Description of a family with a novel progressive myoclonus epilepsy and cognitive impairment

Abstract

We report a family of Algerian origin presenting an unusual, severe form of progressive myoclonus epilepsy characterized by myoclonus, generalized tonic-clonic seizures and moderate to severe cognitive impairment, with probable autosomal recessive inheritance. Disease onset was between 6 and 16 years of age. The diagnosis of Unverricht-Lundborg disease and all other known causes of progressive myoclonus epilepsies were excluded by specific laboratory tests and molecular analysis.

Unverricht‐Lundborg disease

“…Several studies have investigated the molecular mechanisms underlying neuronal hyperexcitability by pairing analyses of neurodegeneration with network changes occurring in the hippocampus following kainate treatment, a proconvulsant that triggers excitotoxicity and epileptic events (Arundine et al ., ). Early in vitro hippocampal slice experiments suggested that during kainate perfusion, afferent synaptic activation evokes multiple population spikes in both Cstb ‐deficient and wild‐type control mice (Franceschetti et al ., ). The appearance of such hyperexcitable responses coincides with a rapid decline in the amplitude of the evoked field potentials in slices from Cstb‐ deficient mice.…”

“…Spontaneous epileptic discharges (SEDs) occur in a subset of slices prepared from wild‐type controls, with a delay of about 15 minutes following the onset of kainite perfusion, and persisting until the end of the kainate exposure. In contrast, in Cstb ‐deficient mice, SEDs begin within minutes of kainate perfusion, and progressively decrease in amplitude, ultimately disappearing along with the field responses evoked by electrical stimulation (Franceschetti et al ., ). To test if increased susceptibility to pro‐convulsant agents can be recapitulated in vivo, Cstb ‐deficient and control mice received intraperitoneal injections of kainate (30 mg/kg), and their behaviour was recorded for two hours thereafter.…”

“…To investigate the extent of seizure‐induced damage, brain damage was evaluated in Cstb‐ deficient mice and controls one day following kainate administration using several markers of neurodegeneration, including Fluoro‐Jade B (Schmued and Hopkins, ). The degree of degeneration correlates with the severity of the seizures, and is higher in Cstb ‐deficient mice than in control mice (Franceschetti et al ., ). In addition, Cstb ‐deficient mice display more neurodegeneration compared to controls with identical seizure scores, suggesting that seizure‐induced brain damage is more pronounced in animals lacking Cstb .…”

“…Kynurenine, the first metabolic intermediate in the TRP kynurenine pathway, is also elevated in the Cstb knockout cerebellum. The myoclonus in ULD is believed to arise from impaired intracortical inhibition leading to secondary hyperexcitability of the motor cortex (Franceschetti et al ., ). Interestingly, Cstb‐ deficient mice exhibit significantly higher levels of 5HT and 5HIAA in the cerebral cortex and cerebellum (Vaarmann et al ., ), the structures where the greatest cellular atrophy and glial appearance have been described (Pennacchio et al ., ; Shannon et al ., ).…”

“…To test if increased susceptibility to pro‐convulsant agents can be recapitulated in vivo, Cstb ‐deficient and control mice received intraperitoneal injections of kainate (30 mg/kg), and their behaviour was recorded for two hours thereafter. Consistent with in vitro findings, in this paradigm, Cstb ‐deficient mice display an increased susceptibility to kainite‐induced seizures, such that the latency to generalized seizure onset is reduced and the behavioural seizure scores (cumulative seizure score and seizure index) are increased (Franceschetti et al ., ). To investigate the extent of seizure‐induced damage, brain damage was evaluated in Cstb‐ deficient mice and controls one day following kainate administration using several markers of neurodegeneration, including Fluoro‐Jade B (Schmued and Hopkins, ).…”