PPP2R1A-Related Neurodevelopmental Disorder: The First Korean Case with a Novel Variant of PPP2R1A and Literature Review.

In 2015, germline mutations in PPP2R1A were found to cause neurodevelopmental disorders (NDDs). To date, fewer than 50 cases of PPP2R1A-related NDDs have been reported. Here, we report the first Korean case of PPP2R1A-related NDD harboring a novel de novo missense PPP2R1A variant with previously unreported clinical features. The proband, a 12-month-old female, presented with developmental delay, intractable epilepsy, microcephaly, and feeding difficulties. Brain magnetic resonance imaging showed a Dandy-Walker continuum with corpus callosum hypoplasia, periventricular leukomalacia, and brainstem and diffuse cerebral atrophy. Next-generation sequencing-based targeted gene panel testing for NDDs revealed a novel heterozygous missense variant of PPP2R1A:c.650A>G, p.(Gln217Arg). Sanger sequencing confirmed it as de novo, as neither parent carried this variant. These findings expand the phenotypic and genotypic spectra of PPP2R1A variants.

Characteristics of febrile seizures with SARS-CoV-2 infection in the Omicron era.

Background: While the pandemic of coronavirus disease 2019 (COVID-19) is ongoing, the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been dominant recently. The Omicron variant causes more seizures in pediatric patients compared with previously circulated variants. This study aimed to investigate the incidence and clinical features of febrile seizure (FS) in pediatric patients with COVID-19 during the Omicron era. Methods: The medical records of pediatric patients (≤18 years of age) diagnosed with COVID-19, who presented with FS between February 2020 and June 2022, were reviewed retrospectively to analyze clinical characteristics of FS in seven university-affiliated hospitals of Korea. Results: Of 664 pediatric patients with COVID-19 during the study period, 46 during the pre-Omicron period and 589 during the Omicron period were included in the study analysis; 29 patients during the transition period were excluded. Among the included patients, 81 (12.8%) had concomitant FS, and most (76.5%) experienced simple FS. All FS episodes occurred during the Omicron period and none of them during pre-Omicron period (P=0.016). Sixty-five (80.2%) and 16 (19.8%) patients were categorized as FS (patient age ≤60 months) and late-onset FS (patient age >60 months), respectively. Underlying neurologic disease (P=0.013) and focal onset seizure (P=0.012) were more common in the late-onset FS group than in the FS group; however, overall clinical manifestations and outcomes including seizures consistent with characteristics of complex FS and subsequent epilepsy were similar between the two groups. Conclusions: As the COVID-19 pandemic persists, the incidence of FS has increased with the emergence of the Omicron variant. About one-fifth of the patients experiencing FS due to infection by the Omicron variant of SARS-CoV-2 were aged >60 months; however, clinical characteristics and outcomes were favorable. More information and long-term prognoses in patients with FS due to COVID-19 should be acquired.

Impact of COVID-19 on the incidence of respiratory viral infections and clinical characteristics of associated febrile seizures.

Background: Viral infections of the upper respiratory tract are one of the most common causes of febrile seizures (FSs). During the coronavirus disease-2019 (COVID-19) pandemic, mitigation measures have contributed to changes in the incidence of respiratory viral infections. Therefore, we aimed to evaluate the impact of the COVID-19 pandemic on the incidence of respiratory viral infections and clinical characteristics of FSs. Methods: We retrospectively reviewed the medical records of 988 episodes of FS (865 before the pandemic and 123 during the pandemic) between March 2016 and February 2022. Seizure characteristics and their outcomes, along with the distribution of identified respiratory viruses were compared before and during the pandemic. Results: The occurrence of FSs decreased during the COVID-19 pandemic compared to that before the pandemic. A substantial reduction in the incidence of influenza virus infections was observed (P<0.001) during the pandemic, while the incidence of rhinovirus infection was not significantly changed (P=0.811). Interestingly, a significantly high incidence of parainfluenza virus (P=0.001) infections was observed during the pandemic. No statistically significant between-group differences were observed in the clinical presentation and outcomes of FSs before and during the pandemic. Conclusions: Despite epidemiological changes in respiratory viral infections, the clinical characteristics and outcomes of FSs before and during the COVID-19 pandemic were comparable.

DHX30-Associated Neurodevelopmental Disorder with Severe Motor Impairment and Absent Language: First Korean Case in Two Siblings and Literature Review.

DHX30 variants have recently been reported in patients with neurodevelopmental disorders with severe motor impairment and absent language (NEDMIAL). We report the first Korean siblings presenting with NEDMIAL and previously unreported clinical features harboring a rare de novo DHX30 missense variant. The proband was a 10-year-old boy presenting with intellectual disability with severe motor impairment, absent language, facial dysmorphism, strabismus, sleep disturbances, and feeding difficulties. We performed whole-exome sequencing using genomic deoxyribonucleic acid isolated from buccal swabs, which revealed a heterozygous missense variant of DHX30: (c.2344C>T, p.Arg782Trp). Sanger sequencing was conducted for the proband, the affected sister, and each parent. The same variant was confirmed in two siblings but not in their parents, suggesting the possibility of de novo germline mosaicism.

The diagnostic values of red flags in pediatric patients with headache.

BACKGROUND: Headache is a common complaint in childhood and adolescence. Differentiating benign primary headaches from ominous secondary headaches is often difficult. Clinicians usually seek red flags to determine the need for neuroimaging. We aimed to evaluate the diagnostic values of red flags in pediatric headaches. METHODS: We retrospectively reviewed the medical records of 1510 pediatric patients (1470 with primary headache, 40 with secondary headache) presenting with headache and underwent neuroimaging from two centers between March 2010 and December 2019. RESULTS: The secondary-headache group exhibited significantly higher frequencies of abnormal neurologic signs/symptoms (40.0% vs 6.8%, p < 0.001), Valsalva maneuver/exercise-induced headache (15.0% vs 4.9%, p = 0.004), headache with vomiting (35.0% vs 17.9%, p = 0.006), and onset under age 6 (25.0% vs 10.3%, p = 0.003) than the primary-headache group, with the following positive likelihood ratio (PLR): 5.88, 3.06, 1.96, and 2.42, respectively. The sensitivity values were as follows: abnormal neurologic signs/symptoms (16/40, 40.0%), headache with vomiting (14/40, 35.0%), onset under age 6 (10/40, 25.0%), and Valsalva maneuver/exercise-induced headache (6/40, 15.0%). The overall sensitivity for ominous secondary headaches requiring surgical treatment was 86.2% (25/29). CONCLUSIONS: Certain red flags, including abnormal neurologic signs/symptoms, Valsalva maneuver/exercise-induced headache, headache with vomiting, and onset under age 6, were more prevalent in the secondary-headache group; nonetheless, their sensitivity values and PLR were relatively low. Notwithstanding, considering these red flags' high overall sensitivity for ominous secondary headaches, neuroimaging in patients presenting these red flags should rely on careful follow-up of symptom progression.

Clinical features and neuropsychiatric comorbidities in pediatric patients with tic disorders: a retrospective chart review study from South Korea.

BACKGROUND: Tic disorders are childhood-onset neuropsychiatric disorders characterized by multiple motor or vocal tics with frequent comorbidities and a broad spectrum of phenotypic presentations. In this study, we aimed to investigate the clinical characteristics and comorbid neuropsychiatric conditions in pediatric patients with tic disorders. METHODS: We retrospectively reviewed the medical records of 119 pediatric patients (89 males, 30 females) who were diagnosed with tic disorders according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) at Uijeongbu St. Mary's Hospital, Republic of Korea, between January 2012 and July 2019. RESULTS: The mean age of tic onset was 6.9 years (range, 1-14) and the mean age at diagnosis was 8 years (range, 1-17). The mean lag between tic onset and diagnosis was 13.3 months (range, 0.25-132). The most common, first-presenting tics were eye blinking (50.4%), followed by jaw or lip movement (29.4%) and throat clearing (29.4%). Thirty-seven (31.1%) patients had at least one co-occurring neuropsychiatric disorder at the time of tic diagnosis. Subtypes of tic disorders, types of initial tics, and presence of neuropsychiatric comorbidities were not associated with tic severity. Tic severity was associated with greater functional impairment and tic noticeability (p < 0.05). A relatively shorter time to diagnosis was associated with tic severity (Spearman's ρ = - 0.14, p = 0.11). CONCLUSIONS: The evolving nature of tic expression and severity, high prevalence of neuropsychiatric comorbidities, and associated functional impairments emphasize the importance of comprehensive assessment during the disease course for determining and prioritizing goals of treatment.

Coexistence of Growth Hormone Deficiency and Pituitary Microadenoma in a Child with Unique Mosaic Turner Syndrome: A Case Report and Literature Review.

Turner syndrome (TS) is a genetic disorder with phenotypic heterogeneity caused by the monosomy or structural abnormalities of the X chromosome, and it has a prevalence of about 1/2500 females live birth. The variable clinical features of TS include short stature, gonadal failure, and skeletal dysplasia. The association with growth hormone (GH) deficiency or other hypopituitarism in TS is extremely rare, with only a few case reports published in the literature. Here, we report the first case of a patient with mosaic TS with complete GH deficiency and pituitary microadenoma, and we include the literature review. During the work-up of the patient for severe short stature, three GH provocation tests revealed peak GH levels of less than 5 ng/mL, which was compatible with complete GH deficiency. Sella magnetic resonance imaging showed an 8 mm non-enhancing pituitary adenoma with mild superior displacement of the optic chiasm. Karyotyping revealed the presence of ring chromosome X and monosomy X (46,X,r(X)/45,X/46,X,psu dic r(X;X)), which indicated a mosaic TS. It is important to consider not only chromosome analyses in females with short stature, but also the possibility of the coexistence of complete GH deficiency accompanying pituitary lesions in TS. In conclusion, the present study reports the first case of GH deficiency and pituitary adenoma in a patient with rare mosaic TS, which extends the genotype-phenotype spectrum for TS.

Unrelated donor hematopoietic stem cell transplantation for pediatric de novo acute myeloid leukemia with intermediate- or high-risk cytogenetics.

The role of unrelated donor HSCT for children with de novo AML in CR1 is controversial. We performed this study to investigate the feasibility of unrelated donor HSCT who initially had intermediate- or high-risk cytogenetics. We retrospectively reviewed medical records of patients with AML who received unrelated HSCT in CR1 at Samsung Medical Center between November 2001 and January 2012. Patients were allocated based on karyotype at diagnosis as follows: (a) low-risk: inv(16), t(16;16), t(8;21), and t(15;17); (b) high-risk: -5, 5q-, -7, 3q abnormalities, t(8;16), t(6;9), t(6;11), t(6;21), t(10;11), complex karyotype (≥3 abnormalities), and acute megakaryocytic leukemia without t(1;22); and (c) IR: all the other karyotypes including normal. Patients in intermediate- or high-risk group who were transplanted with either unrelated CB or matched unrelated BM/mobilized PB in their CR1 were included in this study. The projected OS and EFS rates were 74.9% and 71.1%, respectively, with a median follow-up of 87.3 months after transplantation. The EFS was 70.1%, 80.7%, and 73.9% for CB, BM, and mobilized PB groups, respectively (P = 0.89), and 73.9% and 70.6% for IR and high-risk groups (P = 0.76). The leading cause of death was relapse (n = 8), and only one patient died from non-relapse cause. Unrelated donor HSCT seems a feasible approach for children with intermediate- or high-risk AML in CR1. Relapse remains the leading cause of treatment failure among these patients.

The ketogenic diet for super-refractory status epilepticus patients in intensive care units.

OBJECTIVES: Super-refractory status epilepticus (SRSE) is one of the most challenging issues in intensive care units (ICUs) in that it is associated with high morbidity and mortality. Although the ketogenic diet (KD) has been reported to be effective in treating of SRSE, the use of the diet as therapy can be complicated by concomitant medical problems specific to critically ill patients. In this study, we aimed to describe our experience of the KD for SRSE patients in ICUs. METHODS: We retrospectively reviewed the medical records of 16 patients (10 males, 6 females) with SRSE who were treated with the KD in the ICUs at Samsung Medical Center from July 2005 to July 2017. RESULTS: The median age of seizure onset was 8 years (interquartile range 5-13.5). Prior to diet initiation, the patients were in convulsive or non-convulsive SRSE for a median of 23 days (range, 3-420). The median time to achieve ketosis was 3 days (range, 2-6). The KD was continued for a median of 2.1 months (range, 0.1-15.8). Of the 16 patients, nine (56.3%) achieved seizure freedom, six (37.5%) reported >50% seizure reduction, and one (6.2%) had <50% seizure improvement after the KD. There was no significant change in the number of antiepileptic drugs. The most commonly encountered complication during the KD was gastrointestinal disturbance. CONCLUSIONS: Our experience indicates that the KD is an effective alternative therapeutic strategy for SRSE patients in ICUs with adequate efficacy and safety in reducing seizure frequency and weaning from prolonged mechanical ventilation, although functional outcome was not favorable for most patients. Close monitoring and preventive management of potential adverse effects are critical elements for success with the KD in patients with SRSE.

Use of the Modified Atkins Diet in Intractable Pediatric Epilepsy.

BACKGROUND AND PURPOSE: The modified Atkins diet is a less restrictive alternative to the ketogenic diet (KD), allowing unlimited protein, fat, calories, and fluid intake. Moreover, it can be started on an outpatient basis without requiring a fast. This study evaluated the efficacy, tolerability, and compliance of the modified Atkins diet in intractable pediatric epilepsy. METHODS: We retrospectively reviewed the medical records of 26 pediatric patients (10 males and 16 females) with intractable epilepsy who were treated using the modified Atkins diet at Samsung Medical Center from January 2011 to March 2017. RESULTS: The mean age at initiation of the modified Atkins diet was 10.9 (range, 2-21) years. The diet was continued for a mean duration of 5.9 (range, 1-16) months. After 6 months, 10 (38.5%) remained on the diet, of whom six (60%) had > 50% seizure reduction and two (20%) became seizure free. Four of 26 patients (15.4%) reported side effects of the diet, including constipation (n = 2) and lipid profile elevations (n = 2). Mean body mass index (BMI) was reduced from 22.6 to 20.9 kg/m2 (p < 0.05) in 13 patients who continued the diet for ≥ 3 months. Four of these patients (30.8%) were overweight (BMI > 25 kg/m2) before initiating the diet and were satisfied with their BMI changes from a mean of 30.3 to 27 kg/m2 (p < 0.05). Food refusal (n = 3) and poor parental compliance (n = 3) were the common reasons cited for cessation. CONCLUSIONS: The modified Atkins diet may be an alternative treatment option for children with intractable epilepsy who are unable to tolerate KD because of food intake-related restrictiveness or adverse effects. The continuous support of healthcare professionals and families plays a key role in diet maintenance.

Anti-NMDAR Encephalitis in a 13-Year-Old Female: A 24-Month Clinical Follow-Up.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare autoimmune disorder manifesting as seizures, movement disorders, and psychiatric changes. However, there have been few case reports concerning this disorder in South Korean children. The current case report describes a pediatric patient with anti-NMDAR encephalitis. A 13-year-old female patient developed clonic movements of the right arm followed by aphasia, paresthesia, and right-sided hemiparesis. The electroencephalogram (EEG) results indicated electroclinical seizures arising from the left temporal area. Brain magnetic resonance imaging (MRI) revealed high signal intensity and cortical swelling in left temporal lobe. Anti-NMDAR antibodies were detected in the cerebrospinal fluid (CSF). The patient was treated with intravenous immunoglobulin and high-dose methylprednisolone and showed partial improvement in language skills, paresthesia, and motor power. The brain MRI and EEG results also indicated improvement. However, anti-NMDAR antibodies persisted in the CSF. After four doses of rituximab, the patient exhibited complete recovery of language and motor skills, and was seizure free under treatment with antiepileptic medication. There were no residual anti-NMDAR antibodies in the CSF at her 24-month follow-up visit. This case report elucidates the benefits of early intervention using rituximab to improve neurological deficits and achieve baseline recovery in patients with anti-NMDAR encephalitis.

Desensitization to Oxcarbazepine: Long-Term Efficacy and Tolerability.

BACKGROUND AND PURPOSE: Antiepileptic drug (AED)-associated cutaneous adverse drug reactions can lead to the discontinuation of medications. The aim of this study was to determine the long-term efficacy and safety of performing desensitization to oxcarbazepine. METHODS: This study involved 20 patients who exhibited cutaneous adverse drug reactions associated with oxcarbazepine use between July 2009 and March 2016 at Samsung Medical Center. All of the participants had to discontinue oxcarbazepine despite presenting initially positive responses. Human leukocyte antigen genotyping was performed to detect the genetic predisposition to Stevens-Johnson syndrome. The desensitization to oxcarbazepine was performed with a starting dosage of 0.1 mg/day. Efficacy was evaluated by comparing the frequency of seizures before and at 1 and 3 years after desensitization. Adverse events occurring during desensitization and the retention rate after desensitization were also investigated. RESULTS: Nineteen patients (95%) safely completed the desensitization protocol. One withdrew owing to emotional problems that appeared to be associated with oxcarbazepine. The follow-up period was 4.6±1.2 years (mean±SD), and oxcarbazepine was maintained for more than 3 years after desensitization in 15 patients (83.3%). The response rates were 84.2% and 77.8% at 1 and 3 years after desensitization, respectively. Eight patients remained seizure-free for 3 years, and two discontinued all AEDs. Transient adverse reactions such as mild rash and itching were reported by five patients during desensitization. CONCLUSIONS: This study has demonstrated the long-term efficacy and safety of desensitization to oxcarbazepine in patients exhibiting cutaneous adverse drug reactions. This favorable outcome should encourage the implementation of desensitization in patients presenting with hypersensitivity to oxcarbazepine as an alternative strategy in clinical practice.

First Korean Case of Infantile Hypophosphatasia with Novel Mutation in ALPL and Literature Review.

Hypophosphatasia is a rare hereditary disorder characterized by defective bone and tooth mineralization and deficiency of tissue non-specific alkaline phosphatase activity. The prognosis for the infantile form is poor, with approximately 50% of patients dying within the first year of life from respiratory failure. We describe the clinical and biochemical findings as well as the molecular analysis of a Korean boy with infantile hypophosphatasia and present a literature review. A 1-month-old boy visited the clinic because of poor feeding, frequent vomiting, hypotonia, and failure to thrive from birth. Laboratory tests revealed high total calcium, low phosphorous, low alkaline phosphatase, low parathyroid hormone, and normal 25-hydroxyvitamin D. Intravenous hydration with normal saline was started, and dietary calcium intake was restricted. Skeletal X-rays showed a markedly increased distance of the anterior fontanelle, impaired mineralization, and rachitic changes in the metaphyses. By Sanger sequencing of the ALPL gene, we identified two heterozygous variants, including a missense (c.334G>A; p.Gly112Ser) and a nonsense (c.1039C>T; p.Gln347*) variant. The c.334G>A (p.Gly112Ser) variant had previously been reported in a patient with lethal type hypophosphatasia, while the nonsense c.1039C>T (p.Gln347*) variant was novel. In the current case, the accurate diagnosis and prompt intervention-including dietary calcium intake restriction, tracheostomy to prevent progression to respiratory failure, and fundoplication with gastrostomy to ensure the administration of adequate calories-seemed to play an important role for avoiding preventable morbidity and premature mortality.

Narcolepsy in a three-year-old girl: A case report.

OBJECTIVE: Narcolepsy is characterized by excessive daytime somnolence associated with sleep paralysis, hallucinations when falling asleep or awakening, and cataplexy. Early recognition of pediatric narcolepsy is essential for growth and development. We experienced a case of narcolepsy in a three-year-old girl. METHODS: The patient underwent brain MRI and 24h video-electroencephalogram (EEG) monitoring. Polysomnography (PSG) with multiple sleep latency test (MSLT) and human leukocyte antigen (HLA) DQ typing was performed. RESULTS: The brain MRI was normal. 24h video-EEG monitoring revealed no abnormal slow or epileptiform discharge on interictal EEG, and no EEG change during tongue thrusting, dropping head with laughter, or flopping down, which was consistent with cataplexy associated with narcolepsy. A mean sleep latency of 2.5 min and four episodes of sleep-onset REM periods in five naps were observed in PSG with MSLT. She was positive in HLA-DQB1*0602. Based on these findings, she was diagnosed as narcoleptic with cataplexy. CONCLUSION: The history, combined with PSG and MSLT, was helpful in the diagnosis of narcolepsy. We report a case of early-onset narcolepsy presenting with excessive sleepiness and cataplexy.

Paroxysmal nonepileptic events in pediatric patients.

OBJECTIVES: Paroxysmal nonepileptic events (PNEs) are frequently encountered phenomena in children. Although frequencies and types of PNEs have been extensively studied in adult populations, the data available for children and adolescents are limited, especially in patients without underlying neurologic disorders. In this study, we evaluated and compared the characteristics of PNEs between age groups and according to the presence of neurologic deficits to improve early detection and diagnosis of PNEs. METHODS: We retrospectively reviewed 887 pediatric patients who were admitted to the epilepsy monitoring unit at the Samsung Medical Center between December 2001 and July 2014. One hundred and forty-one patients (15.9%) were diagnosed as having PNEs on the basis of their clinical history and long-term video-electroencephalography (EEG) monitoring (VEM). RESULTS: Children with PNEs were divided into three groups by age: 1) the infant, toddler, and preschool group (<6 years, N=50, 35.5%); 2) the school-age group (6-<12 years, N=30, 21.3%); and 3) the adolescent group (12-<18 years, N=61, 43.3%). Physiologic disorders, such as normal infant behavior, sleep movement, and staring, were more common in patients younger than 6 years of age, whereas psychogenic nonepileptic seizures were predominant in patients older than 6 years. Vasogenic syncope was also frequently observed in the adolescent group and was confirmed by the head-up tilt test. There was no significant difference in specific PNE types between the groups of patients with or without neurologic deficits. CONCLUSIONS: Physiologic symptoms were predominant in the younger age group, whereas psychogenic nonepileptic seizures were observed in older age groups more often. Clinical pattern recognition by age plays an important role in clinical practice, because pediatric patients present various types of PNEs with age-specific patterns. Considering various and inconsistent presentations and the importance of correct diagnosis, long-term VEM can be helpful in diagnosing normal infant behavior and psychogenic nonepileptic seizures.

'Neisseria skkuensis' sp. nov., isolated from the blood of a diabetic patient with a foot ulcer.

A Gram-negative bacterium was isolated from the blood of a patient with diabetes mellitus. However, it could not be identified by conventional microbiological methods, and so was characterized by phenotypic and genotypic analyses. 16S rRNA gene sequence analysis revealed that the strain belonged to the genus Neisseria. Based on the phenotypic and genotypic characteristics, we propose that strain SMC-A9199(T) (=KCTC 22696(T)=JCM 16127(T)) should be classified as a novel species, 'Neisseria skkuensis' sp. nov. The patient was further treated with amoxicillin-clavulanate and ciprofloxacin for 3 weeks.