Genotypically Defined Lissencephalies Show Distinct Pathologies

Abstract

Lissencephaly is traditionally divided into 2 distinct pathologic forms: classic (type I) and cobblestone (type II). To date, mutations in 4 genes, LIS1, DCX, RELN, and ARX, have been associated with distinct type I lissencephaly syndromes. Each of these genes has been shown to play a role in normal cell migration, consistent with the presumed pathogenesis of type I lissencephaly. Based on these data, we hypothesized that all forms of radiographically defined type I lissencephaly independent of genotype would be pathologically similar. To test this hypothesis, we examined brains from 16 patients, including 15 lissencephalic patients and one patient with subcortical band heterotopia. Of these 16 patients, 6 had LIS1 deletions, 2 had DCX mutations, and 2 had ARX mutations. In addition, 6 patients had no defined genetic defect, although the patient with subcortical band heterotopia exhibited the same pattern of malformation expected with an XLIS mutation. In all cases, the cortex was thickened; however, the topographic distribution of the cortical pathology varied, ranging from frontal- to occipital-biased pathology to diffuse involvement of the neocortex. Although brains with LIS1 deletions exhibited the classic 4-layer lissencephalic architecture, patients with DCX and ARX mutations each had unique cytoarchitectural findings distinct from LIS1. Furthermore, 2 of the 5 patients with no known genetic defect showed a fourth type of histopathology characterized by a 2-layered cortex. Interestingly, the 2 brains with the fourth type of lissencephaly showed profound brainstem and cerebellar abnormalities. In summary, we identified at least 4 distinct histopathologic subtypes of lissencephaly that stratify with the underlying genetic defect. Based on these data, a new classification for lissencephaly is proposed that incorporates both pathologic and genetic findings.

Midbrain–hindbrain involvement in lissencephalies

“…Marked to severe MHB hypoplasia was most often found in patients with pachygyria involving the entire cerebrum, relatively thin cortex (5 mm or less), and no cell-sparse zone (vLIS-ND, likely Forman's two-layered cortex lissencephaly). As discussed by previously cited authors, 3 this association could be related to extensive impairment of cortical fibers projecting to the pons as well as hypoplasia of mid-hindbrain nuclei.…”

“…4 These observations were later correlated with neuropathologic findings as mentioned in the introduction. 3 The pattern of cortical brain involvement in cLIS is typically different from what is seen in "cobblestone malformations" associated with defects in O-glycosylation of ␣-dystroglycan. [7][8][9][10][11]16 The agyria/pachygyria complex seen in cLIS and vLIS is mainly the result of incomplete migration of neurons, 2-6 whereas CBSC is primarily a result of overmigration of neurons, many of which pass through gaps in the glial limiting membrane.…”

“…4 The new pathologic classification recently proposed included cerebellum and brainstem abnormalities associated with cLIS (LIS1 and DCX) and vLIS (ARX and two-layered cortex). 3 They found the most severe involvement of the hindbrain (hypoplasia) in vLIS group and, most notably, in two-layered cortex. In our series, the midhindbrain in cLIS ranged from normal to small (more frequently among DCX and DCX-P patients) in agreement with previous studies.…”

“…The authors divided these lissencephalies into two groups: LIS1 and DCX were classified as cLIS, whereas ARX and two-layered lissencephalies were classified as variant lissencephaly (vLIS). 3 Numerous genes have been identified in association with the CBSC (also called dystroglycanopathies). [7][8][9][10][11][12] Most affected patients have symptoms of congenital muscular dystrophies (CMDs) with CNS involvement.…”

“…[1][2][3][4][5][6] A new classification has recently been proposed defining four groups of cLIS differing from each other by genetics and neuropathologic features of the cerebral cortex, cerebellum, and brainstem. 3 …”