Comparative Neuropathology of Lissencephaly with ARX Mutation: Consideration of Neocortical Interneuron Distribution of Various Lissencephalies

Background: Lissencephaly usually shows severe mental retardation and occasionally intractable epilepsy. Recently, X-linked lissencephaly with abnormal genitalia (XLAG) is established as one disease entity. XLAG, showing severe neonatal seizure and developmental delay, is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene, located in Xp22.13. Arx-null mice for human XLAG model showed loss of tangential migration of GABAergic interneurons. However, GABAergic interneuron distribution of XLAG brain has never been reported.

Objectives: In the present study, we investigated subpopulation of GABAergic interneurons in the brain of an infant with XLAG, who had a nonsense mutation of the ARX gene, compared with those of age-matched normal control, Miller-Dieker syndrome (MDS) as a type I lissencephaly, and polymicrogyria of Fukuyama type congenital muscular dystrophy (FCMD) as a type II lissencephaly.

Methods: We used paraffin-embeded brain tissues of two XLAG, three MDS and four FCMD, with an informed consent of their parents and approve of the ethical committee of the institute. We performed immunocytochemistry for interneuron and migration markers.

Results: Glutamic acid decarboxylase (GAD)- and calretinin (CR)-containing cells were significantly very few in the neocortex and, interestingly, located in the white matter and neocortical subventricular zone, while neuropeptide tyrosine and cholecystokinin positive cells were normal. From previous rodent studies, the imbalance of GABAergic interneurons may be derived from the caudal ganglionic eminence tangential migration. Also, in the neocortical subventricular region, the GAD- and CR-containing cells had Mash-1 protein, like a radial migration marker, and nestin protein. On the contrary, MDS showed relative low concentration of GAD-containing cells. FCMD revealed random distribution of these marked cells.

Conclusions: ARX protein controls not only tangential migration of GABAergic interneurons from the ganglionic eminence, but also may serve to induce radial migration from the neocortical subventricular zone. MDS and FCMD also demonstrated abnormal distribution of neocortical interneurons, but those severities are different in each type of lissencephaly.