Kheradmand Kia et al. (2012) reported a consanguineous Turkish family in which 2 sibs were demonstrated to have diffuse asymmetric polymicrogyria extending from the frontal to the temporal, parietal, and occipitals lobes on brain MRI. Other imaging findings ... Kheradmand Kia et al. (2012) reported a consanguineous Turkish family in which 2 sibs were demonstrated to have diffuse asymmetric polymicrogyria extending from the frontal to the temporal, parietal, and occipitals lobes on brain MRI. Other imaging findings included mild ventricular enlargement and thin or short corpus callosum. One patient had mild cerebellar atrophy. The patients were 12 and 14 years old at the time of the report. Both had microcephaly, moderate to severe mental retardation, poor speech, dysarthria, and seizures. One had pyramidal signs. Another family member had moderate mental retardation and seizures, but detailed clinical features were not available. An unrelated 16-year-old boy with diffuse polymicrogyria had microcephaly, severe mental retardation with lack of speech, seizures, and spastic tetraparesis. Two of the patients had normal abdominal ultrasound with situs solitus; 1 had small kidney volume.
In 3 members of a consanguineous Turkish family with polymicrogyria with seizures, Kheradmand Kia et al. (2012) identified a homozygous mutation in the RTTN gene (L932F; 610436.0001). The mutation was identified by autozygosity mapping followed by candidate gene ... In 3 members of a consanguineous Turkish family with polymicrogyria with seizures, Kheradmand Kia et al. (2012) identified a homozygous mutation in the RTTN gene (L932F; 610436.0001). The mutation was identified by autozygosity mapping followed by candidate gene sequencing. Another unrelated patient with a similar disorder carried a different homozygous mutation (C27Y; 610436.0002). Mutant L932F RTTN correctly localized to the basal bodies in patient fibroblasts, but there was a higher percentage of ciliary abnormalities, including short cilia with bulbous tips, compared to control. No ciliary abnormalities were apparent in cells from the patient with the C27Y mutation. However, gene expression profiling in patient fibroblasts with both mutations showed deregulation of several genes involved in brain development and/or known to be regulated at the cilium compared to control fibroblasts. Such genes included SHH (600725), HHIP (606178), WNT5A (164975), and BMP4 (112262). The polymicrogyria was primarily a postmigratory cortical organization defect, consistent with the localization of rotatin to the marginal zone in mouse embryonic brain. The findings supported the involvement of rotatin in the pathogenesis of this cortical malformation, and suggested that aberrant ciliary function contributes to abnormal development and organization of the cortex in humans.