Early onset ataxia with comorbid myoclonus and epilepsy: A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement.

OBJECTIVES: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown. The aim of this study is to investigate the key pathological mechanisms in EOA with myoclonus and/or epilepsy. METHODS: For 154 EOA-genes we investigated (1) the associated phenotype (2) reported anatomical neuroimaging abnormalities, and (3) functionally enriched biological pathways through in silico analysis. We assessed the validity of our in silico results by outcome comparison to a clinical EOA-cohort (80 patients, 31 genes). RESULTS: EOA associated gene mutations cause a spectrum of disorders, including myoclonic and epileptic phenotypes. Cerebellar imaging abnormalities were observed in 73-86% (cohort and in silico respectively) of EOA-genes independently of phenotypic comorbidity. EOA phenotypes with comorbid myoclonus and myoclonus/epilepsy were specifically associated with abnormalities in the cerebello-thalamo-cortical network. EOA, myoclonus and epilepsy genes shared enriched pathways involved in neurotransmission and neurodevelopment both in the in silico and clinical genes. EOA gene subgroups with myoclonus and epilepsy showed specific enrichment for lysosomal and lipid processes. CONCLUSIONS: The investigated EOA phenotypes revealed predominantly cerebellar abnormalities, with thalamo-cortical abnormalities in the mixed phenotypes, suggesting anatomical network involvement in EOA pathogenesis. The studied phenotypes exhibit a shared biomolecular pathogenesis, with some specific phenotype-dependent pathways. Mutations in EOA, epilepsy and myoclonus associated genes can all cause heterogeneous ataxia phenotypes, which supports exome sequencing with a movement disorder panel over conventional single gene panel testing in the clinical setting.

Sleep slow-wave homeostasis and cognitive functioning in children with electrical status epilepticus in sleep.

STUDY OBJECTIVES: Encephalopathy with electrical status epilepticus in sleep (ESES) is characterized by non-rapid eye movement (non-REM)-sleep-induced epileptiform activity and acquired cognitive deficits. The synaptic homeostasis hypothesis describes the process of daytime synaptic potentiation balanced by synaptic downscaling in non-REM-sleep and is considered crucial to retain an efficient cortical network. We aimed to study the overnight decline of slow waves, an indirect marker of synaptic downscaling, in patients with ESES and explore whether altered downscaling relates to neurodevelopmental and behavioral problems. METHODS: Retrospective study of patients with ESES with at least one whole-night electroencephalogram (EEG) and neuropsychological assessment (NPA) within 4 months. Slow waves in the first and last hour of non-REM-sleep were analyzed. Differences in slow-wave slope (SWS) and overnight slope course between the epileptic focus and non-focus electrodes and relations to neurodevelopment and behavior were analyzed. RESULTS: A total of 29 patients with 44 EEG ~ NPA combinations were included. Mean SWS decreased from 357 to 327 µV/s (-8%, p < 0.001) across the night and the overnight decrease was less pronounced in epileptic focus than in non-focus electrodes (-5.6% vs. -8.7%, p = 0.003). We found no relation between SWS and neurodevelopmental test results in cross-sectional and longitudinal analyses. Patients with behavioral problems showed less SWS decline than patients without and the difference was most striking in the epileptic focus (-0.9% vs. -8.8%, p = 0.006). CONCLUSIONS: Slow-wave homeostasis-a marker of synaptic homeostasis-is disturbed by epileptiform activity in ESES. Behavioral problems, but not neurodevelopmental test results, were related to severity of this disturbance.