Polymicrogyria
Polymicrogyria is a type of cortical malformation in which the brain surface is irregular and is presenting with a simplified cytoarchitecture with excessive gyri. The best technique to evidence polymicrogyria is magnetic resonance imaging (MRI). MRI can document the loss of normal gyration pattern, an irregular brain surface, a large number of small gyri (2-5 mm) and shallow sulci. The junction between the cortex and the white matter is irregular. When the perisylvian region is affected (which are the most frequently observed cases), the sylvian fissures are abnormally oriented and extend posteriorly to the parietal convexity. The cortex appears to be abnormally thick (although this is probably caused by the excess of gyri and not by an enlargement of the cortex per se) with a size of approximately 5-10 mm instead of the 2,5-4 mm which are usually observed in an unaffected individual.
Perisylvian polymicrogyria (image from William B. Dobyns, University of Chicago).
Individuals affected with polymicrogyria have various clinical signs depending on the extent and location of the affected area in the brain. When the perisylvian region is affected, the patients usually display speech problems and have difficulties to articulate or acquire langage properly. Almost all patients are mentally retarded, usually midly, and have epilepsy.
The pathogenesis of polymicrogyria is still mysterious. It is known that intrauterine cytomegalovirus infections can cause PMG. However, it is also known that genetic causes do exist for polymicrogyria. Several familial cases of PMG could be X-linked. In certain families, only males are affected whereas in others, males are more severly affected than females. Others pedigrees suggest autosomal dominant or autosomal recessive inheritance. Thus, it seems that polymicrogyria is genetically heterogeneous.
Two loci have been mapped in the human genome for this condition using familial cases and linkage analysis. One locus maps to chromosome 16 (Piao et al., 2002), and the other locus was mapped to the X chromosome (Villard et al., 2002). The chromosome 16 gene has recently been found (Piao et al., 2004). The gene is called GPR56 and it encodes an orphan G protein-coupled receptor (GPCR) which has a large extracellular domain. Mutations in GPR56 cause bilateral frontoparietal polymicrogyria (BFPP) in affected patients. BFPP is characterized by disorganized cortical lamination that is most severe in frontal cortex. This new data suggests that G-protein coupled signalling can affect the normal lamination of the human cerebral cortex. A recent work shows that mutations in GPR56 disturb its intracellular trafficking and membrane localization (Jin et al. 2007).