Cortical Dysplasia, Complex, With Other Brain Malformations 1

A number sign (#) is used with this entry because of evidence that complex cortical dysplasia with other brain malformations-1 (CDCBM1) is caused by heterozygous mutation in the TUBB3 gene (602661) on chromosome 16q24.

Description

Complex cortical dysplasia with other brain malformations (CDCBM) is a disorder of aberrant neuronal migration and disturbed axonal guidance. Affected individuals have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Brain imaging shows variable malformations of cortical development, including polymicrogyria, gyral disorganization, and fusion of the basal ganglia, as well as thin corpus callosum, hypoplastic brainstem, and dysplastic cerebellar vermis. Extraocular muscles are not involved (summary by Poirier et al., 2010).

Mutation in the TUBB3 gene can also cause congenital fibrosis of extraocular muscles-3A (CFEOM3A; 600638), a milder and somewhat different neurologic phenotype.

Genetic Heterogeneity of Complex Cortical Dysplasia With Other Brain Malformations

See also CDCBM2 (615282), caused by mutation in the KIF5C gene (604593) on chromosome 2q23; CDCBM3 (615411), caused by mutation in the KIF2A gene (602591) on chromosome 5q12; CDCBM4 (615412), caused by mutation in the TUBG1 gene (191135) on chromosome 17q21; CDCBM5 (615763), caused by mutation in the TUBB2A gene (615101) on chromosome 6p25; CDCBM6 (615771), caused by mutation in the TUBB gene (191130) on chromosome 6p21; CDCBM7 (610031), caused by mutation in the TUBB2B gene (612850) on chromosome 6p25; CDCBM8 (613180), caused by mutation in the TUBA8 gene (605742) on chromosome 22q11; and CDCBM9 (618174), caused by mutation in the CTNNA2 gene (114025) on chromosome 2p12.

See also lissencephaly (e.g., LIS1, 607432), which shows overlapping features and may result from mutation in tubulin genes.

Clinical Features

Poirier et al. (2010) reported 9 patients from 7 families with mild to severe mental retardation associated with variable degrees of complex cortical dysplasia and other brain malformations. All except 1 had axial hypotonia, and 3 had spastic diplegia or tetraplegia. Most had strabismus combined with nystagmus, but none had external ophthalmoplegia or abnormal funduscopy. Two had seizures, only 1 of whom had refractory seizures. None had congenital contractures or polyneuropathy. Brain imaging showed frontally predominant microgyria in 4 patients and gyral disorganization and simplification in 5. Other brain malformations included dysmorphic and hypertrophic basal ganglia with fusion between putamen and caudate nucleus (8 of 9 patients), dysplasia of the cerebellar vermis (9 of 9), hypoplastic brainstem (8 of 9), and hypoplastic corpus callosum in (8 of 9). There was also evidence of a defect in axonal migration, with misorientation of the pyramidal fibers of the corticospinal tract. Postmortem examination of a 27-week-old fetus showed microlissencephaly with severe brainstem and cerebellar hypoplasia, agenesis of the olfactory bulbs, and optic nerve hypoplasia. There was a severely disorganized cortical plate with a festooned-like pattern, absence of the caudate, putamen, and pallidum, and hypoplastic thalami. There was aberrant localization of cortical interneurons, lack of callosal fibers, absence of corticospinal tracts, and aberrant fiber bundles in the cortex, all consistent with severe defects in neuronal migration and axonal guidance.

Fallet-Bianco et al. (2014) reported a 27-week-old fetus (individual 17) with CDCBM1 manifest as microlissencephaly. He had microcephaly, a thin cortical plate, dispersed heterotopic neurons, and agenesis of the olfactory bulbs. Other features included enlarged granular layer, hypoplastic basal ganglia, complete agenesis of the corpus callosum, severe pontocerebellar hypoplasia, and optic nerve hypoplasia.

Inheritance

Of 7 unrelated families with complex cortical dysplasia and other brain malformations, Poirier et al. (2010) found that 3 showed autosomal dominant inheritance of the disorder and 4 had de novo occurrence of the disorder. In 1 of the autosomal dominant families, they determined that a severely affected girl was homozygous for missense mutation and that her 3 affected sibs and affected mother were heterozygous for the same mutation. DNA from the father was not available for testing, but SNP array testing excluded a TUBB3 deletion and showed a high level of homozygosity in the girl, consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 7 unrelated families with complex cortical dysplasia and other brain malformations, Poirier et al. (2010) identified 6 different heterozygous missense mutations in the TUBB3 gene (see, e.g., 602661.0006-602661.0009). In vitro functional expression studies showed that most of the mutations resulted in impairment of the tubulin heterodimerization process or caused impaired microtubule stability.

In a 27-week-old fetus (individual 17) with CDCBM1 manifest as microlissencephaly, Fallet-Bianco et al. (2014) identified a heterozygous missense mutation in the TUBB3 gene (M388V; 602661.0010). Functional studies of the variant and studies of patient cells were not performed.