DOUBLECORTIN IS THE MAJOR GENE CAUSING X-LINKED SUBCORTICAL LAMINAR HETEROTOPIA (SCLH)

Subcortical laminar heterotopia (SCLH), or 'double cortex', is a corti cal dysgenesis disorder associated with a defect in neuronal migration . Clinical manifestations are epilepsy and mental retardation. This di sorder, which mainly affects females, can be inherited in a single ped igree with lissencephaly, a more severe disease which affects the male individuals. This clinical entity has been described as X-SCLH/LIS sy ndrome. Recently we have demonstrated that the doublecortin gene, whic h is localized on the X chromosome, is implicated in this disorder. We have now performed a systematic mutation analysis of doublecortin in 11 unrelated females with SCLH (one familial and 10 sporadic cases) an d have identified mutations in 10/11 cases. The sequence differences i nclude nonsense, splice site and missense mutations and these were fou nd throughout the gene. These results provide strong evidence that los s of function of doublecortin is the major cause of SCLH, The absence of phenotype-genotype correlations suggests that X-inactivation patter ns of neuronal precursor cells are likely to contribute to the variabl e clinical severity of this disorder in females.