Clinical use of whole exome sequencing in children with developmental delay/intellectual disability.

BACKGROUND: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID. METHODS: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes. RESULTS: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD. CONCLUSION: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Coffin-Siris Syndrome: Case Series of Three Patients and a Novel ARID2 Variant.

Coffin-Siris syndrome (CSS) is a rare congenital disorder characterized by coarse facial features, intellectual disability or developmental delay, and aplasia or hypoplasia of the tips of the fifth finger and/or toes. Mutations in genes affecting the switch/sucrose non-fermenting ATP-dependent chromatin remodeling complex are reported to cause CSS. Here, we describe three CSS patients. Two girls aged 3 and 2 years old presented with global developmental delay, poor growth, and a dysmorphic face. Whole-exome sequencing (WES) was performed and they were diagnosed with CSS due to heterozygous frameshift variants (c.3443_3444del, p.Lys1148ArgfsTer9 and c.2869_2890del, p.Pro957CysfsTer20) in ARID1B A 2-year-old girl presented with gross motor delay and dysmorphic face. She was diagnosed with CSS due to a novel heterozygous frameshift variant (c.4942_4943del: p.Gln1648GlyfsTer8) in ARID2.

Chromosomal Microarray in Children With Developmental Delay: The Experience of a Tertiary Center in Korea.

Background and Objectives: Chromosomal microarray (CMA) is a first-tier genetic test for children with developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), and multiple congenital anomalies (MCA). In this study, we report our experiences with the use of CMA in Korean children with unexplained DD/ID. Methods: We performed CMA in a cohort of 308 children with DD/ID between January 2010 and September 2020. We also retrospectively reviewed their medical records. The Affymetrix CytoScan 750 K array with an average resolution of 100 kb was used to perform CMA. Results: Comorbid neurodevelopmental disorders were ASD (37 patients; 12.0%), epilepsy (34 patients; 11.0%), and attention deficit hyperactivity disorders (12 patients; 3.9%). The diagnostic yield was 18.5%. Among the 221 copy number variants (CNVs) identified, 70 CNVs (57 patients; 18.5%) were pathogenic. Deletion CNVs were more common among pathogenic CNVs (PCNVs) than in non-PCNVs (P < 0.001). The size difference between PCNVs and non-PCNVs was not significant (P = 0.023). The number of included genes within CNV intervals was significantly higher in PCNVs (average 8.6; 0-347) than in non-PCNVs (average 47.5; 1-386) (P < 0.001). Short stature and hearing difficulty were also more common in the PCNV group than in the non-PCNV group (P = 0.010 and 0.070, respectively). Conclusion: This study provides additional evidence for the usefulness of CMA in genetic testing of children with DD/ID in Korea. The pathogenicity of CNVs correlated with the number of included genes within the CNV interval and deletion type of the CNVs, but not with CNV size.

Autophagic defects observed in fibroblasts from a patient with ß-propeller protein-associated neurodegeneration.

Beta-propeller protein-associated neurodegeneration (BPAN) is associated with mutations in the autophagy gene WDR45. The aim of this study was to demonstrate autophagic defects in a patient with BPAN. We assayed autophagic markers using western blot analysis and immunocytochemistry and applied transmission electron microscopy (TEM) to visualize the autophagic structures in fibroblasts from a 7-year-old Korean female with WDR45 splice-site mutation (c.977-1G>A; NM_007075.3). The protein and mRNA expression levels of WDR45 gene were decreased in the patient-derived fibroblasts. The amount of increase in LC3-II upon treatment with an autophagy inducer and inhibitor was reduced in mutant cells compared to control cells, suggesting decreased autophagic flux. TEM showed the accumulation of large vacuoles in mutant cells with a decrease of autophagosomes. Our study demonstrated that the WDR45 mutation in this patient impaired autophagy and provided additional insight into ultrastructural changes of autophagic structures.

Corrigendum: Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

[This corrects the article DOI: 10.3389/fgene.2020.590924.].

Myelin oligodendrocyte glycoprotein antibody-associated disorders: clinical spectrum, diagnostic evaluation, and treatment options.

Inflammatory or immune-mediated demyelinating central nervous system (CNS) syndromes include a broad spectrum of clinical phenotype and different overlapping diseases. Antibodies against myelin oligodendrocyte glycoprotein (MOG-Ab) have been found in some cases of these demyelinating diseases, particularly in children. MOG-Ab is associated with a wider clinical phenotype not limited to neuromyelitis optica spectrum disorder, with most patients presenting with optic neuritis, acute disseminated encephalomyelitis (ADEM) or ADEM-like encephalitis with brain demyelinating lesions, and/or myelitis. Using specific cell-based assays, MOG-Ab is becoming a potential biomarker of inflammatory demyelinating disorders of the CNS. A humoral immune reaction against MOG was recently found in monophasic diseases and recurrent/multiphasic clinical progression, particularly in pediatric patients. This review summarizes the data regarding MOG-Ab as an impending biological marker for discriminating between these diverse demyelinating CNS diseases and discusses recent developments, clinical applications, and findings regarding the immunopathogenesis of MOG-Ab-associated disorders.

Clinical utility of the FilmArray meningitis/encephalitis panel in children at a tertiary center in South Korea.

BACKGROUND: We retrospectively evaluated the pathogens in the cerebrospinal fluid (CSF) of pediatric meningitis/encephalitis (M/E) by FilmArray meningitis/encephalitis panel (FA-MEP), and the characteristics of children showing positive and negative FA-MEP results. METHOD: FA-MEP along with conventional tests (bacterial/viral cultures, and polymerase chain reaction tests) was performed in children who presented symptoms of M/E. Clinical and laboratory data were reviewed to evaluate the characteristics of children with pathogens detected by FA-MEP. RESULTS: The CSF specimens from 110 pediatric M/E patients were enrolled. Mean age of the patients was 5.9 ± 5.2 years. Overall positive rate of FA-MEP was 46.4% (51/110). The pathogens detected in the patients were enterovirus (23/51, 45.1%), parechovirus (10/51, 19.6%), S. pneumoniae (7/51, 13.7%), human herpesvirus type 6 (6/51, 11.8%), S. agalactiae (3/51, 5.9%), herpes simplex virus type 2 (1/51, 2.0%), and E. coli (1/51, 2.0%). Aseptic meningitis (OR, 3.24, 95% CI, 1.18-12.73) and a duration of <2 days from onset of symptoms to CSF test (OR, 3.56, 95% CI, 0.1-0.91) significantly contributed to detection of pathogens by the FA-MEP. Among the 14 children who were administered empiric antibiotics before the CSF test, the detection rate was significantly higher in the FA-MEP than in the conventional test (28.6 vs. 0.0%, p = 0.031). CONCLUSIONS: FA-MEP had a higher detection rate in children with M/E compared with conventional tests, particularly aseptic meningitis, and in case of shorter duration of time-to-test. This test was more effective than the conventional test in pediatric M/E patients that had been administered empiric antibiotics.

Longitudinal changes in insulin resistance in children with epilepsy on ketogenic diet: Prevalence and risk factors.

INTRODUCTION: The aim of the study was to evaluate the incidence of insulin resistance (IR) and the associated risk factors in children with epilepsy on a ketogenic diet (KD). METHODS: This longitudinal cohort study analyzed data of children with epilepsy on KD. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). The HOMA-IR value, fasting serum insulin levels, fasting glucose (FG) levels, and lipid profiles were measured before the initiation of the KD and at 6- to 12-month intervals. RESULTS: A total of 28 children were enrolled. The median age at the initiation of KD was 2.7 ±â€¯2.4 years, and the median follow-up duration was 2.1 ±â€¯1.4 years. The median HOMA-IR (HOMA-IR-1) value before the initiation of KD was 1.2 ±â€¯0.2, which significantly increased to 1.8 ±â€¯0.3 at the last follow-up (HOMA-IR-2; ∆HOMA-IR = 0.6 ±â€¯0.3, p < 0.001). The following factors were associated with patients with higher HOMA-IR-2 values (≥1.9): younger age at seizure onset (0.3 ±â€¯0.2 years, p < 0.001), at the initiation of antiepileptic drugs (AEDs; 0.3 ±â€¯0.3 years, p < 0.001), and at the initiation of KD (1.3 ±â€¯0.5 years, p < 0.001) and higher serum alanine transaminase (ALT; 84.0 ±â€¯17.8 U/L, p = 0.022), total cholesterol (TC; 245.0 ±â€¯20.1 mg/dL, p = 0.001), low-density lipoprotein cholesterol (LDL-C, 103.0 ±â€¯6.7 mg/dL, p = 0.003), and triglyceride (387.0 ±â€¯28.8 mg/dL, p < 0.001) levels. Multivariate regression analysis revealed that the age at seizure onset (p = 0.002), at initiation of AEDs (p = 0.021), and at initiation of KD (p = 0.022) and serum levels of LDL-C (p = 0.012) and triglycerides (p = 0.026) were associated with a significantly high HOMA-IR-2 value. CONCLUSION: Close monitoring of serum lipids levels, especially at younger age, may aid in detecting exacerbation of IR.

Bone health in pediatric patients with neurological disorders.

Patients with neurological disorders are at high risk of developing osteoporosis, as they possess multiple risk factors leading to low bone mineral density. Such factors include inactivity, decreased exposure to sunlight, poor nutrition, and the use of medication or treatment that can cause lower bone mineral density such as antiepileptic drugs, ketogenic diet, and glucocorticoids. In this article, mechanisms involved in altered bone health in children with neurological disorders and management for patients with epilepsy, cerebral palsy, and Duchenne muscular dystrophy regarding bone health are reviewed.

Real-Life Effectiveness and Tolerability of Perampanel in Pediatric Patients Aged 4 Years or Older with Epilepsy: A Korean National Multicenter Study.

BACKGROUND AND PURPOSE: The US Food and Drug Administration approval for perampanel has only recently been expanded to patients as young as 4 years, and so there have been few real-life studies of the effects of perampanel in pediatric patients. The aim of this study was to determine the long-term efficacy, factors affecting treatment response, and tolerability of perampanel as an add-on therapy in pediatric patients aged 4 years or older with epilepsy. METHODS: This multicenter retrospective observational study collected data from pediatric epilepsy centers of four Korean national universities. Changes in the seizure frequency from baseline, adverse events, and retention rates were obtained at 3, 6, and 12 months. Adverse events and discontinuation profiles were obtained to assess tolerability. RESULTS: This study included 220 children and adolescents (117 males and 103 females) aged 4 to 20 years. The overall response rate was 43.6%, and the seizure-freedom rate was 17.7%. Factors affecting a good treatment response were the absence of intellectual disability, small number of concomitant antiepileptic drugs, and low baseline seizure frequency. Eighty-eight patients (40%) experienced adverse events, but they mostly were of mild severity and resolved after the dose reduction or discontinuation of perampanel. The retention rates at 3, 6, and 12 months were 85.0%, 71.8%, and 50.5%, respectively. CONCLUSIONS: Adjunctive treatment with perampanel was efficacious and tolerated in pediatric patients aged 4 years or older with epilepsy. Early perampanel treatment may help to reduce the burden of their seizures and improve their quality of life.

Characteristics of Genetic Variations Associated With Lennox-Gastaut Syndrome in Korean Families.

Lennox-Gastaut syndrome (LGS) is a severe type of childhood-onset epilepsy characterized by multiple types of seizures, specific discharges on electroencephalography, and intellectual disability. Most patients with LGS do not respond well to drug treatment and show poor long-term prognosis. Approximately 30% of patients without brain abnormalities have unidentifiable causes. Therefore, accurate diagnosis and treatment of LGS remain challenging. To identify causative mutations of LGS, we analyzed the whole-exome sequencing data of 17 unrelated Korean families, including patients with LGS and LGS-like epilepsy without brain abnormalities, using the Genome Analysis Toolkit. We identified 14 mutations in 14 genes as causes of LGS or LGS-like epilepsy. 64 percent of the identified genes were reported as LGS or epilepsy-related genes. Many of these variations were novel and considered as pathogenic or likely pathogenic. Network analysis was performed to classify the identified genes into two network clusters: neuronal signal transmission or neuronal development. Additionally, knockdown of two candidate genes with insufficient evidence of neuronal functions, SLC25A39 and TBC1D8, decreased neurite outgrowth and the expression level of MAP2, a neuronal marker. These results expand the spectrum of genetic variations and may aid the diagnosis and management of individuals with LGS.

Prospective research of human parechovirus and cytokines in cerebrospinal fluid of young children less than one year with sepsis-like illness: Comparison with enterovirus.

BACKGROUND: Human parechovirus (PeV) and enterovirus are important pathogens that cause viral infection and aseptic meningitis in young children. We aimed to investigate the rate of HPeV and enterovirus detection, and to characterize cytokine profiles in the cerebrospinal fluid (CSF) of young infants with sepsis-like illness or meningitis/encephalitis. STUDY DESIGN: This was a prospective cohort study. CSF samples were collected from 90 infants less than 1 year of age. PeV and enterovirus detection was performed using reverse transcription polymerase chain reaction. Fifteen cytokines in the CSF were measured simultaneously by using multiplex immunoassays. RESULTS: PeV (PeV-group) and enterovirus (EV-group) were detected in 10 (11.1%) and 12 (13.3%) CSF samples, respectively. Other aseptic meningitis (AM-group) was diagnosed in 22 (24.4%) patients. Forty-six (51.1%) patients exhibited non-central nervous system infection (Ngroup). The PeV-group had the lowest CSF leukocyte (2.1 ± 3.5/mm3, p=0.022) and blood leukocyte (7,953 ± 4,583/mm3, p=0.046) count and Creactive protein levels (0.2 ± 0.1 mg/dL, p=0.036), than did those in the EV- and AM-groups. CSF leukocyte count and protein levels were not significantly different between the PeV- and N-groups. The levels of interleukin (IL)-1ß, IL-5, IL-6, IL-12, and IL-17 were higher in the EVgroup; conversely, IL-2, IL-4, IL-7, and IL-13 were higher in the PeVgroup. CONCLUSIONS: Examinations to detect PeV in the CSF may help identify the etiological basis of undiagnosed febrile illness in young children. Significant differences in CSF and blood laboratory findings were observed between PeV- and enterovirus-infected children.

Utility of Magnetic Resonance Imaging (MRI) in Children With Strabismus.

PURPOSE: Magnetic resonance imaging (MRI) of the brain can provide valuable information about structural abnormalities in strabismus. The aim of this study was to evaluate the utility of MRI in this regard and to identify risk factors for abnormal MRI results in children with strabismus. METHODS: A retrospective analysis of children <18 years of age presenting with strabismus, who underwent brain MRI at Pusan National University Hospital (Busan, Korea) between January 2012 and March 2017, was performed. Clinical characteristics, MRI results, and ophthalmologic findings were reviewed. Findings were classified as normal or abnormal according to MRI results. Additionally, patients were divided according to age to compare characteristics of infantile and childhood strabismus. RESULTS: A total of 90 patients (47 [52.2%] male, 43 [47.8%] female; mean age, 2.19 ± 0.53 years) were enrolled. Of those, 64 (71.1%) presented with normal and 26 (28.9%) with abnormal MRI results. The age at presentation was lower and abnormal findings on fundus examination were more common in the abnormal MRI group (P = .002 and P = .008, respectively). Among the patients, 46 (51.1%) had infantile strabismus and 44 (48.9%) had childhood strabismus. Global developmental delays, speech delays, and MRI abnormalities were more common in patients with infantile than in those with childhood strabismus. Ptosis and headaches were more common in patients with childhood strabismus (P = .025, P = .025, respectively). CONCLUSION: Brain MRI was helpful for accurate diagnosis and treatment of strabismus in younger children, those with abnormal findings on fundus examination, and infants with developmental, especially speech, delays.

Longitudinal change of cardiac electrical and autonomic function and potential risk factors in children with dravet syndrome.

PURPOSE: This study aimed to investigate cardiac electrical and autonomic function, the longitudinal changes, and the associated risk factors in children with Dravet syndrome (DS). METHODS: Twenty-four children with DS (11 boys, 13 girls; mean age, 7.2 ± 2.9 years) and 21 control subjects (9 boys, 12 girls; mean age, 8.2 ± 3.0 years) were enrolled in this study. P dispersion, QTc and QTc dispersion, and heart rate variability (HRV) were evaluated using standard electrocardiography and 24-hr Holter monitoring at the initial and follow-up study of the 6-12 months intervals. RESULTS: The DS group had significantly higher P dispersion (p = 0.017), QT and QTc dispersion values (p < 0.001 for two parameters) than the control group. Most HRV parameters, such as SDNN (p < 0.001), SDANN5 (p < 0.001), SDANN-index (p = 0.001), and RMSSD (p = 0.006) were all significantly lower in the DS group than in the control group. The mean values of initial QTc, QTc dispersion, and HRV parameters showed significantly increase (QTc and QTc dispersion) and decrease (HRV) in the follow-up study (mean duration: 1.2 ± 0.5 years) in 13 DS children. ± On multivariate regression analysis, epilepsy duration had an independently significant effect for the longitudinal change of QTc, QTc dispersion, and HRV. CONCLUSIONS: DS children had significant different values of cardiac electrical and autonomic function compared with control group. Particularly, longer duration of epilepsy was significantly negative effect on the longitudinal change of cardiac autonomic function.

Clinical characterization of anti-GQ1b antibody syndrome in Korean children.

Anti-GQ1b antibody syndrome encompasses Miller Fisher syndrome and its related disorders. We retrospectively identified 11 pediatric patients (5.4-18 years old) with anti-GQ1b antibody syndrome. Diagnoses of patients included acute ophthalmoparesis (n = 6), classical Miller Fisher syndrome (n = 2), Miller Fisher syndrome/Guillain-Barré syndrome (n = 1), acute ataxic neuropathy (n = 1), and pharyngeal-cervical-brachial weakness (n = 1). Nine patients (81.8%) fully recovered. Maturational change in GQ1b antigen expression and the accessibility of anti-GQ1b antibodies might be the cause of the difference of clinical manifestations in children with anti-GQ1b antibody syndrome.

Comparison of conservative therapy and steroid therapy for Bell's palsy in children.

PURPOSE: Bell's palsy is characterized by sudden onset of unilateral facial weakness. The use of corticosteroids for childhood Bell's palsy is controversial. This study aimed to identify clinical characteristics, etiology, and laboratory findings in childhood Bell's palsy, and to evaluate the efficacy of corticosteroid treatment. METHODS: We conducted a retrospective analysis of children under 19 years of age treated for Bell's palsy between January 2009 and June 2017, and followed up for over 1 month. Clinical characteristics, neuroimaging data, laboratory findings, treatments, and outcomes were reviewed. Patients with Bell's palsy were divided into groups with (group 1) and without (group 2) corticosteroid treatment. Differences in onset age, sex, laterality, infection and vaccination history, degree of facial nerve palsy, and prognosis after treatment between the groups were analyzed. RESULTS: One hundred patients were included. Mean age at presentation was 7.4±5.62 years. A total of 73 patients (73%) received corticosteroids with or without intravenous antiviral agents, and 27 (27%) received only supportive treatment. There was no significant difference in the severity, laboratory findings, or neuroimaging findings between the groups. Significant improvement was observed in 68 (93.2%) and 26 patients (96.3%) in groups 1 and 2, respectively; this rate was not significantly different between the groups (P=0.48). CONCLUSION: Childhood Bell's palsy showed good prognosis with or without corticosteroid treatment; there was no difference in prognosis between treated and untreated groups. Steroid therapy in childhood Bell's palsy may not significantly improve outcomes.

Comparison of Cerebrospinal Fluid Cytokine Levels in Children of Enteroviral Meningitis With Versus Without Pleocytosis.

In viral meningitis, proinflammatory cytokines were detected at higher levels in the cerebrospinal fluid (CSF) and might play an important role in the inflammatory process. Our goal was to compare the cytokine profiles in the CSF of children of enteroviral meningitis (EVM) with versus without CSF pleocytosis. In total, 158 patients were enrolled in this prospective cohort study and were classified as EVM (group-A, n = 101), nonenteroviral aseptic meningitis (group-B, n = 27), and control (group-C, n = 30) groups. Of the 101 children with EVM, 71 had CSF pleocytosis (group-A1) and 30 had CSF nonpleocytosis (group-A2). Fifteen cytokines/chemokines in the CSF were measured simultaneously by immunoassay. Significant differences were found in interleukin (IL)-2, IL-6, and IL-8 levels in the CSF across the 3 groups, with the highest levels in group-A, followed by group-B and group-C. The levels of IL-1ß, IL-2, IL-6, IL8, IL-10, interferon-γ, and tumor necrosis factor-α were significantly higher in the CSF of group-A1 than in that of group-A2. Group-A2 was significantly younger than group-A1 (3.4 ± 2.8 years versus 5.5 ± 3.2 years, P = 0.016). Significant differences between CSF pleocytosis and nonpleocytosis in EVM appear to be associated with distinct levels of CSF cytokines.

Cerebrospinal fluid non-pleocytosis in pediatric enteroviral meningitis: Large-scale review.

BACKGROUND: Lack of cerebrospinal fluid (CSF) pleocytosis has been reported in some children with enteroviral meningitis (EVM). The aim of this paper was to investigate the clinical spectrum and related factors in EVM with CSF non-pleocytosis. METHODS: The databases of children diagnosed with EVM on CSF polymerase chain reaction between 2011 and 2014 were retrospectively reviewed. CSF pleocytosis was defined at each age using the criteria. Clinical and laboratory variables were compared between patients with CSF pleocytosis and non-pleocytosis. RESULTS: Of the 802 children of EVM, 25.4% (204/802) had CSF non-pleocytosis. In particular, CSF non-pleocytosis was found in 63.3% of the neonates versus in 22.2% of the children aged ≥1 year old, indicating that the ratio of CSF non-pleocytosis had a negative correlation with age (P < 0.001). As the main symptoms, fever (91.8% vs 86.8%, P = 0.038), headache (80.3% vs 63.7%, P < 0.001), and vomiting (75.9% vs 61.8%, P < 0.001) were significantly more frequent in CSF pleocytosis than in CSF non-pleocytosis. Patients with CSF non-pleocytosis had much lower peripheral leukocytosis (10 656 ± 3,662 vs 12 403 ± 4,207/mm3 , P = 0.014) and C-reactive protein (0.7±0.8 vs 1.2±1.5 mg/dL, P < 0.001), and earlier lumbar puncture <24 h after onset (42.6% vs 21.4%, p<0.001). No significant difference during the summer and autumn months was seen between the two groups (76.9% vs 81.9%, P = 0.169). CONCLUSION: CSF non-pleocytosis in childhood EVM was frequently observed, especially in young infants, regardless of season. We propose that CSF PCR testing for enterovirus can be helpful to recognize EVM in children with CSF non-pleocytosis.