NEXMIF variants are associated with epilepsy with or without intellectual disability.

OBJECTIVES: Variants in NEXMIF had been reported associated with intellectual disability (ID) without epilepsy or developmental epileptic encephalopathy (DEE). It is unkown whether NEXMIF variants are associated with epilepsy without ID. This study aims to explore the phenotypic spectrum of NEXMIF and the genotype-phenotype correlations. MATERIALS AND METHODS: Trio-based whole-exome sequencing was performed in patients with epilepsy. Previously reported NEXMIF variants were systematically reviewed to analyze the genotype-phenotype correlations. RESULTS: Six variants were identified in seven unrelated cases with epilepsy, including two de novo null variants and four hemizygous missense variants. The two de novo variants were absent in all populations of gnomAD and four hemizygous missense variants were absent in male controls of gnomAD. The two patients with de novo null variants exhibited severe developmental epileptic encephalopathy. While, the patients with hemizygous missense variants had mild focal epilepsy with favorable outcome. Analysis of previously reported cases revealed that males with missense variants presented significantly higher percentage of normal intellectual development and later onset age of seizure than those with null variants, indicating a genotype-phenotype correlation. CONCLUSION: This study suggested that NEXMIF variants were potentially associated with pure epilepsy with or without intellectual disability. The spectrum of epileptic phenotypes ranged from the mild epilepsy to severe developmental epileptic encephalopathy, where the epileptic phenotypes variability are potentially associated with patients' gender and variant type.

Association of FAT1 with focal epilepsy and correlation between seizure relapse and gene expression stage.

PURPOSE: The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy. METHODS: Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform. RESULTS: Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalised tonic-clonic seizures. They responded well toantiseizure medication, but seizures relapsed in three cases when antiseizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be "Strong" by the Clinical Validity Framework of ClinGen. CONCLUSIONS: FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration ofantiseizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.

SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation.

Background: Recessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations. Results: SZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant. Significance: This study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.

Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation.

Objective: The PKD1 encodes polycystin-1, a large transmembrane protein that plays important roles in cell proliferation, apoptosis, and cation transport. Previous studies have identified PKD1 mutations in autosomal dominant polycystic kidney disease (ADPKD). However, the expression of PKD1 in the brain is much higher than that in the kidney. This study aimed to explore the association between PKD1 and epilepsy. Methods: Trios-based whole-exome sequencing was performed in a cohort of 314 patients with febrile seizures or epilepsy with antecedent febrile seizures. The damaging effects of variants was predicted by protein modeling and multiple in silico tools. The genotype-phenotype association of PKD1 mutations was systematically reviewed and analyzed. Results: Eight pairs of compound heterozygous missense variants in PKD1 were identified in eight unrelated patients. All patients suffered from febrile seizures or epilepsy with antecedent febrile seizures with favorable prognosis. All of the 16 heterozygous variants presented no or low allele frequencies in the gnomAD database, and presented statistically higher frequency in the case-cohort than that in controls. These missense variants were predicted to be damaging and/or affect hydrogen bonding or free energy stability of amino acids. Five patients showed generalized tonic-clonic seizures (GTCS), who all had one of the paired missense mutations located in the PKD repeat domain, suggesting that mutations in the PKD domains were possibly associated with GTCS. Further analysis demonstrated that monoallelic mutations with haploinsufficiency of PKD1 potentially caused kidney disease, compound heterozygotes with superimposed effects of two missense mutations were associated with epilepsy, whereas the homozygotes with complete loss of PKD1 would be embryonically lethal. Conclusion: PKD1 gene was potentially a novel causative gene of epilepsy. The genotype-phenotype relationship of PKD1 mutations suggested a quantitative correlation between genetic impairment and phenotypic variation, which will facilitate the genetic diagnosis and management in patients with PKD1 mutations.

c.3G>A mutation in the CRYAB gene that causes fatal infantile hypertonic myofibrillar myopathy in the Chinese population.

Infantile hypertonic myofibrillar myopathy is characterized by the rapid development of rigid muscles and respiratory insufficiency soon after birth, with very high mortality. It is extremely rare, and only a few cases having been reported until now. Here we report four Chinese infants with fatal neuromuscular disorders characterized by abdominal and trunk skeletal muscle stiffness and rapid respiratory insufficiency progression. Electromyograms showed increased insertion activities and profuse fibrillation potentials with complex repetitive discharges. Immunohistochemistry staining of muscle biopsies showed accumulations of desmin in the myocytes. Powdery Z-bands with dense granules across sarcomeres were observed in muscle fibers using electron microscopy. All patients carry a homozygous c.3G>A mutation in the CRYAB gene, which resulted in the loss of the initiating methionine and the absence of protein. This study's findings help further understand the disease and highlight a founder mutation in the Chinese population.

[Clinical features of sleep-disordered breathing in children with neuromuscular disease].

OBJECTIVE: To study the clinical features of sleep-disordered breathing (SDB) in children with neuromuscular disease (NMD). METHODS: A retrospective analysis was performed on the medical data of 18 children who were diagnosed with NMD and underwent polysomnography (PSG) (NMD group). Eleven children without NMD who had abnormal sleeping habit and normal sleep structure on PSG were enrolled as the control group. The two groups were compared in terms of the daily and nocturnal symptoms of SDB, incidence rate of obstructive sleep apnea (OSA), pulmonary function, end-tidal partial pressure of carbon dioxide (PetCO2), features of sleep structure, and sleep respiratory events. RESULTS: In the NMD group, 16 children (89%) had related daily and nocturnal symptoms of SDB, and the youngest age was 1 year at the onset of such symptoms. Compared with the control group, the NMD group had significant reductions in total sleep time and sleep efficiency (P < 0.05), a significant reduction in the proportion of rapid eye movement (REM) sleep (P < 0.05), significant increases in obstructive apnea and hypopnea events (P < 0.05) and oxygen reduction events during REM sleep (P < 0.05), and a significant reduction in blood oxygen saturation during REM sleep (P < 0.05). In the NMD group, 17 children (94%) were diagnosed with OSA, and all children had normal lung function and PetCO2. CONCLUSIONS: There is a high proportion of children with SDB among the children with NMD, and SDB can be observed in the early stage of NMD, which results in the damage of sleep structure and the reduction in sleep efficiency. Respiratory events are mainly obstructive events, and oxygen reduction events are mainly observed during REM sleep.

Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy.

AIM: To investigate whether patients with refractory epilepsy and healthy infants differ in gut microbiota (GM), and how ketogenic diet (KD) alters GM. METHODS: A total of 14 epileptic and 30 healthy infants were recruited and seizure frequencies were recorded. Stool samples were collected for 16S rDNA sequencing using the Illumina Miseq platform. The composition of GM in each sample was analyzed with MOTHUR, and inter-group comparison was conducted by R software. RESULTS: After being on KD treatment for a week, 64% of epileptic infants showed an obvious improvement, with a 50% decrease in seizure frequency. GM structure in epileptic infants (P1 group) differed dramatically from that in healthy infants (Health group). Proteobacteria, which had accumulated significantly in the P1 group, decreased dramatically after KD treatment (P2 group). Cronobacter predominated in the P1 group and remained at a low level both in the Health and P2 groups. Bacteroides increased significantly in the P2 group, in which Prevotella and Bifidobacterium also grew in numbers and kept increasing. CONCLUSION: GM pattern in healthy infants differed dramatically from that of the epileptic group. KD could significantly modify symptoms of epilepsy and reshape the GM of epileptic infants.

[Benign infantile convulsions with mild gastroenteritis: clinical analysis of 40 cases].

OBJECTIVE: To investigate the pathogenesis, clinical characteristics and treatment of benign infantile convulsions with mild gastroenteritis (BICG). METHODS: The clinical manifestations and laboratory findings were observed in 40 children with BICG. The antigen and antibodies of rotavirus and calicivirus in stool and cerebral spinal fluid (CSF) were tested by the golden standard method and ELISA. The neurological outcome was evaluated by a follow-up of six months or more. RESULTS: All of the 40 children had mild gastroenteritis with or without minor dehydration. Cluster convulsions were observed in these children. There were normal findings in blood biochemistry (Na+, K+, Ca2+, Cl-, HCO3-, glucose) and cerebral CT or MRI examinations. The interictal EEG showed sprinkle central or frontal epileptiform discharges in 8 children; clear central and parietal epileptiform discharges in 1 child; and no abnormal findings were observed in the other 31 children. Positive rotavirus antigen was detected in 11 children and positive calicivirus antigen in stool samples in 4 children. Positive antibodies of rotavirus and calicivirus in CSF were not seen. Seizures recurred in 22 of 28 children who received prophylactic injections of phenobarbital(5-10 mg/kg). In a 6 months follow-up, one child developed epilepsy and the other 39 children had no seizures and neurological sequelae. CONCLUSIONS: The digestive system manifestations are mild in children with BICG. Convulsions are always clustered in these children. The mechanism underlying convulsions is not clear. Conventional dose of phenobarbital is not effective for prevention of seizures. Most of children with BICG have a good prognosis.

[Follow-up of tuberous sclerosis complex complicated by epilepsy in children].

OBJECTIVE: To investigate the treatment outcome and risk factors for intractable seizures in children with tuberous sclerosis complex(TSC)complicated by epilepsy. METHODS: The medical data of 66 cases of TSC were retrospectively studied. RESULTS: Of the 66 children with TSC, 47 cases were available for follow-up. The follow-up period ranged from 7 months to 9.3 years (average 4.5 + or - 2.6 years). The patients' present average age was (7.7 + or - 4.1) years (median 8 years). Among the 47 cases, 19 (40%) had infantile spasms, 24 (51%) had tonic seizures, 15 (32%) had partial seizures, and 3 (6%) had tonic-clonic seizures, and additionally, multifocal seizures, atonic seizures, atypical absence seizures and hypomotor seizures each appeared in 1 case (2%) respectively. The average number of antiepileptic drugs used was 1.9 + or - 0.86 (median 1). Among the 47 patients, 12 (26%) still had epileptic seizures and 33 (70%)were seizure-free, and 4% were dead. Three cases underwent surgery and continued to receive medication after surgery. The three patients were seizure-free in a 1.5 years follow-up. Among the 30 children over 7 years old, 17 cases (57%) were enrolled in ordinary schools, 3 cases (10%) in special schools and the other 10 cases were off-school for disabilities of intelligence and speech. The non-conditional logistic regression showed that the age of onset (RR=1.8, 95% CI 1.0- 3.2, P=0.050), administration of multiple antiepileptic drugs (RR=4.8, 95% CI 1.2-18.6, P=0.024), tonic seizures (RR=0.003, 95% CI 0.0- 0.2, P=0.04) and sex (RR=0.016, 95% CI 0.0-0.5, P=0.017) were risk factors for intractable seizures. CONCLUSIONS: The majority (70%) of children with TSC complicated by epilepsy can be seizure-free with suitable treatment. The risk factors of poor outcome in seizure control may involve in the early onset age, tonic seizures and the administration for multiple anti-epileptic drugs.