Abstracts

Rationale: Pyridoxine dependent epilepsy (PDE) is a rare autosomal recessive disorder that generally presents as a neonatal epileptic encephalopathy with pharmacoresistant seizures that come under control once daily pharmacologic pyridoxine supplements are administered. With continuous pyridoxine treatment, most affected patients have complete seizure control, but neurodevelopmental sequelae are common. In past work, we examined the largest PDE sample studied to date (n=30), and demonstrated that reductions in callosal area are present across the developmental span, with no clear relation to treatment lag [1]. It remains unknown whether white matter structural features accompany these callosal changes. To address this knowledge gap, four high-functioning adults with PDE and controls were recruited and imaged with MRI to evaluate fractional anisotropy (FA). Methods: Four high-functioning PDE male subjects (mean±SD: 31.00±10.89 years, range 22-47 years) were identified from known United States patients and consented for study. These subjects were compared to age-matched controls (31.50±11.24, range 22-50). Subjects traveled to Seattle Children's Hospital where they were scanned on a Siemens 3T Trio scanner utilizing a 32-channel head coil. Imaging included a high resolution MPRAGE (isotropic 1mm resolution, 160 slices) and DTI (64 direction, B-value 1000, FOV 224, slice thickness 2.2 mm, 55 slices). Callosal data was first analyzed in MATLAB by cross-sectional division as per our previous work [1]. FA maps were computed in FSL, with fiber tracking through the callosum performed in MedInria. Statistics were performed for area measures (SPSS, version 19), with descriptive FA/tract-based maps reviewed and summarized by a radiologist blinded to group. Results: Posterior callosal segments referenced to brain area were reduced (genu (1) to splenium (5); segment 1, no difference, p = ns; segment 2 = -17%, p = 0.076; segment 3 = -38%, p = 0.006; segment 4 = -56%, p = 0.009; segment 5 = -37%, p = 0.006). FA maps demonstrated widespread posterior reductions in the PDE group, with a gradient observed posteriorly corresponding to clinical severity (Figure 1). Example tractography using a callosum region of interest demonstrates fiber density differences with a marked connectivity deficit in the isthmus of the callosum (Figure 2). Conclusions: High-functioning adult PDE subjects demonstrate consistent changes in callosal morphology that appears associated with alterations in white matter structure (posterior>anterior) as measured by FA. These results support that mutations in the ALDH7A1 gene encoding antiquitin create a phenotype that impacts white matter diffusivity. More detailed evaluation of how these changes relate to specific neurodevelopmental deficits will be a fruitful topic for further work. [1] Friedman, SD, et al. Callosal alterations in pyridoxine-dependent epilepsy. Dev Med Child Neurol (in press). Supported by the research endowments of the Division of Neurology, Seattle Childrnen's Hospital.