Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome

Abstract

Aim: Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.

Method: We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6-20y) with genetically proven EAST syndrome.

Results: All children presented with tonic-clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm.

Interpretation: The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.

Figure 1

Patients with EAST syndrome show increased signal intensity of the cerebellar nuclei and cerebellar hypoplasia on brain magnetic resonance imaging. Coronal T2 or fluid-attenuated inversion recovery images show varying degrees of signal hyperintensity in the cerebellar deep nuclei. These ranged from subtle signal changes in comparison with the cerebellar cortex to more obvious changes within both the cerebellar deep nuclei and hilar white matter. (a) patient 1-1, (b) patient 2, (c) patient 4, (d) patient 3, (e) patient 5-1, and (f) patient 5-2.

Figure 2

Other abnormalities on brain magnetic resonance imaging. (a) Axial T2-weighted and coronal volumetric fluid-attenuated inversion recovery images in patient 3 show bilateral symmetrical signal hyperintensity within the cerebellar deep nuclei and hilar white matter (arrow) and a retrocerebellar arachnoid cyst. This child also has a fatty filum terminale but normal position of the conus medullaris and no other spinal dysraphic features (not shown). (b) Coronal and axial T2-weighted images in patient 5-2 show prominence of the cerebellar hemisphere and vermian fissures. Note again the subtle symmetrical dentate nucleus changes (arrow). (c) Sagittal T1-weighted image (patient 1-1) shows normal position of the conus medullaris, a fatty filum terminale, and normal spinal cord volume. (d) Sagittal T1- and axial T2-weighted brain images (patient 2) show global lack of cerebral volume with slightly thin corpus callosum and brainstem and spinal cord hypoplasia.

Figure 3

Comparative size of individual regions in patients (Pat) and matched comparison children (Ctl), represented as z-scores, using the IXI cohort as a normative reference. Coloured discs, individual patients; black discs, patient median; rings, comparison median; black lines, interquartile range of comparison group. Coloured rectangles indicate whether the patient median z-score is larger (red) or smaller (blue) than the comparison median z-score. Regions where the difference is significant (as determined by a Wilcoxon unpaired ranked-sum test, alpha=0.05, no correction for multiple comparisons) are marked with an asterisk (*). The colour intensity of the rectangles also represents significance. Regions are grouped anatomically, with groups separated by dotted lines. From top to bottom: temporal lobe, frontal lobe, cerebellum and brainstem, insula and cingulate gyri, occipital lobe, parietal lobe, central structures, ventricles. R, right; L, left; ant, anterior; temp, temporal; med, medial; lat, lateral; sup, superior; post, posterior; frt, frontal; inf, inferior; ct, cortex; g, gyrus; gg, gyri; l, lobe; rem, remainder; G parahippocamp/amb, gyrus parahippocampalis et ambiens.