Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy

Summary Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems

Comparison of classifications of seizures: A preliminary study with 28 participants and 48 seizures

PubMed ID: 15878306Purpose: Our aim was to compare three available seizure classifications (SCs), namely, the international classification of epileptic seizures published in 1981 (ICES; Epilepsia 1981;22:489-50); the semiological seizure classification (SSC) by H. Lüders, J. Acharya, C. Baumgartner, et al. (Epilepsia 1998;39:1006-13; Acta Neurol Scand 1999;99:137-41); and the proposal of a new diagnostic scheme for seizures (PDSS) by J. Engel, Jr. (Epilepsia 2001;42:796-803) published in 2001. The three SCs were compared with respect to diagnostic success rates, usefulness, and consistency by a large group of neurologists in this preliminary study. Methods: After a training period, 28 blindfed participants with different levels of experience with epilepsy classified videos or written descriptions of 48 randomly selected seizures according to the three SCs. Definite diagnoses of the seizures were established based on all clinical, ictal/interictal EEG, and MRI data. All the participants answered a questionnaire concerning their preferences for SCs after the study. Results: The overall diagnostic success rates were 81.4% for ICES, 80.5% for PDSS, and 87.5%, for SSC. Various parameters concerning experience with epilepsy affected success rates positively, without reaching statistical significance, whereas experience with epilepsy surgery appeared to be a parameter significantly affecting the success rate in all SCs. In reliability analysis, Cronbach's ? was 0.94 for ICES, 0.88 for PDSS, and 0.70 for SSC, all showing good agreement in the group. Nineteen reviewers chose SSC, eight chose ICES, and one chose PDSS as their preference in the questionnaire, completed after the end of the study. Conclusion: The results of this preliminary study demonstrate that with proper training, physicians treating epilepsy patients can handle new SCs, and emphasize the need for revision of the current classification. © 2005 Elsevier Inc. All rights reserved

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems