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Abstract The clinical phenotype linked with mutations in ABCB1, encoding P‐glycoprotein, has never been reported. Here, we describe twin sisters with biallelic mutations in ABCB1 who showed recurrent reversible encephalopathy accompanied by acute febrile or afebrile illness. Whole‐exome sequencing was performed on one of the twin and her healthy parents, and revealed compound heterozygous loss‐of‐function variants in ABCB1. The patient brains displayed substantial loss of xenobiotic clearance ability, as demonstrated by [11C]verapamil positron emission tomography (PET) study, linking this phenotype with ABCB1 function. The endogenous cytokine clearance from the brain was also decreased in LPS‐treated ABCB1 knockout mice compared to controls. The results provide insights into the physiological requirement of ABCB1 in maintaining homeostasis of various compounds for normal brain function.

Abstract Background The search for noninvasive biomarkers of neuroinflammation and neurodegeneration has focused on various neurological disorders, including epilepsy. We sought to determine whether α-synuclein and cytokines are correlated with the degree of neuroinflammation and/or neurodegeneration in children with epilepsy and with acquired demyelinating disorders of the central nervous system (CNS), as a prototype of autoimmune neuroinflammatory disorders. Methods We analyzed serum and exosome levels of α-synuclein and serum proinflammatory and anti-inflammatory cytokines among 115 children with epilepsy and 10 acquired demyelinating disorders of the CNS and compared to 146 controls. Patients were enrolled prospectively and blood was obtained from patients within 48 h after acute afebrile seizure attacks or relapse of neurological symptoms. Acquired demyelinating disorders of the CNS include acute disseminated encephalomyelitis, multiple sclerosis, neuromyelitis optica spectrum disorders, and transverse myelitis. The controls were healthy age-matched children. The serum exosomes were extracted with ExoQuick exosome precipitation solution. Serum α-synuclein levels and serum levels of cytokines including IFN-β, IFN-γ, IL-1β, IL-6, IL-10 and TNF-α were measured using single and multiplex ELISA kits. Data were analyzed and compared with measures of disease severity, such as age at disease onset, duration of disease, and numbers of antiepileptic drug in use. Results Serum α-synuclein levels were significantly increased in patients with epilepsy and acquired demyelinating disorders of the CNS compared to controls (both, p

Purpose Cytokines demonstrate active roles in the occurrence of febrile seizures (FS). However, whether a genetic predisposition to inflammation is implicated in FS, febrile seizure plus (FS+) or genetic epilepsy with febrile seizure plus (GEFS+) are still unclear. Therefore we perform this study to find the association of promotor variants in pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) genes and anti-inflammatory cytokine interleukin 10 (IL-10) genes either with FS, FS+, and GEFS+ in Korean children. Methods Fifty-seven children with FS, 32 FS+, and 12 GEFS+ patients were compared with 108 controls. The allelic and genotypic distributions were compared for TNF-α-238 (rs361525), -308 (rs1800629), -857 (rs1799724), -863 (rs1800630), and IL-10-592 (rs1800872), -819 (rs1800871), -1082 (rs1800896), and -1352 (rs1800893). Results Allelic and genotypic frequencies of TNF-α and IL-10 promotor variants showed no significant differences between FS, FS+, and GEFS+ versus controls. However, AA genotypes at TNF-α-863 were present only in controls. TNF-α-863 (rs1800630) promoter variants showed an association with FS, FS+, and GEFS+ in a recessive mode of inheritance pattern (P

Purpose: We aimed to evaluate the diagnostic yield of epilepsy gene panel testing in epilepsy patients whose seizures began within the first year after birth. We included 112 patients with seizure onset before 12 months and no known etiology.Methods: Deep targeted sequencing with a custom-designed capture probe was performed to ensure the detection of germline or mosaic sequence variants and copy number variations (CNVs).Results: We identified pathogenic or likely pathogenic variants in 53 patients (47.3%, 53/112), including five with pathogenic CNVs. Two putative pathogenic mosaic variants in SCN8A and KCNQ2 were also detected and validated. Those with neonatal onset (61.5%, 16/26) or early infantile onset (50.0%, 29/58) showed higher diagnostic rates than those with late infantile onset (28.5%, 8/28). The diagnostic rate was similar between patients with a specific syndrome (51.9%, 27/52) and those with no recognizable syndrome (43.3%, 26/60).Conclusion: Epilepsy gene panel testing identified a genetic cause in nearly half of the infantile onset epilepsy patients. Since the phenotypic spectrum is expanding and characterizing it at seizure onset is difficult, this group should be prioritized for epilepsy gene panel testing.

Many females who are heterozygous for ornithine carbamoyltransferase (OTC) deficiency are asymptomatic or intermittently symptomatic with great phenotypic variability. Therefore, the diagnosis of this condition is occasionally a challenge and is often delayed. A 12-year-old girl who was initially diagnosed as having attention deficit-hyperactivity disorder (ADHD) became comatose and developed right-sided hemiparesis during her psychiatric admission. Brain magnetic resonance imaging indicated diffuse but extensive swelling in the left hemisphere with multiple lesions suggestive of an old infarction. Repeated evaluations revealed hyperammonemia and orotic aciduria, and she was diagnosed as having an OTC deficiency. Genetic analysis revealed a heterozygous mutation of N47I in the X-linked OTC gene. Her mental status and hemiparesis improved after hyperammonemia treatment. Here, we report a rare case of a manifestating female carrier with severe symptoms of OTC deficiency masquerading as ADHD. [ABSTRACT FROM AUTHOR]