Abstract
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, there has not been a clearly identifiable molecular cause for many patients with clinical and radiologic features of NBIA. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6. In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia–parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome, and together they implicate new cellular pathways in the pathogenesis of these disorders.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Dusek P, Schneider SA. Neurodegeneration with brain iron accumulation. Curr Opin Neurol. 2012;25(4):499–506.
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.
Kruer MC, Boddaert N. Neurodegeneration with brain iron accumulation: a diagnostic algorithm. Semin Pediatr Neurol. 2012;19(2):67–74.
• Hartig MB, Iuso A, Haack T, et al. Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011;89(4):543–50. This reports the original identification of mutations in C19orf12 and phenotypic characterization of patients with MPAN.
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.
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.
Schulte EC, Claussen MC, Jochim A, et al. Mitochondrial membrane protein associated neurodegeneration: a novel variant of neurodegeneration with brain iron accumulation. Mov Discord. 2013;28(2):224–7.
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. doi:10.1111/cge.12137.
Dogu O, Krebs C, Kaleagasi H, Demirtas Z, Oksuz N, Walker R, et al. Rapid disease progression in adult-onset mitochondrial membrane protein-associated neurodegeneration. Clin Genet. 2013;84(4):350–5.
Landouré G, Zhu PP, Lourenço CM, Johnson JO, Toro C, Bricceno KV, et al. Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat. 2013;34(10):1357–60.
Deschauer M, Gaul C, Behrmann C, Prokisch H, Zierz S, Haack TB. C19orf12 mutations in neurodegeneration with brain iron accumulation mimicking juvenile amyotrophic lateral sclerosis. J Neurol. 2012;259(11):2434–9.
• Haack TB, Hogarth P, Kruer MC, et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet. 2012;91(6):1144–9. This reports the original characterization of WDR45 mutations leading to BPAN.
• 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. This is a near-simultaneous description of the role of WDR45 mutations in BPAN.
Kimura Y, Sato N, Sugai K, Maruyama S, Ota M, Kamiya K, et al. MRI, MR spectroscopy, and diffusion tensor imaging findings in patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). Brain Dev. 2013;35(5):458–61.
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(6):1708–17.
Kruer MC, Boddaert N, Schneider SA, et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol. 2012;33(3):407–14.
Eidelberg D, Sotrel A, Joachim C, et al. Adult onset Hallervorden-Spatz disease with neurofibrillary pathology. A discrete clinicopathological entity. Brain. 1987;110(4):993–1013.
Nair U, Cao Y, Xie Z, Klionsky DJ. Roles of the lipid-binding motifs of Atg18 and Atg21 in the cytoplasm to vacuole targeting pathway and autophagy. J Biol Chem. 2010;285(15):11476–88.
Chong ZZ, Shang YC, Wang S, Maiese K. Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Prog Neurobiol. 2012;99(2):128–48.
Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885–9.
Proikas-Cezanne T, Waddell S, Gaugel A, Frickey T, Lupas A, Nordheim A. WIPI-1-alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy. Oncogene. 2004;23:9314–25.
Acknowledgments
Joshua M. Doorn is supported by the Medical Student Scholarship Pathways Program of the Sanford School of Medicine of the University of South Dakota and the American Parkinson Disease Association. Work in Michael C. Kruer’s laboratory is supported by the Child Neurology Foundation, the American Academy of Cerebral Palsy and Developmental Medicine, the T. Denny Sanford Foundation, and the National Institute of Neurological Disorders and Stroke.
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Joshua M. Doorn declares that he has no conflict of interest.
Michael C. Kruer has been a consultant for MedLink Neurology (NBIA), the Department of Defense (dystonia research grant review), and eMedicine (lysosomal storage disease; myoclonic epilepsy). He has received keynote speaker honoraria and travel/accommodation expenses covered or reimbursed by Gundersen Lutheran Health System and the Mayo Clinic.
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Doorn, J.M., Kruer, M.C. Newly Characterized Forms of Neurodegeneration with Brain Iron Accumulation. Curr Neurol Neurosci Rep 13, 413 (2013). https://doi.org/10.1007/s11910-013-0413-9
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DOI: https://doi.org/10.1007/s11910-013-0413-9