SYNGAP1-related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights.

The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole-exome sequencing. All patients exhibited global developmental delay from early infancy, with motor development eventually reaching independent ambulation by 3 years of age. Language developmental delay varied significantly from nonverbal to simple sentences, which plateaued in all patients. Patients with the best language outcomes typically managed 2-3-word sentences, corresponding to a developmental age of 2-3 years. Epilepsy developed in 77% of patients, with onset consistently following developmental delays at a median age of 31 months. Longitudinal EEG data revealed a shift from occipital to frontal epileptiform discharges with age, suggesting a correlation with synaptic maturation. These findings suggest that the critical developmental plateau occurs between the ages of 2 and 5 years and is potentially influenced by epilepsy. By analyzing longitudinal data, our study contributes to a deeper understanding of SYNGAP1-related DEE, provides potential EEG biomarkers, and underlines the importance of early diagnosis and intervention to address this complex disorder.

Outcomes of the second withdrawal of anti-seizure medication in patients with pediatric-onset epilepsy.

Withdrawal of anti-seizure medication (ASM) is challenging, especially in patients with recurrent seizures. Only limited evidence exists regarding the success rate and recurrence risk factors after withdrawal of ASM for a second time in patients with pediatric-onset epilepsy. In this observational study, we evaluated 104 patients with recurrent pediatric-onset epilepsy who had ASM withdrawn for a second time. The success rate was 41.3% after the second withdrawal of ASM. The absence of a self-limiting epilepsy syndrome, shorter seizure-free intervals before the second withdrawal of ASM, and relapse during tapering after the initial withdrawal of ASM were negative factors significantly associated with the success of ASM withdrawal for a second time. Even after a second seizure recurrence, all patients eventually became seizure-free after restarting their previous ASM (78.7%) or readjusting the ASM (21.3%). Our findings that 40% of patients with recurrent pediatric-onset epilepsy could achieve long-term seizure freedom and that all patients with a second seizure recurrence remained seizure-free suggest that ASM may be withdrawn for a second time after carefully stratifying clinical risk.

Cord blood transforming growth factor-ß-induced as predictive biomarker of retinopathy of prematurity in preterm infants.

PURPOSE: To determine whether 14 inflammation-, angiogenesis-, and adhesion-related proteins in cord blood (CB), alone or in combination with conventional perinatal factors, could predict retinopathy of prematurity (ROP) in preterm infants. METHODS: Data from 111 preterm infants (born at ≤ 32.0 weeks) were retrospectively reviewed. The levels of endoglin, E-selectin, HSP70, IGFBP-3/4, LBP, lipocaline-2, M-CSFR, MIP-1α, pentraxin 3, P-selectin, TGFBI, TGF-ß1, and TNFR2 were assessed in stored CB samples collected at birth using ELISA kits. The primary endpoints included severe ROP (≥ stage 3) and type 1 ROP requiring treatment. RESULTS: ROP was diagnosed in 29 infants (26.1%), among whom 14 (12.6%) had severe ROP and seven (6.3%) had type 1 ROP. Multivariate logistic regression showed that decreased CB TGFBI levels were significantly associated with severe ROP and type 1 ROP after adjusting for gestational age at birth. Stepwise regression analysis allowed to design prediction models with good accuracy, which comprised low CB TGFBI levels and low birth weight (BW) as predictors for severe ROP (area under the curve [AUC] = 0.888), and low CB endoglin levels and low BW as predictors for type 1 ROP (AUC = 0.950). None of the other CB proteins evaluated were found to be associated with severe ROP or type 1 ROP. CONCLUSIONS: Low CB TGFBI levels are associated with severe ROP and type 1 ROP, independently of gestational age. Moreover, combined predictive models based on CB TGFBI and endoglin levels, along with BW data, may act as good indicators at birth for the neonatal risk of ROP progression.

Clinico-radiological characteristics of anti-myelin oligodendrocyte glycoprotein antibody-associated autoimmune encephalitis in children.

AIM: To investigate the clinical characteristics and prevalence of paediatric anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated autoimmune encephalitis. METHOD: A total of 94 paediatric patients (46 males, 48 females, median age 9 years 5 months, range: 8 months-17 years 8 months) with autoimmune encephalitis were recruited at Seoul National University Children's Hospital. We evaluated autoantibody status and identified patients with anti-MOG antibody-associated autoimmune encephalitis. Retrospective reviews of medical records were performed to describe clinical presentations, laboratory findings, treatments, and outcomes. RESULTS: Eight patients (five males, three females, median age 11 years 9 months) with anti-MOG antibody-associated encephalitis were identified (8.5% of those with autoimmune encephalitis), one of whom was copositive for anti-N-methyl-d-aspartate receptor (NMDAR) antibodies. Anti-NMDAR antibodies were identified in 23 patients (23 out of 94, 24.5%). Unilateral or bilateral cortical involvement was identified in five patients. Focal contrast enhancement was also identified in three of the five patients with cortical lesions. All patients showed favourable response to immunotherapy with a Modified Rankin Scale ≤2 at the last follow-up. Relapse was found in one patient and clinico-radiological remission was achieved with cyclic intravenous immunoglobulin therapy. INTERPRETATION: Anti-MOG antibody-associated encephalitis accounts for a significant proportion of clinically defined paediatric patients with autoimmune encephalitis. Anti-MOG antibody-associated encephalitis should be included in the clinical spectrum of anti-MOG-associated diseases.

Genetic diagnosis of infantile-onset epilepsy in the clinic: Application of whole-exome sequencing following epilepsy gene panel testing.

This study aimed to evaluate the clinical utility of whole-exome sequencing in a group of infantile-onset epilepsy patients who tested negative for epilepsy using a gene panel test. Whole-exome sequencing was performed on 59 patients who tested negative on customized epilepsy gene panel testing. We identified eight pathogenic or likely pathogenic sequence variants in eight different genes (FARS2, YWHAG, KCNC1, DYRK1A, SMC1A, PIGA, OGT, and FGF12), one pathogenic structural variant (8.6 Mb-sized deletion on chromosome X [140 994 419-149 630 805]), and three putative low-frequency mosaic variants from three different genes (GABBR2, MTOR, and CUX1). Subsequent whole-exome sequencing revealed an additional 8% of diagnostic yield with genetic confirmation of epilepsy in 55.4% (62/112) of our cohort. Three genes (YWHAG, KCNC1, and FGF12) were identified as epilepsy-causing genes after the original gene panel was designed. The others were initially linked with mitochondrial encephalopathy or different neurodevelopmental disorders, although an epilepsy phenotype was listed as one of the clinical features. Application of whole-exome sequencing following epilepsy gene panel testing provided 8% of additional diagnostic yield in an infantile-onset epilepsy cohort. Whole-exome sequencing could provide an opportunity to reanalyze newly recognized epilepsy-linked genes without updating the gene panel design.

Impact of mobile health application on data collection and self-management of epilepsy.

Recent advances in mobile health have enabled health data collection, which includes seizure and medication tracking and epilepsy self-management. We developed a mobile epilepsy management application, integrated with a hospital electronic health record (EHR). In this prospective clinical trial, we assessed whether the mobile application provides quality healthcare data compared to conventional clinic visits, and enhances epilepsy self-management for patients with epilepsy. The study population includes patients with epilepsy (ages 15 years and older) and caregivers for children with epilepsy. Participants were provided access to the application for 90 days. We compared healthcare data collected from the mobile application with data obtained from clinic visits. The healthcare data included seizure records, seizure triggering factors, medication adherence rate, profiles of adverse events resulting from anti-seizure medication (ASM), and comorbidity screenings. In addition, we conducted baseline and follow-up questionnaires after the 90-day period to evaluate how this mobile application improved epilepsy knowledge and self-efficacy in seizure management. Data of 99 participants (18 patients with epilepsy and 81 caregivers) were analyzed. Among 24 individuals who had seizures, we obtained detailed seizure records from 13 individuals through clinic visits and for 18 from the application. Aside from the 6 individuals who reported their medication adherence during clinic visitation, half of the study participants had adherence rates of over 70%, as monitored through the application. However, the adherence rates were not reliable due to high variability. Twenty-three individuals reported 59 adverse reactions on the application, whereas 21 individuals reported 24 adverse reactions during clinic visits. We collected comorbidity data from 4 individuals during clinic visits. In comparison, 64 participants underwent comorbidity self-screening on the application, and 2 of them were referred to neuropsychiatric services. Compared to rare/non-users, app users demonstrated significant improvement in epilepsy knowledge score (p < 0.001) and self-efficacy score (p = 0.038). In conclusion, mobile health technology would help patients and caregivers to record their healthcare data and aid in self-management. Mobile health technology would provide an influential clinical validity in epilepsy care when users engage and actively maintain records on the application.

Analysis of antiseizure drug-related adverse reactions from the electronic health record using the common data model.

OBJECTIVE: Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital. METHODS: We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications. RESULTS: From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group. SIGNIFICANCE: The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

Serum α-synuclein and IL-1ß are increased and correlated with measures of disease severity in children with epilepsy: potential prognostic biomarkers?

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-ß, IFN-γ, IL-1ß, 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 < 0.05) and showed correlation with measures of disease severity both in epilepsy (p < 0.05, r = 0.2132) and in acquired demyelinating disorders of the CNS (p < 0.05, r = 0.5892). Exosome α-synuclein showed a significant correlation with serum α-synuclein (p < 0.0001, r = 0.5915). Serum IL-1ß levels were correlated only with the numbers of antiepileptic drug used in children with epilepsy (p < 0.001, r = 0.3428), suggesting drug resistant epilepsy. CONCLUSIONS: This is the first study in children demonstrating that serum α-synuclein levels were significantly increased in children with epilepsy and with acquired demyelinating disorders of the CNS and correlated with measures of disease severity. Serum IL-1ß levels showed significant correlation only with drug resistance in children with epilepsy. Thus, these data support that serum levels of α-synuclein and IL-1ß are potential prognostic biomarkers for disease severity in children with epilepsy. CNS, central nervous system.

Importance of early diagnosis in LMNA-related muscular dystrophy for cardiac surveillance.

INTRODUCTION: The identification of LMNA-related muscular dystrophy is important because it poses life-threatening cardiac complications. However, diagnosis of LMNA-related muscular dystrophy based on clinical features is challenging. METHODS: We reviewed the clinical phenotypes of 14 children with LMNA variants, focusing on the cardiac function and genotypes. RESULTS: Most patients presented with motor developmental delay or gait abnormalities. Eight (57%) patients had prominent neck extensor weakness or contractures. All patients showed ankle contractures at an early stage. Regular cardiac surveillance allowed for the detection of dysrhythmias in 57% of patients at a mean age of 14 years (range, 5-26). All patients had missense variants; however, there were no clear phenotype-genotype correlations. DISCUSSION: Early diagnosis of LMNA-related muscular dystrophy provides an opportunity for cardiac surveillance, potentially leading to the prevention of cardiac mortality in children.

Consecutive analysis of mutation spectrum in the dystrophin gene of 507 Korean boys with Duchenne/Becker muscular dystrophy in a single center.

INTRODUCTION: Duchenne and Becker muscular dystrophies (DMD and BMD) are allelic X-linked recessive muscle diseases caused by mutations in the large and complex dystrophin gene. METHODS: We analyzed the dystrophin gene in 507 Korean DMD/BMD patients by multiple ligation-dependent probe amplification and direct sequencing. RESULTS: Overall, 117 different deletions, 48 duplications, and 90 pathogenic sequence variations, including 30 novel variations, were identified. Deletions and duplications accounted for 65.4% and 13.3% of Korean dystrophinopathy, respectively, suggesting that the incidence of large rearrangements in dystrophin is similar among different ethnic groups. We also detected sequence variations in >100 probands. The small variations were dispersed across the whole gene, and 12.3% were nonsense mutations. CONCLUSIONS: Precise genetic characterization in patients with DMD/BMD is timely and important for implementing nationwide registration systems and future molecular therapeutic trials in Korea and globally. Muscle Nerve 55: 727-734, 2017.