Polymicrogyria, Perisylvian, With Cerebellar Hypoplasia And Arthrogryposis

A number sign (#) is used with this entry because of evidence that perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis (PMGYCHA) is caused by compound heterozygous mutation in the PI4KA gene (600286) on chromosome 22q11. One such family has been reported.

Clinical Features

Pagnamenta et al. (2015) reported a family in which 3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers. Three had micrognathia and 2 had dolichocephaly. Muscle histology was reported to be within normal limits. The fetuses were conceived by nonconsanguineous parents of European ancestry; the parents had had 3 early miscarriages in addition to the affected fetuses.

Inheritance

The transmission pattern of perisylvian polymicrogyria, cerebellar hypoplasia, and arthrogryposis in the family reported by Pagnamenta et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In tissue samples from 3 affected fetuses, conceived by unrelated parents of European descent, with PMGYCHA, Pagnamenta et al. (2015) identified compound heterozygous mutations in the PI4KA gene (R796X, 600286.0001 and D1854N, 600286.0002). The mutations, which were found by a combination of exome sequencing and linkage analysis, segregated with the disorder in the family. In vitro functional expression assays in COS-7 cells showed that the D1854N mutant enzyme had no detectable catalytic activity, consistent with a loss of function. The findings indicated the importance of phosphoinositide signaling in early brain development.