Neuropediatrics 2001; 32(5): 256-263
DOI: 10.1055/s-2001-19120
Orginal Article

Georg Thieme Verlag Stuttgart · New York

Lissencephaly with Cerebellar Hypoplasia (LCH): A Heterogeneous Group of Cortical Malformations

M. E. Ross1,2,3 , K. Swanson1 , W. B. Dobyns4
  • 1 Department of Neurology, University of Minnesota, Minneapolis, MN, USA
  • 2 Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA
  • 3 Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA
  • 4 Department of Human Genetics, University of Chicago, Chicago, IL, USA
Further Information

Publication History

Publication Date:
18 December 2001 (online)

Abstract

Detailed classification of brain malformations such as lissencephaly has led to the positional cloning of genes required for normal neuronal migration and the identification of unique molecular pathways governing brain structure. While classical magnetic resonance imaging (MRI) patterns of lissencephaly involve primarily the cerebral cortex, malformations in this spectrum can be associated with significant cerebellar underdevelopment and have recently been referred to as lissencephaly with cerebellar hypoplasia (LCH). The phenotypic features of 34 children were found to define 6 subtypes of LCH. Two of these (LCHa and LCHb) were associated with mutation in the LIS1, DCX and RELN genes, respectively. Gene mutations that exemplify four additional classes (LCHc, d, e and f) remained to be determined. Phenotypic features included small head circumference, cortical malformation ranging from agyria to simplification of the gyral pattern and from near normal cortical thickness to marked thickening of the cortical gray matter. Cerebellar manifestations ranged from midline hypoplasia to diffuse volume reduction and disturbed foliation. We conclude that LCH is within the spectrum of DCX and LIS1 mutations, that LCH associated with RELN mutation is distinguished by the severity of cerebellar and hippocampal involvement, and that several distinctive patterns indicate additional genetic mutations that can produce LCH.

References

  • 1 al Shahwan S A, Bruyn G W, al Deeb S M. Non-progressive familial congenital cerebellar hypoplasia.  J Neurol Sci. 1995;  128 71-77
  • 2 Bayer S, Altman J. Neocortical Development. New York; Raven Press 1991
  • 3 D'Arcangelo G, Miao G G, Chen S C, Soares H D, Morgan J I, Curran T. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.  Nature. 1995;  374 719-723
  • 4 D'Arcangelo G, Nakajima K, Miyata T, Ogawa M, Mikoshiba K, Curran T. Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody.  J Neurosci. 1997;  17 23-31
  • 5 des Portes, Pinard J M, Billuart P, Vinet M C, Koulakoff A, Carrie A. 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
  • 6 DeSilva U, D'Arcangelo G, Braden V V, Chen J, Miao G G, Curran T. et al . The human reelin gene: isolation, sequencing, and mapping on chromosome 7.  Genome Res. 1997;  7 157-164
  • 7 Dobyns W B. Absence makes the search grow longer.  Am J Hum Genet. 1996;  58 7-16
  • 8 Dobyns W B, Barkovich A J. Microcephaly with simplified gyral pattern (oligogyric microcephaly) and microlissencephaly: reply.  Neuropediatrics. 1999;  30 104-106
  • 9 Dobyns W B, Berry-Kravis E, Havernick N J, Holden K R, Viskochil D. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia.  Am J Med Genet. 1999;  86 331-337
  • 10 Dobyns W B, Truwit C L, Ross M E, Matsumoto N, Pilz D T, Ledbetter D H. et al . Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly.  Neurology. 1999;  53 270-277
  • 11 Dobyns W B. Lissencephaly: the clinical and molecular genetic basis of diffuse malformations of neuronal migration. Barth PG Neuronal Migration Disorders. London; McKeith (in press)
  • 12 Dulabon L, Olson E C, Taglienti M G, Eisenhuth S, McGrath B, Walsh C A. et al . Reelin binds alpha3beta1 integrin and inhibits neuronal migration.  Neuron. 2000;  27 33-44
  • 13 Feng G, Olson E C, Stukenbuerg P T, Flanagan L A, Kirschner M W, Walsh C A. LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome.  Neuron. 2000;  28 653-664
  • 14 Gilmore E C, Ohshima T, Goffinet A M, Kulkarni A B, Herrup K. Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex.  J Neurosci. 1998;  18 6370-6377
  • 15 Gleeson J G, Allen K M, Fox J W, Lamperti E D, Berkovic S, Scheffer I. 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
  • 16 Harding B N, Copp A. Malformations of the nervous system. Graham DI, Lantos PL Greenfield's Neuropathology. London; Edward Arnold 1997: 397-533
  • 17 Hiesberger T, Trommsdorff M, Howell B W, Goffinet A, Mumby M C, Cooper J A. et al . Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.  Neuron. 1999;  24 481-489
  • 18 Hirotsune S, Takahara T, Sasaki N, Hirose K, Yoshiki A, Ohashi T. et al . The reeler gene encodes a protein with an EGF-like motif expressed by pioneer neurons.  Nat Genet. 1995;  10 77-83
  • 19 Hirotsune S, Fleck M W, Gambello M J, Bix G J, Chen A, Clark G D. et al . Graded reduction of Pafah1b1 (Lis1) gene activity results in neuronal cell autonomous migration defects and early embryonic lethality.  Nature Genet. 1998;  19 333-339
  • 20 Hong S E, Shugart Y Y, Huang D T, Shahwan S A, Grant P E, Hourihane J O. et al . Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations.  Nat Genet. 2000;  26 93-96
  • 21 Kato M, Takizawa N, Yamada S, Ito A, Honma T, Hashimoto M. et al . Diffuse pachygyria with cerebellar hypoplasia: a milder form of microlissencephaly or a new genetic syndrome?.  Ann Neurol. 1999;  46 660-663
  • 22 Kerner B, Graham J M, Golden J A, Pepkowitz S H, Dobyns W B. Familial lissencephaly with cleft palate and severe cerebellar hypoplasia.  Am J Med Genet. 1999;  87 440-445
  • 23 Kroon A A, Smit B J, Barth P G, Hennekam R C. Lissencephaly with extreme cerebral and cerebellar hypoplasia. A magnetic resonance imaging study.  Neuropediatrics. 1996;  27 273-276
  • 24 Kwon Y T, Tsai L H. A novel disruption of cortical development in p35(-/-) mice distinct from reeler.  J Comp Neurol. 1998;  395 510-522
  • 25 Lo Nigro E J, Chong C S, Smith A C, Dobyns W B, Carrozzo R, Ledbetter D H. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.  Hum Mol Genet. 1997;  6 157-164
  • 26 Niethammer M, Smith D S, Ayala R, Peng J, Ko J, Lee M-S. et al . NUDEL is a novel cdk5 substrate that associates with LIS1 and cytoplasmic dynein.  Neuron. 2000;  28 697-711
  • 27 Pilz D T, Matsumoto N, Minnerath S, Mills P, Gleeson J G, Walsh C A. et al . LIS1 and XLIS/doublecortin mutations cause most human classical lissencephaly, but different patterns of malformation.  Hum Mol Genet. 1998;  7 2029-2037
  • 28 Rice D S, Sheldon M, D'Arcangelo G, Nakajima K, Goldowitz D, Curran T. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain.  Development. 1998;  125 3719-3729
  • 29 Ross M E, Allen K M, Srivastava A K, Featherstone T, Gleeson J G, Hirsch B. et al . Linkage and physical mapping of X-linked lissencephaly/SBH (XLIS): A gene causing neuronal migration defects in human brain.  Hum Molec Genet. 1997;  6 555-562
  • 30 Ross M E, Walsh C A. Human brain malformations and their lessons for neuronal migration.  Ann Rev Neurosci. 2001;  24 1041-1070
  • 31 Royaux I, Lambert de Rouvroit C, D'Arcangelo G, Demirov D, Goffinet A M. Genomic organization of the mouse reelin gene.  Genomics. 1997;  46 240-250
  • 32 Sapir T, Elbaum M, Reiner O. Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit.  EMBO J. 1997;  16 6977-6984
  • 33 Sasaki S, Shionoya A, Ishida M, Gambello M J, Yingling J, Wynshaw-Boris A. et al . A LIS1/NUDEL/cytoplasmic dynien heavy chain complex in the developing and adult nervous system.  Neuron. 2000;  28 681-696
  • 34 Sztriha L, Al-Gazali L, Varady E, Nork M, Varughese M. Microlissencephaly.  Pediatr Neurol. 1998;  18 362-365
  • 35 Trommsdorff M, Gotthardt M, Hiesberger T, Shelton J, Stockinger W, Nimpf J. et al . Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2.  Cell. 1999;  97 689-701

M.D., Ph.D. M. Elizabeth Ross

University of Minnesota, Department of Neurology, MMC 295

420 Delaware Street S.E.

Minneapolis, MN 55455

USA

Email: rossx001@tc.umn.edu

    >