PRRT2 gene mutations associated with infantile convulsions induced by sucking and the genotype-phenotype correlation.

Introduction: PRRT2 is a major causative gene for self-limited familial neonatal-infantile epilepsy, paroxysmal kinesigenic dyskinesia, and paroxysmal kinesigenic dyskinesia with infantile convulsions. Voluntary movement trigger is prominent in adolescence and adulthood, but the triggers are unknown in infants. Methods: A gene panel designed for targeted next-generation sequencing (NGS) was used to screen genetic abnormalities in a cohort of 45 cases with infantile convulsions. The copy number variation was detected by a computational method based on the normalized depth of coverage and validated by a quantitative real-time polymerase chain reaction (RT-qPCR) method. The genotype-phenotype correlation of the PRRT2 mutation gene was analyzed. Results: A de novo heterozygous PRRT2 deletion was identified in a child who had infantile convulsions induced by vigorous sucking. Seizures happened during the change of feeding behavior from breast to formula, which led to hungry and vigorous sucking. Ictal electroencephalograms recorded seizures with focal origination, which provided direct evidence of epileptic seizures in infants with PRRT2 mutations. Seizures stopped soon after the feeding behavior was changed by reducing feeding interval time and extending feeding duration. Data reanalysis on our previously reported cases with PRRT2 mutations showed that six of 18 (33.3%) patients had infantile convulsions or infantile non-convulsion seizures during feeding. The mutations included two truncating mutations (c.579dupA/p.Glu194Argfs*6, and c.649dupC/p.Arg217Profs*8) that were identified in each of the three affected individuals. Conclusions: This study suggests that feeding, especially vigorous sucking, is potentially a trigger and highlights the significance of feeding behavior in preventing seizures in infants with PRRT2 mutations. Identification of PRRT2 haploinsufficiency mutations in the patients with infantile convulsions induced by sucking suggested a potential genotype-phenotype correlation.

CHD4 variants are associated with childhood idiopathic epilepsy with sinus arrhythmia.

AIMS: CHD4 gene, encoding chromodomain helicase DNA-binding protein 4, is a vital gene for fetal development. In this study, we aimed to explore the association between CHD4 variants and idiopathic epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 482 patients with childhood idiopathic epilepsy. The Clinical Validity Framework of ClinGen and an evaluating method from five clinical-genetic aspects were used to determine the association between CHD4 variants and epilepsy. RESULTS: Four novel heterozygous missense mutations in CHD4, including two de novo mutations (c.1597A>G/p.K533E and c.4936G>A/p.E1646K) and two inherited mutations with co-segregation (c.856C>G/p.P286A and c.4977C>G/p.D1659E), were identified in four unrelated families with eight individuals affected. Seven affected individuals had sinus arrhythmia. From the molecular sub-regional point of view, the missense mutations located in the central regions from SNF2-like region to DUF1087 domain were associated with multisystem developmental disorders, while idiopathic epilepsy-related mutations were outside this region. Strong evidence from ClinGen Clinical Validity Framework and evidences from four of the five clinical-genetic aspects suggested an association between CHD4 variants and epilepsy. CONCLUSIONS: CHD4 was potentially a candidate pathogenic gene of childhood idiopathic epilepsy with arrhythmia. The molecular sub-regional effect of CHD4 mutations helped explaining the mechanisms underlying phenotypic variations.

[Damage to peripheral nerves induced by Campylobacter jejuni exotoxin].

OBJECTIVE: To explore the pathogenesis of the damage to peripheral nerves induced by Campylobacter jejuni exotoxin (CJT). METHODS: (1) Animal models: (1) The CJT was extracted from PEN 19-CJ and injected perineurally and intravenously to Wistar rats. (2) The sera and the supernatants of peripheral blood mononuclear cells (PBMCs), taken from the rats immunized with the CJT, were injected perineurally at sciatic nerves of experimental rats and intravenously, respectively. (2) Histopathologic study of sciatic nerves: the animals were sacrificed and their sciatic nerves were examined for tease fibers, transverse section with toluidine blues staining and electron microscopy. (3) Immunohistochemistry: sections of sciatic nerves of either normal rats or human which were incubated with CJT and the sciatic nerves with pathological changes induced by CJT were obtained for observation of the binding capability of CJT with peripheral nerves by SABC and FITC-immunofluorescence methods, and nucleic acid hybridization techniques for detection of TNF-alpha mRNA expression in pathological sciatic nerves samples. RESULTS: (1) Remarkable peripheral neuropathies with axon degeneration and/or demyelination were found in the nerves induced by both CJT injection perineurally and intravenously. The axon degeneration was more obvious. Pathological changes were identified in 76.8% (2,763/3,600) of teasing fibers after perineural injection, but only 9.6% (230/2,400) of fibers were damaged in control group (P < 0.01). The peak severity of fiber damage was found on the 3rd day after CJT intravenous injection with the incidence of abnormal fibers was 19.5% (390/2,000), and abnormalities of 15.5% (310/2000) on the 14th day. However, no abnormal changes were demonstrated in control group (P < 0.01). So was in the groups injected with anti-CJT sera and the supernatants of PBMCs compared with control (P > 0.05). (2) Binding of CJT to the nerve was found dominant in the sciatic nerves taken from normal rats or human either incubated with CJT or in the pathological sciatic nerves induced by CJT to various degrees. The binding of CJT to all these nerves was determined. (3) After intravenous injection with CJT, no histopathologic change could be found in the other viscera of the rats, with the exception of remarkable pathological change in peripheral nerves. CONCLUSIONS: (1) CJT could remarkably damage the peripheral nerves in rats. Specific pathogenicity of CJT to peripheral nerves was well shown, because no histopathologic abnormalities could be found in the other viscera, such as brain, liver and kidney etc. although there was remarkable pathological change along the peripheral nerve in the animals. (2) No immunological pathogenicity of CJT could be demonstrated in the nerves of rats after immunization with CJT.