSTM1 and MANEAL cause a complex neurodegenerative disorder with NBIA-like brain abnormalities. Eur J Hum Genet. 2017;25(9):1092–5.Google Scholar
Meyer, E, Carss, KJ, Rankin, J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet. 2017;49(2):223–37.Google Scholar
Drecourt, A, Babdor, J, Dussiot, M, et al. Impaired transferrin receptor palmitoylation and recycling in neurodegeneration with brain iron accumulation. Am J Hum Genet. 2018;102(2):266–77.CrossRefGoogle ScholarPubMed
Brunetti, D, Dusi, S, Giordano, C, et al. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain. 2014;137(Pt 1):57–68.Google Scholar
Orellana, DI, Santambrogio, P, Rubio, A, et al. Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med. 2016;8(10):1197–211.Google Scholar
Zhao, YG, Sun, L, Miao, G, et al. The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy. 2015;11(6):881–90.Google Scholar
Schultheis, PJ, Fleming, SM, Clippinger, AK, et al. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited alpha-synuclein accumulation and age-dependent sensorimotor deficits. Hum Mol Genet. 2013;22(10):2067–82.Google Scholar
Zhao, Z, Zhang, X, Zhao, C, et al. Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation. Endocrinology. 2010;151(7):3038–48.Google Scholar
Hogarth, P, Kurian, MA, Gregory, A, et al. Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN). Mol Genet Metab. 2017;120(3):278–87.Google Scholar
Klopstock, T, Tricta, F, Neumayr, L, et al. A randomized trial of deferiprone for pantothenate kinase-associated neurodegeneration (abstr 471). Mov Disord. 2018;33(Suppl 2):S219.Google Scholar
Elbaum, D, Beconi, MG, Monteagudo, E, et al. Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models. PLoS One. 2018;13(3):e0192028.Google Scholar
Cif, L, Kurian, MA, Gonzalez, V, et al. Atypical PLA2G6-associated neurodegeneration: social communication impairment, dystonia and response to deep brain stimulation. Mov Disord Clin Pract. 2014;1(2):128–31.Google Scholar
Kinghorn, KJ, Castillo-Quan, JI, Bartolome, F, et al. Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction. Brain. 2015;138(Pt 7):1801–16.Google Scholar
Gregory, A, Kurian, MA, Maher, ER, Hogarth, P, Hayflick, S. PLA2G6-associated neurodegeneration. GeneReviews®. 2008;Jun 19 (updated Mar 23, 2017).Google Scholar
Dusek, P, Schneider, SA, Aaseth, J. Iron chelation in the treatment of neurodegenerative diseases. J Trace Elem Med Biol. 2016;38:81–92.Google Scholar
Timmermann, L, Pauls, KA, Wieland, K, et al. Dystonia in neurodegeneration with brain iron accumulation: Outcome of bilateral pallidal stimulation. Brain. 2010;133(Pt 3):701–12.Google Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×