Polymicrogyria, Bilateral Perisylvian, Autosomal Recessive

A number sign (#) is used with this entry because bilateral perisylvian polymicrogyria with autosomal recessive inheritance is caused by homozygous deletion of one 15-bp tandem repeat in a regulatory region of exon 1m of the ADGRG1 gene (604110) on chromosome 16q21. Mutations in the ADGRG1 gene also cause bilateral frontoparietal polymicrogyria (606854).

Description

Autosomal recessive bilateral perisylvian polymicrogyria is characterized by strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure. Affected individuals have intellectual and language difficulty and seizures, but no motor disability (Bae et al., 2014).

Clinical Features

Bae et al. (2014) examined more than 1,000 individuals with gyral abnormalities and identified 5 individuals from 3 families (1 Turkish and 2 Irish American) with strikingly restricted polymicrogyria limited to the cortex surrounding the Sylvian fissure, which suggested a rare, genetically distinctive condition. Affected individuals suffered intellectual and language difficulty, as well as refractory seizures with onset ranging from 7 months to 10 years, but had no motor disability. MRI and quantitative gyral analysis showed abnormal inferior and middle gyri in prefrontal and motor cortex, with mildly affected temporal lobes. Broca's area in the left hemisphere and the corresponding areas of the right hemisphere were most severely affected. Affected neocortical surface showed abnormally numerous, small gyral-like folds that fused in coarse, irregular patterns, with abnormal and highly irregular white matter protrusions, consistent with polymicrogyria, along with widening of the Sylvian fissure. Pedigree 1 consisted of female and male sibs from a consanguineous Turkish family. The daughter had intellectual disability with an IQ of 48 and mild delay, but she could read and write. She had left eye esotropia, nystagmus, and mild bilateral thenar atrophy. Her brother had intellectual disability with an IQ of 57 and received special education; he could not read. Additionally, he was obese. Pedigree 2 consisted of 2 sisters of an Irish American family in whom the parents were third cousins. One sister received special education in math but completed a regular school. The other girl was reported to have an 'odd component and manner of behaving' similar to that of her sib. Pedigree 3 consisted of unaffected consanguineous Irish American parents and a son with perisylvian polymicrogyria. The boy had no reported cognitive or motor development abnormalities, but did have generalized convulsions with tonic stiffening and vocalization.

Molecular Genetics

All 5 patients from the 3 families reported by Bae et al. (2014) were homozygous for a 15-bp deletion in a regulatory element of GPR56 noncoding exon 1m (604110.0009). The mutated element normally contains 2 copies of this 15-bp tandem repeat and is located just upstream of the noncoding exon 1m transcription start site. The deletion was heterozygous in parents of the affected individuals, who manifested no obvious clinical signs, and was absent from thousands of control chromosomes in the dbSNP and 1000 Genomes Project databases. The 2 Irish American families carried the mutation on the same chromosomal haplotype, reflecting a common founder. The Turkish family carried the same deletion on a distinct haplotype, indicating that the mutation arose independently.