What is Lissencephaly?

Lissencephaly represents a developmental disorder resulting from abnormal neuronal migration. A wide spectrum of cerebral pathology can be seen in lissencephaly – from pachygyria and agyria (reduction and absence of cerebral convolutions, respectively) to subcortical band heterotopia where cerebral convolutions appear normal.

Management of the disease

The severe underlying malformations of the brain are not amenable to treatment, thus supportive care is appropriate to ensure comfort and nursing requirements. Such symptomatic approach depends on the severity and locations of the brain malformations.

Although medical management of seizures is available, it must be noted that epilepsy associated with lissencephaly and accompanying seizures are usually resistant to conventional therapy. Adrenocorticotropic hormones are a viable, but not completely effective option in the treatment of infantile spasms.

For children with serious feeding difficulties, a gastrotomy feeding tube placement is often considered in order to preserve adequate nutrition. Ventriculoperitoneal shunts and encephalocele repair is pursued in certain cases of Walker-Warburg syndrome.

Prognosis

The outlook for all patients with lissencephaly is not good, especially for those with the identifiable syndromes. Children with isolated lissencephaly may sit or roll, and rare patients with mild agyria and pachygyria will walk. Nevertheless, a majority of patients show no significant development beyond the 5-month level.

Even though the vast majority of patients dies before the age of two (regardless of the type of lissencephaly), survival to late childhood with near-normal intelligence is occasionally observed. As mentioned, certain mutations may result in milder cortical changes that are compatible with a substantially better prognosis.

Potential novel therapeutic strategies

Deeper insights into genes involved in lissencephaly and their mechanism of actions may lead to novel therapies, and the experiments on rats and mice look promising. For example, by reexpressing DCX gene after birth, aberrantly positioned neurons are stimulated to restart migration and restore neuronal patterning.

Furthermore, inhibitors of calpain-dependent proteolysis have the ability to protect LIS1 from degrading, which results in the upsurge of LIS1 levels in mouse embryonic fibroblast cells and dorsal root ganglia neurons. This can overturn the aberrant distribution of cytoplasmic dynein and other intracellular components responsible for lissencephaly and other similar disorders.

A long-term goal of this kind of research is to think of ways how to translate the findings into human patients, which is not an easy task. It is hard to predict when such breakthrough will occur; in the meantime, further understanding of genes and mechanisms is a step in the right direction.