8.3 Lissencephaly
Lissencephaly, literally meaning ‘smooth brain’, is characterised by the absence of sulci and gyri, and by a four-layered cortex, instead of the usual six layers, with the majority of cortical neurons in layer four (Figure 22). Babies born with lissencephaly have a very poor prognosis; the disease proving lethal before their second birthday. Behaviourally, lissencephaly results in epilepsy, mental retardation, motor impairment and a general lack of developmental progress.
Lissencephaly results from a mutation in the LIS1 gene. (Note: the nomenclature used here is correct for human genes, e.g. LIS1, and their products, e.g. LIS1P, and differs from the nomenclature used for Drosophila in Section 6.4.) A mutant form of this gene produces a non-functioning protein, which is lethal very early in prenatal development when it occurs on both chromosomes, i.e. when both alleles are defective. In this case the genome is said to be homozygous for it. However, in the heterozygous condition, where both forms are present, a certain amount of development occurs and it has been possible to establish the precise role of LIS1 using heterozygous knockout mice. Heterozygous mice show cortical disorganisation consistent with disordered neuronal migration.
During the development of the brain, neurons are born at the ventricular surface, where brain tissue meets the cerebrospinal fluid of the ventricles. Newly born neurons (neuroblasts) move away from the banks of the ventricles towards the outer surface (the pial surface) of the brain. In terms of the number of items (neuroblasts) moving, this is an unimaginably vast migration. The movement of the neuroblasts involves a number of activities, one of which ensures that the nucleus stays within its cell, and doesn't get left behind. This is nucleokinesis. The protein product of LIS1, LIS1P, pulls the nucleus along and so is important in nucleokinesis. In the homozygous mutant condition, the protein is absent/defective and there is nothing to pull the nucleus along, so nucleokinesis and hence cell migration, cannot occur, resulting in the early death of the organism. In the heterozygous condition, some LIS1P is made and so some nucleokinesis can occur, though the exact extent depends on the amount of LIS1P produced and which other genes are present.
Lissencephaly is a congenital disease, meaning simply that the symptoms of the disease are present at birth. In contrast to Wilson's disease, lissencephaly is untreatable. This is because intervention would need to happen more or less at conception, be continuous throughout development and target neuroblasts at the ventricular surface.
Although relatively rare, more than 25 different syndromes with abnormal neuronal migrations have been described in humans. Some authorities suggest they account for up to one-third of all cases of severe epilepsy.