Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5′ end and 3′ extension of precursor‐U8. There was no obvious genotype–phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3′ end processing of precursor‐U8.

Background and Objectives:It remains unknown to what extent ictal scalp EEG can accurately predict the localization of the intra-cerebral seizure onset in pre-surgical evaluation of drug resistant epilepsies. In this study, we aimed to define homogeneous ictal scalp EEG profiles (based on their first ictal abnormality) and assess their localizing value using simultaneously recorded scalp EEG and Stereo-EEG.Methods:We retrospectively included consecutive patients with drug-resistant focal epilepsy who had simultaneous stereo-EEG and scalp EEG recordings of at least one seizure, in the epileptology unit in Nancy, France. We analyzed one seizure per patient and used hierarchical cluster analysis to group similar seizure profiles on scalp EEG and then performed a descriptive analysis of their intra-cerebral correlates.Results:We enrolled 129 patients in this study. The hierarchical cluster analysis showed six profiles on scalp EEG first modification. None was specific to a single intra-cerebral localization. The “normal EEG” and “blurred EEG” clusters (early muscle artifacts) comprised only five patients each and corresponded to no preferential intra-cerebral localization. The “temporal discharge” cluster (n=46) was characterized by theta or delta discharges on ipsilateral anterior temporal scalp electrodes and corresponded to a preferential mesial temporal intra-cerebral localization. The “posterior discharge” cluster (n=42) was characterized by posterior ipsilateral or contralateral rhythmic alpha discharges or slow waves on scalp and corresponded to a preferential temporal localization. However, this profile was the statistically most frequent scalp EEG correlate of occipital and parietal seizures. The “diffuse suppression” cluster (n=9) was characterized by a bilateral and diffuse background activity suppression on scalp and corresponded to mesial, and particularly insulo-opercular, localization. Finally, the “frontal discharge” cluster (n=22) was characterized by bilateral frontal rhythmic fast activity or pre-ictal spike on scalp and corresponded to preferential ventrodorsal frontal intra-cerebral localizations.Discussion:Hierarchical cluster analysis identified six seizure profiles regarding the first abnormality on scalp EEG. None of them was specific of a single intra-cerebral localization. Nevertheless, the strong relationships between the “temporal”, “frontal”, “diffuse suppression” and “posterior” profiles and intra-cerebral discharges localizations may contribute to hierarchize hypotheses derived from ictal scalp EEG analysis regarding intra-cerebral seizure onset.

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