Lissencephaly represents a term for a spectrum of severe and rare brain malformations caused by a failure in migration of neurons that were supposed to reach designated positions in the cerebral cortex during embryogenesis. As a result, there is a significant simplification (pachygyria) or even total absence (agyria) of brain convolutions.
Based on the physical structure of the brain, lissencephaly can be generally divided into two distinct pathological forms: type I or classical lissencephaly, and type II or cobblestone lissencephaly. Additional forms of the disease that do not belong to neither of these two categories are also described in the medical literature.
Type I or classical lissencephaly is seen in a number of genetic syndromes, but can also appear on its own in a condition known as isolated lissencephaly sequence. The latter usually arises due to mutations or deletions in two important genes involved in brain development – LIS1 and DCX.
Miller-Dieker syndrome represents a syndromic form of classical lissencephaly. In this syndrome, the effects of the deletions in the LIS1 gene have a tendency to extend to nearby genes required for normal development of other organ systems. Hence, patients with Miller-Dieker syndrome present with more severe clinical manifestation when compared to isolated lissencephaly sequence.
Pathologic examination of the brain in type I lissencephaly shows a four-layered cerebral cortex (instead of six layers found in normal cerebral cortex). First layer corresponds to the molecular layer, second contain neurons of normal layers III, V and VI, while third layer represents persistence of the fetal subplate zone, and fourth contains heterotopic, incompletely migrated neurons.
Type II lissencephaly is also called cobblestone dysplasia in the medical literature due to the pebbled appearance of the cerebral cortex surface. In this type of the disease there is complete displacement of the brain cortex, with clusters of cortical neurons separated by glio-mesenchymal tissue.
Disorders associated with type II lissencephaly include cobblestone lissencephaly without other birth defects, Walker-Warburg syndrome (also known as HARD±E syndrome), Fukuyama congenital muscular dystrophy, as well as muscle-eye-brain disease. Most of these entities are related autosomal recessive disorders caused by mutations in the genes POMT1 and FCMD.
Other types of lissencephaly
Other types of dysmorphology syndromes with lissencephaly have been described that cannot be placed in one of the two aforementioned groups. For example, Norman-Roberts syndrome clinically presents similarly to type I lissencephaly or Miller-Dieker syndrome, but there is no deletion of the chromosome 17 that is typical for the latter syndrome.
Neu-Laxova syndrome represents a rare disorder manifesting with severe malformations that result in prenatal or early postnatal mortality. It is caused by homozygous mutations in phosphoglycerate dehydrogenase enzyme. Lissencephaly that is observed in this syndrome is also known as type III lissencephaly by some research groups, albeit it is still not included in any formal classifications.