Lissencephaly represents a term for a spectrum of severe and rare brain malformations caused by a failure in the 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. These types include type I, or classical lissencephaly, and type II, or cobblestone lissencephaly. Additional forms of the disease that do not belong to either of these two categories are also described in the medical literature.
Local nine-year-old battle the odds as Lissencephaly to be recognized as an official day in Abilene
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, which include 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 the normal development of other organ systems. Hence, patients with Miller-Dieker syndrome present with more severe clinical manifestations when compared to the isolated lissencephaly sequence.
Pathologic examination of the brain in type I lissencephaly shows a four-layered cerebral cortex instead of the six layers found in a normal cerebral cortex. The first layer of the cortex corresponds to the molecular layer, with the second layer containing neurons of normal layers III, V, and VI. The third layer represents the persistence of the fetal subplate zone, and the fourth layer contains heterotopic, incompletely migrated neurons.
Type II lissencephaly is also referred to as cobblestone dysplasia in the medical literature due to the pebbled appearance of the cerebral cortex surface. In this type of lissencephaly, there is a complete displacement of the brain cortex, with clusters of cortical neurons separated by glial-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 diseases are related to autosomal recessive disorders that are 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 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. This condition is caused by homozygous mutations in the phosphoglycerate dehydrogenase enzyme. The 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.