X-linked lissencephaly with abnormal genitalia

X-linked lissencephaly with abnormal genitalia (XLAG) is a severe neurological disorder that affects genotypic males. It is characterized by a type of brain malformation known as lissencephaly, where the brain surface appears smooth. In XLAG, the brain has a posterior-to-anterior gradient with a moderate increase in cortical thickness compared to classical lissencephaly. Additionally, the corpus callosum, which normally connects the two sides of the brain, is absent. People with this condition often experience severe neonatal-onset epilepsy and have issues with hypothalamic function, leading to problems with temperature regulation. The syndrome also includes abnormal genital development, such as ambiguous genitalia, micropenis, and cryptorchidism. This makes XLAG distinct from other forms of lissencephaly which involve mutations in different genes.

Common symptoms and signs include a smooth brain surface due to lissencephaly, absence of the corpus callosum, severe epilepsy beginning in the neonatal period, and difficulties with temperature regulation due to hypothalamic dysfunction. Additionally, there are genital abnormalities such as ambiguous genitalia, micropenis, and cryptorchidism.

XLAG is caused by mutations in the ARX gene, located on the X chromosome. These mutations are often premature termination mutations such as large deletions, frameshift, nonsense mutations, or splice site mutations, with some missense mutations also reported. Since the condition is X-linked, it predominantly affects genotypic males. Studies in mice and humans show that ARX is important for brain development and testicular differentiation.

Information about treatment is currently limited for this condition.

Information about prognosis is currently limited for this condition.

Research has focused on understanding the role of the ARX gene in brain and genital development. Studies using mouse models have helped to reveal how ARX mutations affect the migration and differentiation of brain cells, particularly GABAergic neurons. Ongoing research continues to explore the wide range of phenotypes associated with ARX mutations and aims to better understand the spectrum of outcomes from severe forms like XLAG to milder conditions.