1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Genomics and Human Genetics
  4. Volume 16, 2015
  5. Article

Annual Review of Genomics and Human Genetics

Volume 16, 2015

Neurodegeneration with Brain Iron Accumulation: Genetic Diversity and Pathophysiological Mechanisms

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive disorders with the common feature of excessive iron deposition in the brain. Over the last decade, advances in sequencing technologies have greatly facilitated rapid gene discovery, and several single-gene disorders are now included in this group. Identification of the genetic bases of the NBIA disorders has advanced our understanding of the disease processes caused by reduced coenzyme A synthesis, impaired lipid metabolism, mitochondrial dysfunction, and defective autophagy. The contribution of iron to disease pathophysiology remains uncertain, as does the identity of a putative final common pathway by which the iron accumulates. Ongoing elucidation of the pathogenesis of each NBIA disorder will have significant implications for the identification and design of novel therapies to treat patients with these disorders.

Keyword(s): BPAN, CoA metabolism, CoPAN, iron metabolism, MPAN, NBIA, PKAN, PLAN
Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-090314-025011
2015-08-24
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/genom/16/1/annurev-genom-090314-025011.html?itemId=/content/journals/10.1146/annurev-genom-090314-025011&mimeType=html&fmt=ahah

Literature Cited

  1. Alfonso-Pecchio A, Garcia M, Leonardi R, Jackowski S. 1.  2012. Compartmentalization of mammalian pantothenate kinases. PLOS ONE 7:e49509 [Google Scholar]
  2. Bao S, Miller DJ, Ma Z, Wohltmann M, Eng G. 2.  et al. 2004. Male mice that do not express group VIA phospholipase A2 produce spermatozoa with impaired motility and have greatly reduced fertility. J. Biol. Chem. 279:38194–200 [Google Scholar]
  3. Barbeito AG, Garringer HJ, Baraibar MA, Gao X, Arredondo M. 3.  et al. 2009. Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J. Neurochem. 109:1067–78 [Google Scholar]
  4. Barbeito AG, Levade T, Delisle MB, Ghetti B, Vidal R. 4.  2010. Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy. Mol. Neurodegener. 5:50 [Google Scholar]
  5. Batista-Nascimento L, Pimentel C, Menezes RA, Rodrigues-Pousada C. 5.  2012. Iron and neurodegeneration: from cellular homeostasis to disease. Oxid. Med. Cell. Longev. 2012:128647 [Google Scholar]
  6. Beck G, Sugiura Y, Shinzawa K, Kato S, Setou M. 6.  et al. 2011. Neuroaxonal dystrophy in calcium-independent phospholipase A2β deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. J. Neurosci. 31:11411–20 [Google Scholar]
  7. Behrends C, Sowa ME, Gygi SP, Harper JW. 7.  2010. Network organization of the human autophagy system. Nature 466:68–76 [Google Scholar]
  8. Bosveld F, Rana A, van der Wouden PE, Lemstra W, Ritsema M. 8.  et al. 2008. De novo CoA biosynthesis is required to maintain DNA integrity during development of the Drosophila nervous system. Hum. Mol. Genet. 17:2058–69 [Google Scholar]
  9. Bredesen DE, Rao RV, Mehlen P. 9.  2006. Cell death in the nervous system. Nature 443:796–802 [Google Scholar]
  10. Brunetti D, Dusi S, Giordano C, Lamperti C, Morbin M. 10.  et al. 2014. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model. Brain 137:57–68 [Google Scholar]
  11. Brunetti D, Dusi S, Morbin M, Uggetti A, Moda F. 11.  et al. 2012. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model. Hum. Mol. Genet. 21:5294–305 [Google Scholar]
  12. Campanella A, Privitera D, Guaraldo M, Rovelli E, Barzaghi C. 12.  et al. 2012. Skin fibroblasts from pantothenate kinase-associated neurodegeneration patients show altered cellular oxidative status and have defective iron-handling properties. Hum. Mol. Genet. 21:4049–59 [Google Scholar]
  13. Chen G, Jing CH, Liu PP, Ruan D, Wang L. 13.  2013. Induction of autophagic cell death in the rat brain caused by iron. Am. J. Med. Sci. 345:369–74 [Google Scholar]
  14. Clarke PG. 14.  1990. Developmental cell death: morphological diversity and multiple mechanisms. Anat. Embryol. 181:195–213 [Google Scholar]
  15. Cozzi A, Rovelli E, Frizzale G, Campanella A, Amendola M. 15.  et al. 2010. Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy. Neurobiol. Dis. 37:77–85 [Google Scholar]
  16. Crichton RR, Dexter DT, Ward RJ. 16.  2011. Brain iron metabolism and its perturbation in neurological diseases. J. Neural Transm. 118:301–14 [Google Scholar]
  17. Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG. 17.  et al. 2001. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat. Genet. 28:350–54 [Google Scholar]
  18. Dan P, Edvardson S, Bielawski J, Hama H, Saada A. 18.  2011. 2-Hydroxylated sphingomyelin profiles in cells from patients with mutated fatty acid 2-hydroxylase. Lipids Health Dis. 10:84 [Google Scholar]
  19. Dehay B, Ramirez A, Martinez-Vicente M, Perier C, Canron MH. 19.  et al. 2012. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. PNAS 109:9611–16 [Google Scholar]
  20. Deng X, Vidal R, Englander EW. 20.  2010. Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy. Neurosci. Lett. 479:44–48 [Google Scholar]
  21. di Patti MC, Maio N, Rizzo G, De Francesco G, Persichini T. 21.  et al. 2009. Dominant mutants of ceruloplasmin impair the copper loading machinery in aceruloplasminemia. J. Biol. Chem. 284:4545–54 [Google Scholar]
  22. Dick KJ, Eckhardt M, Paisán-Ruiz C, Alshehhi AA, Proukakis C. 22.  et al. 2010. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum. Mutat. 31:E1251–60 [Google Scholar]
  23. Dusek P, Jankovic J, Le W. 23.  2012. Iron dysregulation in movement disorders. Neurobiol. Dis. 46:1–18 [Google Scholar]
  24. Dusi S, Valletta L, Haack TB, Tsuchiya Y, Venco P. 24.  et al. 2014. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 94:11–22 [Google Scholar]
  25. Edvardson S, Hama H, Shaag A, Gomori JM, Berger I. 25.  et al. 2008. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am. J. Hum. Genet. 83:643–48 [Google Scholar]
  26. Garcia M, Leonardi R, Zhang YM, Rehg JE, Jackowski S. 26.  2012. Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism. PLOS ONE 7:e40871 [Google Scholar]
  27. Gregory A, Hayflick SJ. 27.  2014. Neurodegeneration with brain iron accumulation disorders overview. GeneReviews RA Pagon, MP Adam, HH Ardinger, TD Bird, CR Dolan, et al. Seattle: Univ. Wash. http://www.ncbi.nlm.nih.gov/books/NBK121988
  28. Grünewald A, Arns B, Seibler P, Rakovic A, Münchau A. 28.  et al. 2012. ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome. Neurobiol. Aging 33:1843e1–7 [Google Scholar]
  29. Guo L, Zhou D, Pryse KM, Okunade AL, Su X. 29.  2010. Fatty acid 2-hydroxylase mediates diffusional mobility of raft-associated lipids, GLUT4 level, and lipogenesis in 3T3-L1 adipocytes. J. Biol. Chem. 285:25438–47 [Google Scholar]
  30. Gusdon AM, Zhu J, Van Houten B, Chu CT. 30.  2012. ATP13A2 regulates mitochondrial bioenergetics through macroautophagy. Neurobiol. Dis. 45:962–72 [Google Scholar]
  31. Haack TB, Hogarth P, Kruer MC, Gregory A, Wieland T. 31.  et al. 2012. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91:1144–49 [Google Scholar]
  32. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R. 32.  et al. 2010. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–67 [Google Scholar]
  33. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y. 33.  et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885–89 [Google Scholar]
  34. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD. 34.  1995. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. PNAS 92:2539–43 [Google Scholar]
  35. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E. 35.  et al. 2011. Absence of an orphan mitochondrial protein, C19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am. J. Hum. Genet. 89:543–50 [Google Scholar]
  36. Hayflick SJ. 36.  2014. Defective pantothenate metabolism and neurodegeneration. Biochem. Soc. Trans. 42:1063–68 [Google Scholar]
  37. Hayflick SJ, Hogarth P. 37.  2011. As iron goes, so goes disease?. Haematologica 96:1571–72 [Google Scholar]
  38. Hayflick SJ, Kruer MC, Gregory A, Haack TB, Kurian MA. 38.  et al. 2013. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 136:1708–17 [Google Scholar]
  39. Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA. 39.  et al. 2003. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N. Engl. J. Med. 348:33–40 [Google Scholar]
  40. He C, Klionsky DJ. 40.  2009. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43:67–93 [Google Scholar]
  41. Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W. 41.  et al. 2013. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80:268–75 [Google Scholar]
  42. Iuso A, Sibon OC, Gorza M, Heim K, Organisti C. 42.  et al. 2014. Impairment of Drosophila orthologs of the human orphan protein C19orf12 induces bang sensitivity and neurodegeneration. PLOS ONE 9:e89439 [Google Scholar]
  43. Jeong SY, David S. 43.  2006. Age-related changes in iron homeostasis and cell death in the cerebellum of ceruloplasmin-deficient mice. J. Neurosci. 26:9810–19 [Google Scholar]
  44. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J. 44.  et al. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880–84 [Google Scholar]
  45. Kono S, Suzuki H, Oda T, Shirakawa K, Takahashi Y. 45.  et al. 2007. Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in aceruloplasminemia. J. Hepatol. 47:844–50 [Google Scholar]
  46. Kono S, Yoshida K, Tomosugi N, Terada T, Hamaya Y. 46.  et al. 2010. Biological effects of mutant ceruloplasmin on hepcidin-mediated internalization of ferroportin. Biochim. Biophys. Acta 1802:968–75 [Google Scholar]
  47. Kroemer G, Mariño G, Levine B. 47.  2010. Autophagy and the integrated stress response. Mol. Cell 22:280–93 [Google Scholar]
  48. Kruer MC, Hiken M, Gregory A, Malandrini A, Clark D. 48.  et al. 2011. Novel histopathologic findings in molecularly-confirmed pantothenate kinase-associated neurodegeneration. Brain 134:947–58 [Google Scholar]
  49. Kruer MC, Paisán-Ruiz C, Boddaert N, Yoon MY, Hama H. 49.  et al. 2010. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann. Neurol. 68:611–18 [Google Scholar]
  50. Kuo YM, Duncan JL, Westaway SK, Yang H, Nune G. 50.  et al. 2005. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum. Mol. Genet. 14:49–57 [Google Scholar]
  51. Kurian MA, Hayflick SJ. 51.  2013. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. Int. Rev. Neurobiol. 110:49–71 [Google Scholar]
  52. Leonardi R, Rock CO, Jackowski S, Zhang YM. 52.  2007. Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. PNAS 104:1494–99 [Google Scholar]
  53. Leonardi R, Zhang YM, Rock CO, Jackowski S. 53.  2005. Coenzyme A: back in action. Prog. Lipid Res. 44:125–53 [Google Scholar]
  54. Leonardi R, Zhang YM, Yun MK, Zhou R, Zeng FY. 54.  et al. 2010. Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain. Chem. Biol. 17:892–902 [Google Scholar]
  55. Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S. 55.  et al. 2012. Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol. Genet. Metab. 105:463–71 [Google Scholar]
  56. Lu Q, Yang P, Huang X, Hu W, Guo B. 56.  et al. 2011. The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes. Dev. Cell 21:343–57 [Google Scholar]
  57. Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M. 57.  et al. 2008. Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am. J. Pathol. 172:406–16 [Google Scholar]
  58. Mariño G, Pietrocola F, Eisenberg T, Kong Y, Malik SA. 58.  et al. 2014. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53:710–25 [Google Scholar]
  59. Martin DD, Ladha S, Ehrnhoefer DE, Hayden MR. 59.  2015. Autophagy in Huntington disease and huntingtin in autophagy. Trends Neurosci. 38:26–35 [Google Scholar]
  60. Martínez A, Portero-Otin M, Pamplona R, Ferrer I. 60.  2010. Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. Brain Pathol. 20:281–97 [Google Scholar]
  61. Martinez DL, Tsuchiya Y, Gout I. 61.  2014. Coenzyme A biosynthetic machinery in mammalian cells. Biochem. Soc. Trans. 42:1112–17 [Google Scholar]
  62. Menzies FM, Moreau K, Rubinsztein DC. 62.  2011. Protein misfolding disorders and macroautophagy. Curr. Opin. Cell Biol. 23:190–97 [Google Scholar]
  63. Miyajima H, Takahashi Y, Kono S. 63.  2003. Aceruloplasminemia, an inherited disorder of iron metabolism. Biometals 16:205–13 [Google Scholar]
  64. Mizushima N, Komatsu M. 64.  2011. Autophagy: renovation of cells and tissues. Cell 147:728–41 [Google Scholar]
  65. Mizushima N, Yoshimori T, Ohsumi Y. 65.  2011. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27:107–32 [Google Scholar]
  66. Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P. 66.  et al. 2006. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat. Genet. 38:752–54 [Google Scholar]
  67. Núñez MT, Urrutia P, Mena N, Aguirre P, Tapia V, Salazar J. 67.  2012. Iron toxicity in neurodegeneration. Biometals 25:761–76 [Google Scholar]
  68. Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J. 68.  et al. 2014. Potential function for the Huntingtin protein as a scaffold for selective autophagy. PNAS 111:16889–94 [Google Scholar]
  69. Orsi A, Razi M, Dooley HC, Robinson D, Weston AE. 69.  et al. 2012. Dynamic and transient interactions of Atg9 with autophagosomes, but not membrane integration, are required for autophagy. Mol. Biol. Cell 23:1860–73 [Google Scholar]
  70. Paisán-Ruiz C, Li A, Schneider SA, Holton JL, Johnson R. 70.  et al. 2012. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol. Aging 33:814–23 [Google Scholar]
  71. Park JS, Mehta P, Cooper AA, Veivers D, Heimbach A. 71.  et al. 2011. Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism. Hum. Mutat. 32:956–64 [Google Scholar]
  72. Patel BN, Dunn RJ, Jeong SY, Zhu Q, Julien JP, David S. 72.  2002. Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury. J. Neurosci. 22:6578–86 [Google Scholar]
  73. Potter KA, Kern MJ, Fullbright G, Bielawski J, Scherer SS. 73.  et al. 2011. Central nervous system dysfunction in a mouse model of FA2H deficiency. Glia 59:1009–21 [Google Scholar]
  74. Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D. 74.  et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38:1184–91 [Google Scholar]
  75. Rana A, Seinen E, Siudeja K, Muntendam R, Srinivasan B. 75.  et al. 2010. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration. PNAS 13:6988–93 [Google Scholar]
  76. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. 76.  2010. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12:747–57 [Google Scholar]
  77. Rouault TA. 77.  2013. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat. Rev. Neurosci. 14:551–64 [Google Scholar]
  78. Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S. 78.  et al. 2013. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45:445–49 [Google Scholar]
  79. Schultheis PJ, Fleming SM, Clippinger AK, Lewis J, Tsunemi T. 79.  et al. 2013. Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits. Hum. Mol. Genet. 22:2067–82 [Google Scholar]
  80. Shinzawa K, Sumi H, Ikawa M, Matsuoka Y, Okabe M. 80.  et al. 2008. Neuroaxonal dystrophy caused by group VIA phospholipase A2 deficiency in mice: a model of human neurodegenerative disease. J. Neurosci. 28:2212–20 [Google Scholar]
  81. Siudeja K, Srinivasan B, Xu L, Rana A, de Jong J. 81.  et al. 2011. Impaired coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration. EMBO Mol. Med. 3:755–66 [Google Scholar]
  82. Strokin M, Seburn KL, Cox GA, Martens KA, Reiser G. 82.  2012. Severe disturbance in the Ca2+ signaling in astrocytes from mouse models of human infantile neuroaxonal dystrophy with mutated Pla2g6. Hum. Mol. Genet. 21:2807–14 [Google Scholar]
  83. Tooze SA, Yoshimori T. 83.  2010. The origin of the autophagosomal membrane. Nat. Cell Biol. 12:831–35 [Google Scholar]
  84. Tsunemi T, Krainc D. 84.  2014. Zn2+ dyshomeostasis caused by loss of ATP13A2/PARK9 leads to lysosomal dysfunction and alpha-synuclein accumulation. Hum. Mol. Genet. 23:2791–801 [Google Scholar]
  85. Usenovic M, Tresse E, Mazzulli JR, Taylor JP, Krainc D. 85.  2012. Deficiency of ATP13A2 leads to lysosomal dysfunction, α-synuclein accumulation, and neurotoxicity. J. Neurosci. 32:4240–46 [Google Scholar]
  86. Venco P, Dusi S, Valletta L, Tiranti V. 86.  2014. Alteration of the coenzyme A biosynthetic pathway in neurodegeneration with brain iron accumulation syndromes. Biochem. Soc. Trans. 42:1069–74 [Google Scholar]
  87. Vidal R, Miravalle L, Gao X, Barbeito AG, Baraibar MA. 87.  et al. 2008. Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. J. Neurosci. 28:60–67 [Google Scholar]
  88. Wada H, Yasuda T, Miura I, Watabe K, Sawa C. 88.  et al. 2009. Establishment of an improved mouse model for infantile neuroaxonal dystrophy that shows early disease onset and bears a point mutation in Pla2g6. Am. J. Pathol. 175:2257–63 [Google Scholar]
  89. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. 89.  2014. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol. 13:1045–60 [Google Scholar]
  90. Wu Z, Li C, Lv S, Zhou B. 90.  2009. Pantothenate kinase-associated neurodegeneration: insights from a Drosophila model. Hum. Mol. Genet. 18:3659–72 [Google Scholar]
  91. Zhang YM, Chohnan S, Virga KG, Stevens RD, Ilkayeva OR. 91.  et al. 2007. Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. Chem. Biol. 14:291–302 [Google Scholar]
  92. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. 92.  2001. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet. 28:345–49 [Google Scholar]
  93. Zöller I, Meixner M, Hartmann D, Büssow H, Meyer R. 93.  et al. 2008. Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration. J. Neurosci. 28:9741–54 [Google Scholar]
/content/journals/10.1146/annurev-genom-090314-025011
Loading
Neurodegeneration with Brain Iron Accumulation: Genetic Diversity and Pathophysiological Mechanisms
Annual Review of Genomics and Human Genetics 16, 257 (2015); https://doi.org/10.1146/annurev-genom-090314-025011
/content/journals/10.1146/annurev-genom-090314-025011
/content/journals/10.1146/annurev-genom-090314-025011
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error