Lissencephaly, Genetics of

Abstract

The term lissencephaly (literally ‘smooth brain’) covers rare malformations of the brain characterised by a paucity of normal gyri and sulci with absent (agyria) or abnormally wide gyri (pachygyria) associated with an abnormal cortical layering. Different forms of lissencephalies have been described: classical lissencephalies (also called type I) and their variants, and cobblestone lissencephalies (also called type II). Classical lissencephalies include lissencephalies with mutations in LIS1, DCX, ARX or TUBA1 genes, isolated lissencephalies without any identified genetic defect, lissencephalies with severe microcephaly (microlissencephaly) and lissencephalies associated with syndromes including multiple malformations. The cobblestone lissencephaly is observed in three related syndromes characterised by an overmigration of neurons and glial cells into the arachnoid space: Walker–Warburg, Fukuyama and muscle–eye–brain (MEB) syndromes, caused by mutations in genes involved in O‐glycosylation of α‐dystroglycan.

Key Concepts

  • Lissencephaly is defined by a ‘smooth brain’ with absent (agyria) or abnormal wide gyri (pachygyria).
  • Lissencephaly is caused by abnormal neuronal migration during corticogenesis.
  • Neuropathological analysis distinguishes several types of lissencephalies: classical lissencephalies and cobblestone lissencephalies.
  • Classical lissencephalies are caused by mutations in LIS1, DCX, ARX and Tubulin genes.
  • Cobblestone lissencephalies are caused by defects in O‐glycosylation of α‐dystroglycan.
  • Microlissencephalies are caused by dysfunctions of centrosomal‐dependent neuronal progenitor proliferation and of neuronal migration.

Keywords: neuronal migration; LIS1; DCX; tubulinopathies; alpha‐dystroglycanopathies

Figure 1. Classical lissencephaly (LIS1 gene mutation). (a) Axial brain section showing agyria–pachygyria with anterior–posterior gradient (anterior being more severe) and the classical figure‐eight appearance of shallow Sylvian fissures. (b) Coronal brain section showing the preserved cerebellum.
Figure 2. Cobblestone lissencephaly. (a) Axial brain section showing pachygyry and polymicrogyry with anterior–posterior gradient, and hydrocephalus. (b) Sagittal brain section showing brain stem and cerebellar hypoplasia.
close

References

Allias F, Buenerd A, Bouvier R, et al. (2004) The spectrum of type III lissencephaly: a clinicopathological update. Fetal and Pediatric Pathology 23 (5–6): 305–317.

Bahi‐Buisson N and Cavallin M (2016) Tubulinopathies overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A and Ledbetter N (eds) GeneReviews® [Internet]. Seattle, WA: University of Washington.

Barkovich AJ, Kuzniecky RI and Dobyns WB (2001) Radiologic classification of malformations of cortical development. Current Opinion in Neurology 14 (2): 145–149.

Barkovich AJ, Guerrini R, Kuzniecky RI, Jackson GD and Dobyns WB (2005) A developmental and genetic classification for malformations of cortical development. Neurology 65 (12): 1873–1887.

Beltran‐Valero de Bernabe D, Currier S, Steinbrecher A, et al. (2002) Mutations in the O‐mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker–Warburg syndrome. American Journal of Human Genetics 71 (5): 1033–1043.

Beltran‐Valero de Bernabe D, Voit T, Longman T, et al. (2004) Mutations in the FKRP gene can cause muscle‐eye‐brain disease and Walker–Warburg syndrome. Journal of Medical Genetics 41 (5): e61.

Berry‐Kravis E and Israel J (1994) X‐linked pachygyria and agenesis of the corpus callosum: evidence for an X chromosome lissencephaly locus. Annals of Neurology 36 (2): 229–233.

Caspi M, Atlas R, Kantor A, et al. (2000) Interaction between LIS1 and doublecortin, two lissencephaly gene products. Human Molecular Genetics 9 (15): 2205–2213.

Cavallin M, Rujano MA, Bednarek N, et al. (2017) WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. Brain 140 (10): 2597–2609.

Chen Y, Beffert U, Ertunc M, et al. (2005) Reelin modulates NMDA receptor activity in cortical neurons. Journal of Neuroscience 25 (36): 8209–8216.

Devisme L, Bouchet C, Gonzalès M, et al. (2012) Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain 135: 469–482.

Dobyns WB and Truwit CL (1995) Lissencephaly and other malformations of cortical development: 1995 update. Neuropediatrics 26 (3): 132–147.

Evsyukova I, Plestant C and Anton ES (2013) Integrative mechanisms of oriented neuronal migration in the developing brain. Annual Review of Cell and Developmental Biology 29: 299–353.

Florio M and Huttner WB (2014) Neural progenitors, neurogenesis and the evolution of the neocortex. Development 141 (11): 2182–2194.

Forster E, Jossin Y, Zhao S, et al. (2006) Recent progress in understanding the role of Reelin in radial neuronal migration, with specific emphasis on the dentate gyrus. European Journal of Neuroscience 23 (4): 901–909.

Friocourt G, Kappeler C and Saillour Y (2005) Doublecortin interacts with the ubiquitin protease DFFRX, which associates with microtubules in neuronal processes. Molecular and Cellular Neurosciences 28 (1): 153–164.

Gdalyahu A, Ghosh I, Levy T, et al. (2004) DCX, a new mediator of the JNK pathway. EMBO Journal 23 (4): 823–832.

Handley MT, Morris‐Rosendahl DJ, Brown S, et al. (2013) Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype‐phenotype correlations in warburg micro syndrome and Martsolf syndrome. Human Mutation 34 (5): 686–696.

Harding BN, Moccia A, Drunat S, et al. (2016) Mutations in citron kinase cause recessive microlissencephaly with multinucleated neurons. American Journal of Human Genetics 99 (2): 511–520.

Jiang X and Nardelli J (2016) Cellular and molecular introduction to brain development. Neurobiology of Disease 92: 3–17.

Kato M and Dobyns WB (2005) X‐linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term “interneuronopathy”. Journal of Child Neurology 20 (4): 392–397.

Kawauchi T (2015) Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration. Frontiers in Cellular Neuroscience 9: 394.

Kobayashi K, Nakahori Y, Miyake M, et al. (1998) An ancient retrotransposal insertion causes Fukuyama‐type congenital muscular dystrophy. Nature 394 (6691): 388–392.

Kuwano A, Ledbetter SA, Dobyns WB, et al. (1991) Detection of deletions and cryptic translocations in Miller–Dieker syndrome by in situ hybridization. American Journal of Human Genetics 49 (4): 707–714.

Li J, Lee WL and Cooper JA (2005) NudEL targets dynein to microtubule ends through LIS1. Nature Cell Biology 7 (7): 686–690.

Martin PT (2005) The dystroglycanopathies: the new disorders of O‐linked glycosylation. Seminars in Pediatric Neurology 12 (3): 152–158.

Miyata H, Chute DJ, Fink J, et al. (2004) Lissencephaly with agenesis of corpus callosum and rudimentary dysplastic cerebellum: a subtype of lissencephaly with cerebellar hypoplasia. Acta Neuropathologica (Berlin) 107 (1): 69–81.

Peyre E, Silva CG and Nguyen L (2015) Crosstalk between intracellular and extracellular signals regulating interneuron production, migration and integration into the cortex. Frontiers in Cellular Neuroscience 9: 129.

Poirier K, Van Esch H, Friocourt G, et al. (2004) Neuroanatomical distribution of ARX in brain and its localisation in GABAergic neurons. Brain Research. Molecular Brain Research 122 (1): 35–46.

des Portes V, Pinard JM, Billuart P, et al. (1998) A novel CNS gene required for neuronal migration and involved in X‐linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92 (1): 51–61.

van Reeuwijk J, Brunner HG and van Bokhoven H (2005) Glyc‐O‐genetics of Walker–Warburg syndrome. Clinical Genetics 67 (4): 281–289.

van Reeuwijk J, Maugenre S, van den Elzen C, et al. (2006) The expanding phenotype of POMT1 mutations: from Walker–Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Human Mutation 27 (5): 453–459.

Reiner O, Carrozzo R, Shen Y, et al. (1993) Isolation of a Miller–Dieker lissencephaly gene containing G protein beta‐subunit‐like repeats. Nature 364 (6439): 717–721.

Ross ME, Swanson K and Dobyns WB (2001) Lissencephaly with cerebellar hypoplasia (LCH): a heterogeneous group of cortical malformations. Neuropediatrics 32 (5): 256–263.

Sarnat HB and Flores‐Sarnat L (2003) Etiological classification of CNS malformations: integration of molecular genetic and morphological criteria. Epileptic Disorders 5: S35–S43.

Tsai JW, Chen Y, Kriegstein AR and Vallee RB (2005) LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. Journal of Cell Biology 170 (6): 935–945.

Valence S, Garel C, Barth M, et al. (2016) RELN and VLDLR mutations underlie two distinguishable clinico‐radiological phenotypes. Clinical Genetics 90 (6): 545–549.

Verloes A, Di Donato N, Masliah‐Planchon J, et al. (2015) Baraitser‐Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. European Journal of Human Genetics 23 (3): 292–301.

Yoshida A, Kobayashi K, Manya H, et al. (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Developmental Cell 1 (5): 717–724.

Further Reading

Clark GD (2004) The classification of cortical dysplasias through molecular genetics. Brain & Development 26 (6): 351–362.

Francis F, Meyer G, Fallet‐Bianco C, et al. (2006) Human disorders of cortical development: from past to present. European Journal of Neuroscience 23 (4): 877–893.

Friocourt G, Poirier K, Rakic S, et al. (2006) The role of ARX in cortical development. European Journal of Neuroscience 23 (4): 869–876.

Gleeson JG (2001) Neuronal migration disorders. Mental Retardation and Developmental Disabilities Research Review 7 (3): 167–171.

Gressens P (2006) Pathogenesis of migration disorders. Current Opinion in Neurology 19 (2): 135–140.

Guerrini R and Filippi T (2005) Neuronal migration disorders, genetics, and epileptogenesis. Journal of Child Neurology 20 (4): 287–299.

Kato M and Dobyns WB (2003) Lissencephaly and the molecular basis of neuronal migration. Human Molecular Genetics 12 (1): R89–R96.

Keays DA, Tian G, Poirier K, et al. (2007) Mutations in alpha‐tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128 (1): 45–57.

Leventer RJ (2005) Genotype‐phenotype correlation in lissencephaly and subcortical band heterotopia: the key questions answered. Journal of Child Neurology 20 (4): 307–312.

Mochida GH and Walsh CA (2004) Genetic basis of developmental malformations of the cerebral cortex. Archives of Neurology 61 (5): 637–640.

Pilz D, Stoodley N and Golden JA (2002) Neuronal migration, cerebral cortical development, and cerebral cortical anomalies. Journal of Neuropathology and Experimental Neurology 61 (1): 1–11.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Passemard, Sandrine, Chalard, François, Verloes, Alain, and Gressens, Pierre(Feb 2018) Lissencephaly, Genetics of. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020224.pub2]