Abstract
The malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders (NMDs) causing severe, global neurological impairment. Abnormalities of the LIS1, DCX, ARX, and RELN genes have been associated with these malformations. Recent work has also established a relationship of lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis, and cerebellar hypoplasia and, at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (KIF2A, KIF5C, TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, TUBG1, and DYNC1H1) regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubilinopathies. MCDs only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, cause neurological and cognitive impairment that vary from severe to mild deficits. They have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous and only in a small minority of patients has a definite genetic cause been identified. Megalencephaly with normal cortex by imaging, megalencephaly with polymicrogyria, dysplastic megalencephaly (including hemimegalencephaly), and focal cortical dysplasia can all result from mutations of the same genes in the PI3K-AKT-mTOR pathway which are often postzygotic and can be limited to the dysplastic tissue in the less diffuse forms.
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Abbreviations
- a > p:
-
Anterior > posterior
- BFPP:
-
Bilateral frontoparietal PMG
- BPP:
-
Bilateral perisylvian PMG
- CNV:
-
Copy number variants
- EEG:
-
Electroencephalogram
- ILS:
-
Isolated LIS
- LIS:
-
Lissencephaly
- MCD:
-
Malformations of cortical development
- MDS:
-
Miller-Dieker syndrome
- MLPA:
-
Multiplex ligation-dependent probe amplification
- MRI:
-
Magnetic resonance imaging
- p > a:
-
Posterior > anterior
- PMG:
-
Polymicrogyria
References
Barkovich AJ, Guerrini R, Kuzniecky RI et al (2012) A developmental and genetic classification for malformations of cortical development: update 2012. Brain 135:1348–1369
Blümcke I, Thom M, Aronica E et al (2011) The clinicopathologic spectrum of focal cortical dysplasias: a consensus classifi cation proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52:158–174
Cardoso C, Leventer RJ, Dowling JJ et al (2002) Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1). Hum Mutat 19:4–15
Conti V, Carabalona A, Pallesi-Pocachard E et al (2013) Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. Brain 136:3378–3394
Crino PB (2009) Focal brain malformations: seizures, signaling, sequencing. Epilepsia 50(Suppl 9):3–8
Cushion TD, Dobyns WB, Mullins JG et al (2013) Overlapping cortical malformations and mutations in TUBB2B and TUBA1A. Brain 136:536–548
DeMyer W (1986) Megalencephaly: types, clinical syndromes, and management. Pediatr Neurol 2:321–328
D'Gama AM, Geng Y, Couto JA et al (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720–725
Dobyns WB, Mirzaa G, Christian SL et al (2008) Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2. Am J Med Genet A 146A:1637–1654
Dobyns WB, Guerrini R, Leventer RL (2012) Malformations of cortical development. In: Swaiman KF, Ashwal S, Ferriero DM, Schor NF (eds) Swaiman’s pediatric neurology: principles and practice, 5th edn. Elsevier Saunders, Edinburgh, pp 202–231
Gleeson JG, Walsh CA (2000) Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci 23:352–359
Gleeson JG, Minnerath S, Kuzniecky RI et al (2000) Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am J Hum Genet 67:574–581
Guerrini R, Barba C (2010) Malformations of cortical development and aberrant cortical networks: epileptogenesis and functional organization. J Clin Neurophysiol 27:372–379
Guerrini R, Dobyns WB (2014) Malformations of cortical development: clinical features and genetic causes. Lancet Neurol 13:710–726
Guerrini R, Parrini E (2010) Neuronal migration disorders. Neurobiol Dis 38:154–166
Guerrini R, Moro F, Andermann E et al (2003) Nonsyndromic mental retardation and cryptogenic epilepsy in women with doublecortin gene mutations. Ann Neurol 54:30–37
Guerrini R, Mei D, Sisodiya S et al (2004) Germline and mosaic mutations of FLN1 in men with periventricular heterotopia. Neurology 63:51–56
Guerrini R, Dobyns W, Barkovich A (2008) Abnormal development of the human cerebral cortex: genetics, functional consequences and treatment options. Trends Neurosci 31:154–162
Jaglin XH, Poirier K, Saillour Y et al (2009) Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet 41:746–752
Lee JH, Huynh M, Silhavy JL et al (2012) De novo somatic mutations in components of the PI3K-AKT3-MTOR pathway cause hemimegalencephaly. Nat Genet 44:941–945
Lim JS, Kim WI, Kang HC et al (2015) Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 21:395–400
Matsumoto N, Leventer RJ, Kuc JA et al (2001) Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia. Eur J Hum Genet 9:5–12
Mei D, Lewis R, Parrini E et al (2008) High frequency of genomic deletions and duplication in the LIS1 gene in lissencephaly: implications for molecular diagnosis. J Med Genet 45:355–361
Mirzaa G, Ashwal S, Dobyns WB (2012a) Disorders of brain size. In: Swaiman KF, Ashwal S, Ferriero DF, Schor NF (eds) Swaiman’s pediatric neurology: principles and practice, 5th edn. Elsevier Saunders, Edinburgh, pp 173–201
Mirzaa GM, Conway RL, Gripp KW et al (2012b) Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A 158A:269–291
Mirzaa GM, Conti V, Timms AE et al (2015) Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: a next-generation sequencing study. Lancet Neurol 14:1182–1195
Parrini E, Ramazzotti A, Dobyns WB et al (2006) Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain 129:1892–1906
Piao X, Hill RS, Bodell A et al (2004) G protein-coupled receptor-dependent development of human frontal cortex. Science 303:2033–2036
Poduri A, Evrony GD, Cai X et al (2012) Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48
Poirier K, Lebrun N, Broix L et al (2013) Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet 45:639–647
Rivière JB, Mirzaa GM, O’Roak BJ, Finding of Rare Disease Genes (FORGE) Canada Consortium et al (2012) De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44:934–940
Robin NH, Taylor CJ, McDonald-McGinn DM et al (2006) Polymicrogyria and deletion 22q11.2 syndrome: window to the etiology of a common cortical malformation. Am J Med Genet A 140:2416–2425
Sheen VL, Ganesh VS, Topcu M et al (2004) Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet 36:69–76
Sutton VR, Van den Veyver IB (2006) Aicardi syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, pp 1993–2015
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Guerrini, R., Parrini, E. (2018). Malformations of Cortical Development in Newborns: Genetic Aspects. In: Buonocore, G., Bracci, R., Weindling, M. (eds) Neonatology. Springer, Cham. https://doi.org/10.1007/978-3-319-18159-2_270-2
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DOI: https://doi.org/10.1007/978-3-319-18159-2_270-2
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Malformations of Cortical Development in Newborns: Genetic Aspects- Published:
- 13 February 2018
DOI: https://doi.org/10.1007/978-3-319-18159-2_270-2
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Malformations of Cortical Development in Newborns: Genetic Aspects- Published:
- 02 January 2017
DOI: https://doi.org/10.1007/978-3-319-18159-2_270-1