Understanding the pathology of PMG has taken on new interest and importance with the discovery of many PMG syndromes and several associated genes (9
). This is combined with the longstanding recognition that PMG may also result from teratogenic, infectious or ischemic insult to the brain (1
). While the pathologic features of PMG have been described in many papers, reviews, and chapters, the laminar organization has received little attention. Based on recently defined markers of the laminar organization of the cerebral cortex, our data indicate that, although there is a reduction in the overall thickness of the cortex, neurons are positioned in the appropriate layers in PMG. Our finding that laminar organization is preserved combined with the fact that most cases show few white matter neurons argue against a primary neuronal migration disorder. We also found considerable heterogeneity in the histopathology with overlap in the various types, even within a single case. This also raises doubt regarding the validity of distinguishing PMG by the number of laminae.
A second major implication of our study is that separation of PMG into 2-, 4- or 6-layer types appears artificial (1
). We found that different numbers of layers of PMG were frequently present within the same case. Thus, identification of findings accompanying PMG will likely be of greater importance. The presence of porencephaly, extensive leptomeningeal heterotopia, or periventricular nodular heterotopia (all associated pathologies found in our series as well as by others) will likely contribute to understanding the various pathogeneses of PMG. For example, the finding of porencephaly with accompanying abnormalities such as iron deposition more likely indicates a disruption/vascular event underlying the pathogenesis of the PMG (10
). In contrast, the presence of extensive bilateral PMG with microcephaly may indicate a specific genetic defect such as a mutation in WDR62
A number of gene mutations have recently been linked to PMG. In addition to WDR62
, mutations in SRPX2 have been associated with perisylvian PMG; the affected patients exhibit language and cognitive defects along with epilepsy (13
). Additional genes associated with PMG include PAX6, TBR2, KIAA1279, RAB3GAP1,
); these account for a small minority of cases but there is no known pathology for any of these specific genetic disorders. Nonetheless, identifying specific pathologic patterns of PMG in different patients with specific genetic disorders or other known etiologies will significantly aid in guiding genetic evaluations and testing for patients with PMG. A large series of PMG cases highlights its clinical heterogeneity and points to the importance of identifying its genetic and pathobiologic basis (14
Mutations in Occludin
), an integral component of tight junctions, were found to be associated with the band-like calcification with simplified gyration and PMG syndrome, also known as pseudo-TORCH syndrome (6
). While tight junctions are essential for the structure and function of glial-vascular integrity, it remains uncertain whether OCLN
mutations result in vascular disruption as the pathogenesis of the PMG and calcifications, or if there is some other developmental event that is disrupted.
Mutations in GPR56
were first reported to be associated with PMG, specifically frontoparietal PMG and white matter defects (15
). Subsequent evaluation of the pathology revealed that the cerebral malformation included extensive leptomeningeal heterotopia and over migration (16
). The similarity of the pathology in these cases with that reported in O-glycosylation disorders suggests that mutations in GPR56
are a part of this pathway rather than a PMG gene (16
Finally, 2 cases in our series had a recognized metabolic defect along with PMG. Although both pyruvate dehydrogenase deficiency and carnitine palmitoyl transferase deficiency have been associated with PMG (17
), the pathology of PMG has been confirmed in only rare cases. Our cases provide further confirmation of an association of PMG with these disorders.
In summary, our analysis of 19 cases of PMG, the largest series of PMG reported in the pathology literature, has identified several important pathologic characteristics of PMG. First, the histopathologic distinction of PMG into 2-, 4-, and 6-layer PMG is likely artificial and does not have biological significance. Second, neurons in the cases of PMG we studied appear to be positioned in the appropriate laminae, suggesting that PMG is not a migration disorder. It remains possible that other cases of PMG, when similarly studied, will identify laminar disruptions; these will be of extreme interest and may point to specific genetic defects. Finally, we propose that the minimal criteria for PMG should be fusion of the molecular layer with festooning of the cortical surface independent of other cortical changes.