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.

Early epilepsy in children with Zika‐related microcephaly in a cohort in Recife, Brazil: Characteristics, electroencephalographic findings, and treatment response

“…All of these abnormalities may be involved in the development of early Zika‐related epilepsy. In lissencephalies of the other causes, especially those of genetic origin, there is a similar abnormal neuronal migration, with loss of cortical architecture and macroscopic simplification of the cortical mantle; however, gliosis and calcifications are not observed . We hypothesize that these differences may alter clinical manifestations, at least in early ages, during which the onset of Zika‐related seizures was not as frequent.…”

“…Classical lissencephaly is recognized as a neuronal migration disorder. The migration and differentiation of neurons are critical to appropriate electrophysiological functions of the cortex . The incidence of seizures in these cases is approximately 90%, with typical onset before 6 months of age.…”

“…The migration and differentiation of neurons are critical to appropriate electrophysiological functions of the cortex. 28,31 The incidence of seizures in these cases is approximately 90%, with typical onset before 6 months of age. Experimental ZIKV infection models have demonstrated that ZIKV is a neurotropic virus, with a predilection for neuronal progenitor cells.…”

“…In lissencephalies of the other causes, especially those of genetic origin, there is a similar abnormal neuronal migration, with loss of cortical architecture and macroscopic simplification of the cortical mantle; however, gliosis and calcifications are not observed. 28,31 We hypothesize that these differences may alter clinical manifestations, at least in early ages, during which the onset of Zika-related seizures was not as frequent. Because the participants were primarily severe microcephalic cases with major neuroimaging abnormalities, the correlation between imaging findings and the risk of specific epileptic syndromes could not be evaluated in this study.…”

Genetic mimics of cerebral palsy

“…Some children with a CP phenotype have a cerebral malformation as the primary cause of their neurological syndrome, which is readily recognized on brain imaging. There are now a number of causative genes associated with disorders of neuronal migration and cortical development, such as lissencephaly, polymicrogyria, schizencephaly, and focal cortical dysplasia . In severe cases, associated clinical features typically include seizures and intellectual disability …”