X-linked lissencephaly (XLAG)

X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG) is a severe malformation syndrome that is only observed in boys. The anatomoclinical spectrum includes lissencephaly with posterior-to-anterior gradient and only moderate increase of the cortical thickness, absent corpus callosum, poorly delineated and cavitated basal ganglia, postnatal microcephaly, neonatal-onset epilepsy, hypothalamic dysfunction including deficient temperature regulation, chronic diarrhoea, and ambiguous genitalia with micropenis and cryptorchidism. Early death is not uncommon.

Mutations of the X-linked aristaless-related homeobox gene (ARX) were identified in individuals with XLAG and in some female relatives. Females carrying ARX usually have normal cognitive level and may either have normal brain MRI scan or show partial or complete agenesis of the corpus callosum. However, mild mental retardation and epilepsy has been reported in rare female carriers.  Arx deficient mice shows deficient tangential migration and abnormal differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex. These characteristics recapitulate some of the clinical features of XLAG in humans and might account for the severe neonatal epileptic encephalopathy with suppression burst EEG that is often observed in affected boys.

The mutations of the ARX gene in XLAG patients are in prevalence premature termination mutations. Missense mutations are less common and essentially located in the homeobox domain. Patients carrying nonconservative missense mutations within the homeodomain showed less severe XLAG, while conservative substitution in the homeodomain caused Proud Syndrome (ACC with abnormal genitalia). A non conservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. ARX mutations are also associated with milder phenotypes without cortical malformations including X linked infantile spasms, Partington’s syndrome and X-linked nonsyndromic mental retardation.

We have characterized mutations of the ARX gene  and established phenotype-genotype correlations in patients with XLAG and in patients with infantile spasms (LINK Infantile Spasms epilepsy section). We are continuing to enrol patients/families with XLAG to continue these studies.

If you have a child who you think may have this condition and you would like us to review the diagnosis or provide genetic testing please contact us at neuroscience@meyer.it.