A Developmental and Genetic Classification for Malformations of Cortical Development

Update 2012

A. James Barkovich; Renzo Guerrini; Ruben I. Kuzniecky; Graeme D. Jackson; William B. Dobyns


Brain. 2012;135(5):1348-1369. 

In This Article

Discussion and Rationale for Changes in New Classification

Mutations of many genes have been newly described in patients with malformations of cortical development and these, along with the new advances concerning normal development discussed in the previous section, form the basis for this update. The overall framework of the classification remains largely the same (Appendix 1 and Supplementary Table 2) making it useful in everyday practice, while providing a theoretical basis for posing of academic questions. Group I remains 'Malformations secondary to abnormal neuronal and glial proliferation or apoptosis' and Group II remains 'Malformations Secondary to Abnormal Neuronal Migration'. The name of Group III has been changed from 'Malformations secondary to abnormal cortical organization' to 'Malformations secondary to Abnormal Postmigrational Development', as the process of cortical organization begins before the termination of neuronal migration. Another structural change is that Group IV, 'Malformations of cortical development, Not otherwise classified', has been eliminated and the disorders previously listed there have been moved. A third change is that disorders are classified according to their mode of inheritance (autosomal recessive, autosomal dominant, X-linked, polygenic in rare cases, etc.) and whether the disorder is clinically or genetically defined. This change should help clinicians classify their patients more easily, particularly in complicated disorders such as microcephalies. One concern is that the division into genetically defined and clinically defined disorders moves the classification, at least partially, from one based upon underlying mechanisms to one based upon current understanding. With the proliferation of gene discovery, it has become clear that different mutations of the same gene can result in completely different syndromes; thus, disorders defined by gene alone quickly become excessive and confusing. The optimal classification will not be based on genes but pathways and mechanism of protein action, with variations based on how the specific gene mutation alters protein function in the affected pathway. Clinically defined disorders may rapidly become obsolete. However, our current understanding of pathways and mechanisms of protein action is not adequate to classify disorders on that basis, while genetic knowledge has advanced to the point where the old classification was becoming less useful. This revision can be viewed as an intermediate system that should prove useful while the foundations of the pathway-based classification are constructed. Genes, genetic loci and references for each disorder are in Appendix 1. The references should make Appendix 1 more useful to clinicians trying to make a diagnosis. Some disorders in Appendix 1 have no associated reference, either because they are well known and can be accessed in any textbook (such as ganglioglioma or isolated periventricular nodular heterotopia), or because the specific entities are not published, but have been identified as specific entities by the authors.