Cortical Dysplasia, Complex, With Other Brain Malformations 7

A number sign (#) is used with this entry because of evidence that complex cortical dysplasia with other brain malformations-7 (CDCBM7) is caused by heterozygous mutation in the TUBB2B gene (612850) on chromosome 6p25.

Description

Complex cortical dysplasia with other brain malformations-7 is an autosomal dominant, clinically heterogeneous disorder showing a wide spectrum of abnormalities of cortical brain development. The most severely affected patients are fetuses with microlissencephaly, absence of the cortical plate, agenesis of the corpus callosum, and severely hypoplastic brainstem and cerebellum. Other patients have lissencephaly, polymicrogyria, cortical dysplasia, or neuronal heterotopia. Those with less severe malformations can survive, but usually have some degree of neurologic impairment, such as mental retardation, seizures, and movement abnormalities (summary by Chang et al., 2006; Fallet-Bianco et al., 2014).

For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).

Clinical Features

Caraballo et al. (2000) reported a mother and son with unilateral right focal polymicrogyria. Both had cognitive impairment (IQ of 85 and 80, respectively) and congenital contralateral hemiparesis. The son also had focal seizures. Brain imaging of both patients showed right frontoparietal cortical dysplasia consistent with polymicrogyria. Autosomal dominant inheritance was suggested.

Chang et al. (2006) reported 4 unrelated families in which 2 members of each family had unilateral right-sided polymicrogyria. Common clinical features included developmental delay, variable cognitive defects, contralateral (left) hemiparesis, and focal seizures. In 1 family, both affected sibs also had left hemianopia. Three families had 2 affected sibs born of nonconsanguineous unaffected parents; the fourth family that was previously reported by Caraballo et al. (2000) had affected mother and son. Familial occurrence strongly suggested a germline genetic etiology, although the pattern of inheritance was unclear. Chang et al. (2006) noted that features typically seen in DiGeorge /velocardiofacial syndrome (DGS, 188400; VCFS, 192430) were not present in their patients.

Jaglin et al. (2009) reported 4 patients with asymmetric polymicrogyria. All had microcephaly, and 3 had severe neuromotor impairment with mental retardation. Three also had seizures. Brain imaging studies showed asymmetric polymicrogyria predominantly in the frontal, temporal, and parietal lobes, with dysmorphic caudate, cerebellar atrophy, and abnormalities of the corpus callosum and brainstem.

Guerrini et al. (2012) reported 3 unrelated children with polymicrogyria. All had delayed psychomotor development, microcephaly, and mental retardation. Two had oromotor dyspraxia, 2 had hypotonia, and 1 had seizures. Brain MRI revealed diffuse polymicrogyria in 2 patients, more severe in the perisylvian region in 1 and with an irregular cortex resembling cobblestone cortex in the other. MRI of the third patient showed pachygyria with cortical thickening and irregular folding in the postrolandic and parietoposterior temporal regions. One patient had a small pons and another had a thin corpus callosum. The cerebellum was normal in all 3 patients.

Fallet-Bianco et al. (2014) reported 6 unrelated fetuses with CDCBM7. Two of the fetuses (individuals 13 and 19) had a more severe phenotype of microlissencephaly, with microcephaly, enlarged germinal zone, complete agenesis of the corpus callosum, severe cerebellar hypoplasia/dysplasia, and pontine hypoplasia with focal overmigration. Another fetus (14) was classified as having lissencephaly, with a thick 4-layered cortex, heterotopia, complete agenesis of the corpus callosum, and mild pontocerebellar hypoplasia. The last 3 fetuses (16, 15, and 12) had polymicrogyria with cortical dysplasia, including heterotopia in 2 and agenesis of the olfactory bulb in 1, complete agenesis of the corpus callosum in 2, and mild cerebellar hypoplasia in all. These 6 fetuses were part of a cohort of 26 fetuses with malformations of cortical development associated with mutations in various tubulin genes. All of the fetuses carried heterozygous missense mutations in the TUBB2B gene (see, e.g., 612850.0001 and 612850.0008). Functional studies of the variants and studies of patient cells were not performed.

Laquerriere et al. (2016) reported a 15-week-old fetus with CDCBM7 manifest as microlissencephaly. Postmortem examination showed microcephaly, smooth brain surface, a 2-layered cortex, absent olfactory tracts, and hypoplastic brainstem and cerebellum.

Clinical Variability

Cederquist et al. (2012) found a heterozygous missense mutation in the TUBB2B gene (E421K; 612850.0007) in a mother and her 2 daughters with polymicrogyria, intellectual disability, and congenital fibrosis of the extraocular muscles (CFEOM). The family had originally been reported by Flaherty et al. (2001). The daughters were noted to have ptosis and limitation of eye movements shortly after birth. Both girls showed delayed psychomotor development with moderate intellectual disability. Ophthalmic examination confirmed CFEOM with limited eye movements. Brain MRI of both girls showed polymicrogyric cortical dysplasia with dilation of the left lateral ventricle, hypoplasia of the left caudate body, and fusion of an enlarged caudate head with the underlying putamen. There was also thinning of the extraocular muscles. The mother had low intellectual functioning and limited extraocular movements. Her brain MRI showed mild bilateral polymicrogyria with asymmetry of the ventricles and basal ganglia, similar to her daughters. All 3 patients had a thinned corpus callosum.

Cytogenetics

Robin et al. (2006) reviewed clinical data including brain imaging on 21 patients from their subject database and 11 patients from the literature, all with polymicrogyria associated with deletion 22q11.2 (DGS/VCFS). The authors found that the cortical malformation consisted of perisylvian polymicrogyria of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (p = 0.008).

Molecular Genetics

In 4 unrelated patients and a fetus with asymmetric polymicrogyria, Jaglin et al. (2009) identified 5 different heterozygous mutations in the TUBB2B gene (see, e.g., 612850.0001-612850.0003). In vitro studies of some of the mutant proteins showed impaired formation of functional alpha/beta tubulin heterodimers and impaired incorporation into well-defined microtubules. The patients showed some phenotypic variability, but most had neuromotor impairment, mental retardation, and seizures. Brain imaging studies showed asymmetric polymicrogyria predominantly in the frontal, temporal, and parietal lobes, with dysmorphic caudate, cerebellar atrophy, and abnormalities of the corpus callosum and brainstem.

In 3 (2.3%) of 128 unrelated children with polymicrogyria, Guerrini et al. (2012) identified 3 different heterozygous mutations in the TUBB2B gene (612850.0004-612850.0006). De novo occurrence of the mutation was proven in 2 patients and suspected in 1. The mutations were predicted to interfere with normal function of microtubules.

In a fetus with microlissencephaly, Laquerriere et al. (2016) identified a de novo heterozygous missense mutation in the TUBB2B gene (C239F; 612850.0008). In vitro functional expression studies showed that the mutant protein caused impairment of the tubulin heterodimerization process. Cellular transfection of the mutant protein showed that it incorporated into microtubules, but there were high levels of unpolymerized cytosolic tubulin heterodimers, indicating that it incorporated poorly into the cytoskeleton. The mutation also altered microtubule dynamics, with an accelerated rate of repolymerization compared to controls.