In the complete lissencephalies, the lateral and third ventricles enlarge because of a lack of the normal quantities of surrounding cerebral tissue (i.e., the aforementioned hydranencephaly). The cerebellar cortex is also abnormal. In some lissencephalic brains, there is slight sulcation presenting as abnormally broad or narrow convolutions, with thick, poorly laminated cortex; these are called pachygyrias or microgyrias, respectively, but the fundamental migratory abnormality is basically the same. The cerebellum is also abnormal, usually showing hypoplasia or aplasia involving the vermis or neocerebellum.
In the severe defects, the cranium is small at birth. In one type, which is inherited as an autosomal recessive trait, there are subtle craniofacial features (short nose, small mandible, ear abnormalities) as well as congenital heart disease. In another group, there is an associated familial congenital muscular dystrophy, placing the case between the Fukuyama and Walker-Warburg syndromes (see “Congenital Muscular Dystrophy” in Chap. 45).
Alobar and lobar holoprosencephalies are other examples of sulcation defects with craniofacial abnormalities in which development has gone awry in the fifth and sixth weeks of gestation (see Volpe, 1995). In these subtypes, the two cerebral hemispheres, either totally or only in part, form as a single telencephalic mass. In nearly all cases the cerebral defect is reflected by a single eye (cyclopia) and the absence of the nose, imparting an astonishing and diagnostic appearance.
Most of the severe disorders are sporadic, and the infants seldom survive for long. In a few of the malformations, a congenital infection with CMV or rubella has been implicated (Hayward et al).
The Dandy-Walker syndrome represents a more restricted form of migration and neural tube defect. There is cerebellar vermian hypoplasia with or without hydrocephalus and, in some cases, an added agenesis of the corpus callosum with cerebral cortical dysgeneses (Landrieu). This defect, which is identified by the cystic enlargement of the fourth ventricle, is discussed further on, with the dysraphic neural tube defects.
That some instances of lissencephaly have a genetic basis has already been mentioned (see Table 37-3). Two genes that modify microtubular function have been identified: LIS1 and “doublecortin” or DCX. Large chromosomal deletions that span LIS1 cause Miller-Dieker syndrome, in which lissencephaly is associated with distinctive facial abnormalities; small defects in the same gene cause only lissencephaly. Lissencephaly with cerebellar hypoplasia is caused by mutations in the human “reelin” gene (RELN), the analogue of the defective gene in reelin mice (which have a reeling gait and abnormal cortical neuronal lamination). Defects in the transcription factor ARX are associated with X-linked lissencephaly, agenesis of the corpus callosum, and hypogonadism. Periventricular nodular heterotopia is caused by another gene defect, filamin A gene on the X chromosome. Some cases of holoprosencephaly have been traced to mutations in the sonic hedgehog gene.