We identified three new TUBB2B mutations in three unrelated patients (3 out of 128; 2.3%) with a diffuse and rather symmetrical cortical abnormality, including diffuse polymicrogyria in two and bilateral regional pachygyria in one.
By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG.
Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria.
Autosomal recessive missense Rotatin (RTTN) mutations are responsible for syndromic forms of malformation of cortical development, ranging from isolated polymicrogyria to microcephaly associated with primordial dwarfism and other major malformations.
RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism.
Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD).
Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration.
Our findings confirm that cortical malformations should be considered to fall within the phenotypic spectrum of COL4A1 mutations and show that not only schizencephaly but also polymicrogyria can also be found in mutated individuals.
We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event.
These were as follows (number of patients in brackets): Aicardi-Goutières syndrome (33), cerebroretinal microangiopathy with calcification and cysts (10), band-like calcification with simplified gyration and polymicrogyria (6), COL4A1-related disease (3), Degos disease (2), Krabbe disease (2), Alexander disease (1), mitochondrial disease (1), and tetrasomy 15 (1).
Fukuyama-type congenital muscular dystrophy (FCMD) results from a mutation in a gene on chromosome 9q31, fukutin, and is characterized pathologically by micropolygyria of the cerebral and cerebellar cortices.
Finally, in Fukuyama congenital muscular dystrophy, the deficient fukutin gene product may also be linked to the basal lamina, permitting overmigration of neuronal cells which lead to micropolygyria in the brain, and at the same time cause basal lamina defects in the extracellular matrix of skeletal muscle, which leads to muscular dystrophy.
Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria).
Mutations in Factor-Induced-Gene 4 (FIG4) gene have been identified in Charcot-Marie-Tooth disease type 4J (CMT4J), Yunis-Varon syndrome and epilepsy with polymicrogyria.