Genetic Basis of Brain Malformations

Abstract

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 causing severe global neurological impairment. Abnormalities of the LIS1, DCX, ARX, RELN, VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and DYNC1H1), regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes and cause neurological and cognitive impairment that vary from severe to mild deficits. 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, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms.

Keywords: Cortical development; Lissencephaly; Malformation.

Fig. 1

Brain MRI of patients with different malformations of the cerebral cortex. A T1-weighted axial section. Posterior to anterior pachygyria in a boy with LIS1 mutation. B T2-weighted axial section. Diffuse SBH in a girl with DCX mutation. C, D T2-weighted axial section and T1-weighted sagittal section. Lissencephaly and cerebellar hypoplasia in a girl with RELN mutation. E, F T1-weighted axial section and T1-weighted sagittal section. Thickened cortex with simplified gyral pattern and cerebellar hypoplasia in a girl with TUBA1A mutation. G T1-weighted axial section. Diffuse simplified gyral pattern with prominent thickening and infolding of the sylvian fissures in a boy with TUBB2B mutation. H T1-weighted axial section. Typical, classical bilateral PNH in a girl with an FLNA mutation. Bilateral nodules of subependymal heterotopia are contiguous and rather symmetric, extensively lining the ventricular walls. I, J T2-weighted axial section showing mild colpocephaly with unilateral PNH (white arrowhead) and T2-weighted sagittal section through the midline, showing cerebellar vermis hypoplasia (black arrowhead) with mega cisterna magna in a patient carrying a deletion in the 6q27 chromosomal region. K T2-weighted axial section. Bilateral frontoparietal polymicrogyria in a boy with GPR56 mutation. L, M T2-weighted axial section and T1-weighted coronal section. Pachygyria and perisylvian polymicrogyria in a girl with DYNC1H1 mutation. N Axial T1-weighted section in a patient with a mosaic PIK3R2 mutation. O, P T1-weighted and T2-weighted axial images form patients carrying mosaic mutations in the MTOR gene with different percentages of mosaicism [O: p.Thr1977Ile, 20% of mosaicism in blood, P: p.Ser2215Phe, 5.5% of mosaicism in dysplastic brain tissue) showing bilateral cortical dysgyria (O) and focal cortical dysplasia (P, white arrowhead)].