Neuronal Migration Disorders Health Article

Definition

Neuronal migration disorders are a diverse group of congenital brain abnormalities that arise specifically from defective formation of the central nervous system. During early brain development, neurons are born and move over large distances to reach their targets and thereby give rise to the different parts of the brain. The control of this process is highly orchestrated and dependent on the expression of various environmental and genetic factors that continue to be discovered in genetic studies of mice and humans. The critical role neuronal migration plays in brain development is evident from the variety of gross malformations that can occur when it goes wrong. Defective neuronal migration leads to a broad range of clinical syndromes, and most affected patients will have a combination of mental retardation and epilepsy.

Description

Neuronal migration disorders include lissencephaly as part of the agyria-pachygyria-band spectrum, cobblestone lissencephaly, periventricular heterotopia, and other variants such as Zellweger and Kallman syndrome. Patients may have only focal collections of abnormally located neurons known as heterotopias. The common factor in these disorders is a defect in neuronal migration, a key process in brain development that occurs during weeks 12 to 16 of gestation. Some disorders such as polymicrogyria and schizencephaly are presumably due to abnormal neuronal migration due to studies showing heterotopias in other parts of the brain, but the exact relationship is unclear. Early in brain development, neurons are born in specific locations in the brain and migrate to their final destinations to create distinct brain regions. Each step of this process, from starting, continuing, and stopping migration, is controlled by distinct molecular mechanisms that are regulated by the activity of genes. Defects in these genes lead to the various presentations of neuronal migration disorders seen in clinical practice.

Lissencephaly

Lissencephaly is the most extreme example of defective neuronal migration. In lissencephaly or agyria, neuronal migration fails globally, causing the brain to appear completely smooth and have abnormal layering in the cortex. Various genes have been associated with varying levels of severity of lissencephaly giving rise to a spectrum of disorders ranging from classical lissencephaly to milder forms such as double cortex syndrome or pachygyria. Classical or type I lissencephaly differs from type II or cobblestone lissencephaly. In cobblestone lissencephaly, the defect is presumably an overmigration of neurons past their targets, giving rise to the abnormally bumpy surface.

Periventricular heterotopia

Periventricular heterotopia is a disorder where neurons fail to begin the process of migration. Neurons are generated near the ventricular zone but do not start the process of migration to their destinations. Instead, they are stuck and collect around the ventricles, giving rise to the distinct appearance on brain imaging.

Other neuronal migration disorders

Zellweger syndrome is a disorder of neuronal migration that may consist of abnormally large folds (pachygyria) and heterotopias spread throughout the brain. It is thought to be due to a defect in peroxisome metabolism, a pathway by which cells break down waste products. The relationship between this metabolic defect and neuronal migration is unclear at this time. Kallman syndrome is a disorder where cells fail to migrate to the portion of the brain controlling smell as well as the hypothalamus, a region that controls hormone secretion. The mechanism underlying this disease is unclear.

Schizencephaly is grouped as a neuronal migration disorder although the exact etiology is unknown. Schizencephaly is an example of abnormal neuronal migration that may occur locally rather than globally. In schizencephaly, an early insult to the brain in the form of an infection, stroke, orgenetic defect leads to abnormal migration of neurons in a portion of the brain and subsequent lack of developed brain tissue, giving rise to the characteristic brain clefts that define this syndrome. Schizencephaly may show a wide range of presentations, with bilateral clefts that vary in size and extent of involvement.

Polymicrogyria refers to an abnormal amount of small convolutions (gyri) in affected areas of the cerebral cortex and is believed to be a neuronal migration disorder, although the exact etiology is unknown.

Demographics

Neuronal migration disorders are rare overall, but the exact incidence is unknown. Patients may have very mild degrees of the different disorders and may not be diagnosed if they do not manifest symptoms, making the actual incidence difficult to determine.