Abstracts

We report the first study in the living human brain of the structural consequences of a missense mutation of the [gamma]2 subunit (R43Q) of the gamma-aminobutyric acid A (GABA[sub]A[/sub]) receptor associated with inherited generalized epilepsy (IGE) and febrile convulsions. Previous studies in individuals affected by this mutation have demonstrated enhanced cortical excitability associated with widespread reduction in benzodiazepine receptor binding. The GABA[sub]A[/sub] receptor is known to play an important role during brain development by affecting neuronal differentiation and migration. Visual inspection of MRI scans in subjects with the mutation suggested a consistent difference in callosal morphology. Here, we sought to examine this structural abnormality systematically.
Subjects comprised 10 subjects affected by the GABA[sub]A[/sub] [gamma]2 subunit mutation (3 males; mean age: 43 years) and 47 controls (23 males; mean age: 34 years). All subjects underwent high resolution T[sub]1[/sub]-weighted MR images. The images were placed in a standard stereotaxic coordinate space and, using a semi-automated algorithm, the corpus callosum was segmented and callosal thickness was measured at 39 equally spaced nodes along its length. The statistical significance of differences in regional callosal thickness between groups was assessed using a non-parametric permutation test.
The posterior midbody of the callosum was significantly thinner in individuals with the GABA[sub]A[/sub] mutation than in controls. Gray matter and white matter volumes were also measured in subjects affected by the mutation and a subset of age-matched normal subjects. No significant difference in volume was observed.
These findings provide compelling [italic]in vivo[/italic] evidence of a role for the GABA[sub]A[/sub] receptor in brain development and in particular the development of the corpus callosum. Previous studies have demonstrated subtle abnormalities in brain architecture in patients with IGE. It is possible that the morphological consequences of the R43Q mutation are part of the link between genotype and clinical phenotype.