The incidence of mutations in the X-linked gene doublecortin in patients with “double cortex” syndrome (DC; also called subcortical band heterotopia or laminar heterotopia) and familial DC with lissencephaly was investigated in a cohort of 8 pedigrees and 47 sporadic patients with DC examined at the Division of Neurogenics, Beth Israel Deaconess Medical Center, Boston, and multiple centers in the US and abroad. Mutations were identified in all of the DC pedigrees and in 38% of sporadic cases. Single amino acid substitution mutations were identified more frequently in inherited DC, whereas protein truncation mutations were found in sporadic cases. Single amino acid substitution mutations have less reproductive disadvantage than protein truncation mutations. Two regions of the predicted amino acid sequence where mutations clustered were critical for the function of the DC protein. [1]

COMMENT. Double cortex (DC) syndrome and X-linked lissencephaly are neuronal migration disorders with incomplete migration of neurons from the ventricular zone to the cortex. Neurons form a second layer of gray matter in DC, and abnormal migration leads to generalized disorganization of cortex in lissencephaly. Most DC patients are female, suggesting an X-linked dominant disease. Affected males develop lissencephaly because all the neurons express the mutant DC/XLIS allele. Females with heterozygous DCX gene mutations develop DC, and males with DCX hemizygous mutations develop lissencephaly. Lissencephaly has two genetic forms, LIS1 and DCX, showing similar cortical pathology, but LIS1 mutations are associated with more severe migrational abnormalities of the brainstem.

In an Editorial, discussing both the Gleeson article on DC syndrome and another on classical lissencephaly in the same issue [2], Clark GD and Naebels JL of Baylor College of Medicine, Houston, point out the importance of genotype-phenotype correlations in understanding the overlapping of clinical/pathological manifestations of migration disorders and the value in genetic counseling. Asymptomatic mothers of children with DCX mutations are at risk of further transmitting the disorder, whereas no germline transmission of LIS1 mutations have been described.