Focal Cortical Dysplasia: A Review of Pathological Features, Genetics, and Surgical Outcome

Vincent Y. Wang, M.D. Ph.D.; Edward F. Chang, M.D.; Nicholas M. Barbaro, M.D.


Neurosurg Focus. 2006;20(1) 

In This Article

Genetics Of FCD

Focal cortical dysplasia is thought to be a neuronal migration disorder. It lies at the milder end of the spectrum of neuronal migration disorders that exhibit only focal abnormalities. The other end of spectrum includes diseases such as lissencephaly, in which there is a significant reduction of gyri and thickening of gray matter over a large area of the brain.

Although all of these diseases involve neuronal migration as part of their pathogenesis, the underlying causes of neuronal migration dysfunction in the various disorders may be different. Lissencephaly, periventricular nodular heterotopia, and subcortical band heterotopia (double cortex) are single-gene disorders involving proteins that interact with the cytoskeleton.[14] Lissencephaly, the most severe neuronal migration disorder, is characterized by a smooth brain surface, marked reduction of gyri, and increased cortical thickness.[27] Mutations in five different genes (LIS1, DCX, 14-3-3ε, RELN, and ARX) have been shown to cause lissencephaly.[27] Although mutations in each of these genes have been associated with lissencephaly, a different phenotype exists depending on the gene in which the mutation occurs. For example, mutations in DCX and RELN are more likely to lead to anterior cortex involvement, and mutations in LIS1, 14-3-3∈, and ARX are more likely to lead to posterior cortex involvement.[27] Mutations in DCX lead to a characteristic subcortical band of heterotopic neuronal elements, and hence the name doublecortin has been given to the protein encoded by DCX.[27] Each of the proteins encoded by these genes has some interaction with the cytoskeleton. The LIS1 protein, for example, interacts with tubulin and suppresses microtubule dynamics.[27] The DCX protein also has a motif that binds to tubulin and may interact with the LIS1 protein. The protein encoded by RELN, on the other hand, is an extracellular protein that interacts with integrin and lipoprotein receptors, which in turn act on downstream protein kinases that regulate cytoskeletal formation.[27] Mutations in filamin1 have been identified in another class of disease, periventricular nodular heterotopia, which is characterized by differentiated neurons inside misplaced nodules.[14] Filamin1 protein has been thought to be involved in the formation of filopodia, the cell processes that lead and guidea cell's migration, and disruption of filopodia formation may lead to dysfunction in neuronal migration.[14] A common theme in all of these disorders is involvement of proteins that interact with or regulate cytoskeleton formation.

Lissencephaly and periventricular nodular heterotopia are the best studied neuronal migration disorders. The mechanisms of other diseases are less well understood. Recent evidence has suggested that mutations in other classes of genes may also cause neuronal migration disorders. For example, mutations in Emx2, which encodes a transcription factor involved in forebrain formation, have been found in patients with schizencephaly, although not in all cases.[20] Schizencephaly is characterized by clefts extending from the pial surface to the lateral ventricle that are lined with abnormally laminated polymicrogyric cortex. It is unclear how Emx2 mutations lead to neuronal migration problems in these patients.

Both congenital and genetic causes have been proposed for FCD. Some evidence supports a genetic basis for FCD or at least a genetic contribution to its pathogenesis. In two studies, patients with FCD were noted to have a family history of epilepsy.[35,36] In addition, a positive family history of epilepsy was found to predict an earlier age at onset of seizures in patients with FCD.[35] Studies that include larger numbers of patients are needed to determine whether FCD has a genetic basis or genetic modifiers.

Overlapping clinical and pathological findings have been noted in brains of patients with tuberous sclerosis and in those of patients with other types of cortical dysplasia. Authors of several interesting papers have suggested that TSC1 is involved in the pathogenesis of FCD.[5,17] Mutations in TSC1 are known to cause tuberous sclerosis, which, like FCD, is characterized by balloon cells, but also has a number of other clinical features.[20] Amino acid polymorphisms involving exons 5 and 17 in TSC1 and silent base substitutions in exons 14 and 22 were found in a significantly higher proportion of patients with focal dysplasia, compared with controls.[5] In addition, loss of TSC1 heterozygosity has been noted in focal cortical dysplastic lesions themselves.[5] This loss of heterozygosity is specific to TSC1, as no genomewide genetic instability has been observed.[17] It is still unclear how mutation or dysfunction of TSC1 leads to neuronal migration disorder. In a recent study, however, the protein encoded by TSC1 was found to be part of the mTOR signaling pathway, a protein kinase pathway involved in cell growth, apoptosis, and cell cycle regulation.[31] Loss of function of TSC1 affects soma size and dendritic spine formation.[49] If the formation of some of these neuronal processes is involved in neuronal migration, this relationship would explain the role of TSC1 in regulation of neuronal migration; however, the exact mechanism is still unclear.

Other proteins that have been shown to be altered in FCD neurons are the Notch and Wnt pathway proteins. These two signaling pathways are known to be involved in neuronal migration.[12] It is unlikely that patients with FCD have a mutation in the genes that encode these proteins, as mutations in the genes for the key proteins in these pathways usually have widespread phenotypes; however, mutations in genes for the regulators of these genetic pathways may be one cause of FCD. Indeed, it is thought that one mechanism by which Emx2 mutations cause schizencephaly is through alteration of the Wnt1 expression level.[33]

Indirect evidence from experimental models has suggested that interruption of genetic material can lead to FCD. For example, application of radiation or methylazoxymethanol, which both act to disrupt DNA structure, has been used to create models of FCD.[7]

There are several reasons why no single genetic mutation has been shown to cause cortical dysplasia. First, FCD represents a rather diverse group of neuron structural abnormalities. As described earlier, FCD can be classified into several types (Types IA, IB, IIA, and IIB) on the basis of histopathological criteria. A second reason is that most surgical series have involved only 20 to 60 patients (see later), and these numbers are too low for detection of most rare events. Third and most important, FCD is unlikely to be associated with a single gene mutation, as is lissencephaly or periventricular nodular heterotopia. Rather, it is likely to be associated with subtle polymorphism mutations in the regulatory elements, or to involve multiple genes, as observed in the case of TSC1. Candidate genes that could cause FCD are those involved in neuronal migration pathways, such as the Notch or Wnt signaling pathways.[13] Mutations in these genes that lead to a loss of function, however, are usually lethal in the embryo. Thus, it is more likely that hypomorphic mutations, or mutations in the regulatory elements, are associated with FCD. Detecting such mutations is much more difficult and requires studies involving large numbers of patients. New mutation analysis methods and new genome investigations such as the International HapMap Project should shed light on the pathogenesis of FCD.


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