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The Genetic Basis of Human Cerebral Cortical Malformations

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Principles of Molecular Medicine

Abstract

Malformations of cortical development occur when the normal process of brain development is disrupted. With the widespread use of high-resolution neuroimaging, brain malformations are increasingly being recognized as a relatively common cause orefractory epilepsy, mental retardation, and other neurological disorders. The molecular and genetic bases of many cortical malformations have been elucidated in recent years, both expanding our understanding of the underlying biological processes in brain development and informing our approach to these disorders in clinical practice. This chapter highlights some of these malformations, including disorders of microcephaly, gray matter hetero-topia, lissencephaly syndromes, and polymicrogyria.

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Selected References

  • Aigner L, Uyanik G, Couillard-Despres S, et al. Somatic mosaicism and variable penetrance in doublecortin-associated migration disorders. Neurology 2003;60:329–332.

    Article  PubMed  CAS  Google Scholar 

  • Anton ES, Kreidberg JA, Rakic P. Distinct functions of a3 and av integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron 1999;22:277–289.

    Article  PubMed  CAS  Google Scholar 

  • Barkovich AJ. Imaging of the cobblestone lissencephalies. AJNR Am J Neuroradiol 1996;17:615–618.

    PubMed  CAS  Google Scholar 

  • Barkovich AJ, Kuzniecky RI. Neuroimaging of focal malformations of cortical development. J Clin Neurophysiol 1996,13:481–494.

    Article  PubMed  CAS  Google Scholar 

  • Barkovich AJ, Kuziecky RI. Gray matter heterotopia. Neurology 2000;55:1603–1608.

    PubMed  CAS  Google Scholar 

  • Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB. Classification system for malformations of cortical development: Update 2001. Neurology 2001;57:2168–2178.

    PubMed  CAS  Google Scholar 

  • Beltrán-Valero de Bernabé D, Currier S, Steinbrecher A, et al. Mutations in the O-Mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033–1043.

    Article  Google Scholar 

  • Bienvenu T, Poirier K, Friocourt G, et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet 2002;11:981–991.

    Article  PubMed  CAS  Google Scholar 

  • Bond J, Roberts E, Mochida GH, et al. ASPM is a major determinant of cerebral cortical size. Nat Genet 2002;32:316–320.

    Article  PubMed  CAS  Google Scholar 

  • Brockington M, Blake DJ, Prandini P, et al. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin a2 deficiency and abnormal gly-cosylation of a-dystroglycan. Am J Hum Genet 2001;69:1198–1209.

    Article  PubMed  CAS  Google Scholar 

  • Cardoso C, Leventer RJ, Ward HL, et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003;72:918–930.

    Article  PubMed  CAS  Google Scholar 

  • Caspi M, Atlas R, Kantor A, Sapir T, Reiner O. Interaction between LIS1 and doublecortin, two lissencephaly gene products. Hum Mol Genet 2000;9:2205–2213.

    PubMed  CAS  Google Scholar 

  • Chang BS, Piao X, Bodell A, et al. Bilateral frontoparietal polymicro-gyria: Clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 2003;53:596–606.

    Article  PubMed  CAS  Google Scholar 

  • Corbin JG, Nery S, Fishell G. Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain. Nat Neurosci 2001;4:1177–1182.

    Article  PubMed  CAS  Google Scholar 

  • Couillard-Despres S, Winkler J, Uyanik G, Aigner L. Molecular mechanisms of neuronal migration disorders, quo vadis? Curr Mol Med 2001; 1:677–688.

    Article  PubMed  CAS  Google Scholar 

  • Crino PB, Miyata H, Vinters H. Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations. Brain Pathol 2002;12:212–233.

    Article  PubMed  CAS  Google Scholar 

  • D’Arcangelo G, Miao GG, Chen SC, et al. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 1995;374:719–723.

    Article  PubMed  CAS  Google Scholar 

  • des Portes V, Pinard JM, Billuart P, et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998;92:51–61.

    Article  PubMed  Google Scholar 

  • DeSilva U, D’arcangelo G, Braden UV, et al. The human reelin gene: isolation, sequencing, and mapping on chromosome 7. Genome Res 1997;7:157–164.

    Article  PubMed  CAS  Google Scholar 

  • Dobyns WB, Berry-Kravis E, Havernick NJ, Holden KR, Viskochil D. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. Am J Med Genet 1999;86:331–337.

    Article  PubMed  CAS  Google Scholar 

  • Dobyns WB, Truwit CL, Ross ME, et al. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology 1999;53:270–277.

    PubMed  CAS  Google Scholar 

  • Eksioglu YZ, Scheffer IE, Cardenas P, et al. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 1996;16:77–87.

    Article  PubMed  CAS  Google Scholar 

  • Fox JW, Lamperti ED, Eksioglu YZ, et al. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron 1999;21:1315–1325.

    Article  Google Scholar 

  • Gambello MJ, Darling DL, Yingling J, Tanaka T, Gleeson JG, Wynshaw-Boris A. Multiple dose-dependent effects of Lis1 on cerebral cortical development. J Neurosci 2003;23:1719–1729.

    PubMed  CAS  Google Scholar 

  • Gleeson JG. Classical lissencephaly and double cortex (subcortical band heterotopia): LIS1 and doublecortin. Curr Opin Neurol. 2000;13:121–125.

    Article  PubMed  CAS  Google Scholar 

  • Gleeson JG, Walsh CA. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci 2000;23:352–359.

    Article  PubMed  CAS  Google Scholar 

  • Gleeson JG, Allen KA, Fox JW, et al. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 1998;92:63–72.

    Article  PubMed  CAS  Google Scholar 

  • Guerreiro MM, Andermann E, Guerrini R, et al. Familial perisylvian polymicrogyria: a new familial syndrome of cortical maldevelop-ment. Ann Neurol 2000;48:39–48.

    Article  PubMed  CAS  Google Scholar 

  • Guerrini R, Barkovich AJ, Sztriha L, Dobyns WB. Bilateral frontal polymicrogyria: a newly recognized brain malformation syndrome. Neurology 2000;54:909–913.

    PubMed  CAS  Google Scholar 

  • Guerrini R, Dubeau F, Dulac O, et al. Bilateral parasagittal parietooccipi-tal polymicrogyria and epilepsy. Ann Neurol 1997;41:65–73.

    Article  PubMed  CAS  Google Scholar 

  • Harding B, Copp AJ. Malformations. In: Graham DI, Lantos PL, eds. Greenfield’s Neuropathology, 6th ed., London: Arnold, 1997; pp. 397–533.

    Google Scholar 

  • Hong SE, Shugart YY, Huang DT, et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000;26:93–96.

    Article  PubMed  CAS  Google Scholar 

  • Huyton T, Bates PA, Zhang X, Sternberg MJ, Freemont PS. The BRCA1 C-terminal domain: structure and function. Mutat Res 2000;460:319–332.

    PubMed  CAS  Google Scholar 

  • Jackson AP, Eastwood H, Bell SM, et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 2002;71:136–142.

    Article  PubMed  CAS  Google Scholar 

  • Jackson AP, McHale DP, Campbell DA, et al. Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter. Am J Hum Genet 1998;63:541–546.

    Article  PubMed  CAS  Google Scholar 

  • Jamieson CR, Fryns JP, Jacobs J, et al. Primary autosomal recessive microcephaly: MCPH5 maps to 1q25-q32. Am J Hum Genet 2000; 67:1575–1577.

    Article  PubMed  CAS  Google Scholar 

  • Jamieson CR, Govaerts C, Abramowicz MJ. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am J Hum Genet 1999;65:1465–1469.

    Article  PubMed  CAS  Google Scholar 

  • Kim MH, Cierpicki T, Derewenda U, et al. The DCX-domain tandems of doublecortin and doublecortin-like kinase. Nat Struct Biol 2003; 10:324–333.

    Article  PubMed  CAS  Google Scholar 

  • Kitamura K, Yanazawa M, Sugiyama N, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet 2002;32:359–369.

    Article  PubMed  CAS  Google Scholar 

  • Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet 2001;102:125–135.

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi K, Nakahori Y, Miyake M, et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 1998;394:388–392.

    Article  PubMed  CAS  Google Scholar 

  • Kolehmainen J, Black GCM, Saarinen A, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intra-cellular protein transport. Am J Hum Genet 2003;72:1359–1369.

    Article  PubMed  CAS  Google Scholar 

  • Leventer RJ, Cardoso C, Ledbetter DH, Dobyns WB. LIS1: from cortical malformation to essential protein of cellular dynamics. Trends Neurosci 2001;24:489–492.

    Article  PubMed  CAS  Google Scholar 

  • Marin O, Rubenstein JLR. A long, remarkable journey: tangential migration in the telencephalon. Nat Rev Neurosci 2001;2:780–790.

    Article  PubMed  CAS  Google Scholar 

  • Mercuri E, Sewry C, Brown SC, Muntoni F. Congenital muscular dystrophies. Semin Pediatr Neurol 2002;9:120–131.

    Article  PubMed  Google Scholar 

  • Michele DE, Barresi R, Kanagawa M, et al. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 2002;418:417–422.

    Article  PubMed  CAS  Google Scholar 

  • Mochida GH, Walsh CA. Molecular genetics of human microcephaly. Curr Opin Neurol 2001;14:151–156.

    Article  PubMed  CAS  Google Scholar 

  • Moore SA, Saito F, Chen J, et al. Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 2002;418:422–425.

    Article  PubMed  CAS  Google Scholar 

  • Moynihan L, Jackson AP, Roberts E, et al. A third novel locus for primary autosomal recessive microcephaly maps to chromosome 9q34. Am J Hum Genet 2000;66:724–727.

    Article  PubMed  CAS  Google Scholar 

  • Nadarajah B, Parnavelas JG. Modes of neuronal migration in the developing cerebral cortex. Nat Rev Neurosci 2002;3:423–432.

    Article  PubMed  CAS  Google Scholar 

  • Olson EC, Walsh CA. Smooth, rough and upside-down neocortical development. Curr Opin Genet Dev 2002; 12:320–327.

    Article  PubMed  CAS  Google Scholar 

  • Pattison L, Crow YJ, Deeble VJ, et al. A fifth locus for primary autosomal recessive microcephaly maps to chromosome 1q31. Am J Hum Genet 2000;67:1578–1580.

    Article  PubMed  CAS  Google Scholar 

  • Piao X, Basel-Vanagaite L, Straussberg R, et al. An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21. Am J Hum Genet 2002;70:1028–1033.

    Article  PubMed  CAS  Google Scholar 

  • Piao X, Hill RS, Bodell A, et al. G protein-coupled receptor-dependent development of human frontal cortex. Science 2004;303:2033–2036.

    Article  PubMed  CAS  Google Scholar 

  • Pilz D, Stoodley N, Golden JA. Neuronal migration, cerebral cortical development, and cerebral cortical anomalies. J Neuropathol Exp Neurol 2002;61:1–11.

    PubMed  Google Scholar 

  • Raybaud CGN, Canto-Moreira N, Poncet M. High-definition magnetic resonance imaging identification of cortical dysplasias: micropolygyria versus lissencephaly. In: Guerrini R, Canapicchi R, Zifkin BG, et al., eds. Dysplasias of Cerebral Cortex and Epilepsy. Philadelphia: Lippincott-Raven, 1996, pp. 57–64.

    Google Scholar 

  • Reiner O, Carrozzo R, Shen Y, et al. Isolation of a Miller-Dieker lissencephaly gene containing G protein B-subunit-like repeats. Nature 1993;364: 717–721.

    Article  PubMed  CAS  Google Scholar 

  • Rice DS, Curran T. Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 2001;24:1005–1039.

    Article  PubMed  CAS  Google Scholar 

  • Roberts E, Hampshire DJ, Pattison L, et al. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet 2002;39:718–721.

    Article  PubMed  CAS  Google Scholar 

  • Roberts E, Jackson AP, Carradice AC, et al. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1-13.2. Eur J Hum Genet 1999;7:815–820.

    Article  PubMed  CAS  Google Scholar 

  • Robertson SP, Twigg SR, Sutherland-Smith AJ, et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 2003;33:487–491.

    Article  PubMed  CAS  Google Scholar 

  • Sheen VL, Dixon PH, Fox JW, et al. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet 2001;10:1775–1783.

    Article  PubMed  CAS  Google Scholar 

  • Sheen VL, Topcu M, Berkovic S, et al. Autosomal recessive form of periventricular heterotopia. Neurology 2003;60:1108–1112.

    PubMed  CAS  Google Scholar 

  • Stossel TP, Condeelis J, Cooley L, et al. Filamins as integrators of cell mechanics and signalling. Nat Rev Mol Cell Biol 2001;2:138–145.

    Article  PubMed  CAS  Google Scholar 

  • Stromme P, Bakke SJ, Dahl A, Gecz J. Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX. J Neurol Neurosurg Psychiatry 2003;74:536–538.

    Article  PubMed  CAS  Google Scholar 

  • Stromme P, Mangelsdorf ME, Scheffer IE, Gecz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev 2002;24:266–268.

    Article  PubMed  Google Scholar 

  • Stromme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002;30:441–445.

    Article  PubMed  CAS  Google Scholar 

  • Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz J. Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. Am J Med Genet 2002;112:405–411.

    Article  Google Scholar 

  • Villard L, Nguyen K, Cardoso C, et al. A locus for bilateral perisylvian polymicrogyria maps to Xq28. Am J Hum Genet 2002;70:1003–1008.

    Article  PubMed  CAS  Google Scholar 

  • Yoshida A, Kobayashi K, Manya H, et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltrans-ferase, POMGnT1. Dev Cell 2001;1:717–724.

    Article  PubMed  CAS  Google Scholar 

  • Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000;23:217–247.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Neurogenetics, Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, Department of Neurology, Harvard Medical School, Boston, MA

    Bernard S. Chang & Christopher A. Walsh

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  1. Bernard S. Chang
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  2. Christopher A. Walsh
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Editors and Affiliations

  1. Department of Medicine, Division of Cardiology Carolina Cardiovascular Biology Center, University of North Carolina School of Medicine, Chapel Hill, NC

    Marschall S. Runge MD, PhD  & Cam Patterson MD  & 

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© 2006 Humana Press Inc.

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Chang, B.S., Walsh, C.A. (2006). The Genetic Basis of Human Cerebral Cortical Malformations. In: Runge, M.S., Patterson, C. (eds) Principles of Molecular Medicine. Humana Press. https://doi.org/10.1007/978-1-59259-963-9_111

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  • DOI: https://doi.org/10.1007/978-1-59259-963-9_111

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-202-5

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