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

Abstract

AIMRecently, 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.METHODWe 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.RESULTSAll 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.INTERPRETATIONThe 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.

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs

“…The fact that all dogs had ataxia, but only some dogs had seizures, myokymia or neuromyotonia, is not surprising, as it is well known that potassium channel diseases can be phenotypically heterogeneous (variability of clinical signs and severity) in dogs 33 and humans. 1,2,43 The mildly delayed latencies of waves I and II, and the loss of waves III, IV and V, was repetitively found on the BAER tests of our affected dogs. This suggests a peripheral as well as central localisation for dysfunction within the auditory pathway.…”

“…45 In humans, the ataxia seems to be nonprogressive and the seizures are in most cases easily controlled with antiepileptic drugs. 43 In mice, general knockout of KIR4.1 leads to neonatal mortality. 47 In Jack Russel Terriers, the ataxia also seems to be nonprogressive, but the myokymia and neuromyotonia worsen gradually over several months, leading to killing of most dogs.…”

Of dogs and men

“…This reflects our experience with MRI imaging of human patients, which were initially reported as normal, 3 and only after careful examination of imaging from multiple patients were subtle changes in the cerebellum and spinal tract noted. 7 This also parallels the experience of the previous report of kcnj10 mutations in Jack Russell Terriers, as MRI images were reported as normal, yet histopathological investigations revealed spinocerebellar myelopathy. 9 However, there are also limitations to the comparability of manifestations of kcnj10 disease between dogs and men.…”

“…In addition, they suffer from recurrent seizures. 7 There is no specific treatment for EAST syndrome, and animal models are needed to identify and test potential drugs. 8 It is in this context that the finding of a canine equivalent of EAST syndrome is of interest.…”

Magnesium in Man: Implications for Health and Disease

“…SeSAME/EAST patients suffer from a severe neurological phenotype consisting of tonic-clonic seizures in infancy, cerebellar ataxia, and hearing loss. Moreover, magnetic resonance imaging evidenced subtle symmetrical signal changes in the cerebellar dentate nuclei (96 , Cl Ϫ , and HCO 3 Ϫ , were normal. Urinary Mg 2ϩ excretion was increased, whereas Ca 2ϩ excretion was slightly lowered (172).…”