Genetic differences in susceptibility to anticonvulsant drug-induced developmental defects

The teratogenicity associated with gestational exposure to anticonvulsant medications remains a significant clinical therapeutic concern. Although most effective antiepileptic agents have been implicated as potential teratogens, the adverse developmental effects associated with phenytoin, trimethadione and valproic acid remain unequivocal. Although approximately 12,000 infants are exposed in utero annually in the United States to these compounds, only 10% will present with the clinical features associated with anticonvulsant drug embryopathies, clearly suggesting the presence of a genetic basis of susceptibility that certain infants inherit. In this article, the genetic basis for such variability in expression, with emphasis on the biochemical and morphological differences that might predominate, are examined in light of recent experimental evidence.