A Mild Form of COG5 Defect Showing Early-Childhood-Onset Friedreich's-Ataxia-Like Phenotypes with Isolated Cerebellar Atrophy.

Progressive cerebellar ataxias are rare diseases during childhood, especially under 6 years of age. In a single family, three affected siblings exhibited Friedreich's-ataxia-like phenotypes before 2 years of age. They had progressive cerebellar atrophy, intellectual disability, and scoliosis. Although their phenotypes were similar to those observed in patients with autosomal recessive cerebellar ataxias, other phenotypes (e.g., seizure, movement disorders, ophthalmologic disturbance, cardiomyopathy, and cutaneous disorders) were not noted in this family. Whole-exome sequencing of the family members revealed one potential heterozygous mutation (c.1209delG, NM_181733.2; p.Met403IlefsX3, NP_859422.2) of the gene encoding conserved oligomeric Golgi complex subunit 5 (COG5). The heterozygous deletion at the fifth base in exon 12 of COG5 caused a frameshift and premature stop. Western blotting of COG5 proteins in the skin tissues from an affected proband showed a significantly decreased level of full length COG5 and smaller, aberrant COG5 proteins. We reported a milder form of COG5 defect showing Friedreich's-ataxia-like phenotypes without hypotonia, microcephaly, and short stature that were observed in most patients with COG5 defect.

Advance organizers in a gross anatomy dissection course and their effects on academic achievement.

We presented two kinds of advance organizers (AOs), video clips and prosection, for a gross anatomy dissection course and compared their effects on academic achievement and student perception of the learning experience. In total, 141 students at Chonnam National University Medical School were randomly assigned to two groups: Group 1 (n = 70) was provided with video clips AO, whereas Group 2 (n = 71) was provided with prosection AO, the use of cadaveric specimens dissected by the course instructor. Student self-assessment scores regarding the learning objectives of upper limb anatomy improved significantly in both groups. Academic achievement scores in Group 2 were significantly higher than those in Group 1, although the self-assessment scores were not significantly different between the groups. Additionally, students in Group 2 responded significantly more positively to the statements about perception of the learning experience such as helping them understand the course content and concepts, decreasing anxiety about the dissection course, and participating actively in the dissection. It would seem that the application of prosection as an AO improved academic achievement and increased student engagement and satisfaction. This study will contribute to designing effective AOs and developing a teaching and learning strategy for a gross anatomy dissection course.

Neurologic adverse events following influenza A (H1N1) vaccinations in children.

BACKGROUND: Since the monovalent pandemic influenza A (H1N1) vaccine was recommended worldwide in October 2009, there has been a shortage of pediatric clinical data for post-vaccine neurologic adverse events (NAE), including Guillain-Barré syndrome. We reviewed pediatric NAE data following H1N1 vaccinations and for patients with peripheral neuropathy, we followed their progress. METHODS: In our single-center study, we retrospectively reviewed 14 cases of children who visited the Division of Pediatric Neurology in the Department of Pediatrics of Chonnam National University Hospital due to NAE following monovalent influenza A (H1N1) vaccination between November 2009 and March 2010. RESULTS: Clinical diagnoses for major NAE included: polyneuropathy in the extremities (11/14, 78.6%), sensory mononeuropathy with numbness in the left fibula area (1/14, 7.1%), Bell's palsy (1/14, 7.1%) and recent-onset acute headache only (1/14, 7.1%). Therefore, most patients were diagnosed as having peripheral neuropathy (13/14, 92.9%), and two met the Brighton Collaboration Guillain-Barré syndrome definition criteria for level 3 (the lowest level of diagnostic certainty). CONCLUSIONS: Post-vaccine NAE were mainly motor weakness due to polyneuropathy, which had a good prognosis of complete improvement within a few months without sequelae.

Prevalence of primary immunodeficiency in Korea.

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Clinical Significance of Gray to White Matter Ratio after Cardiopulmonary Resuscitation in Children.

Cardiopulmonary resuscitation (CPR) successfully restores systemic circulation approximately 50% of the time; however, many successfully restored patients have severe neurologic damage. In adults, the gray matter to white matter attenuation ratio (GWR) in brain computed tomography (CT) correlates with the neurologic outcome. However, in children, the clinical significance of GWR still remains unclear. The aim of this study was to evaluate the clinical characteristics of children who underwent CPR for cardiac arrest according to the survival and to demonstrate the differentiation of grey/white matter by Hounsfield units of brain CT and to characterize the attenuations of grey and white matters. METHODS: This is a retrospective single-center study. We enrolled those who underwent brain CT within 24 h after return of spontaneous circulation (ROSC) from January 2005 to June 2018. Brain CTs were taken within 24 h of ROSC. We measured the attenuation of grey and white matter in Hounsfield units and calculated GWR. They were compared with healthy controls. Patients were analyzed as follows: survivors vs. non-survivors and better neurologic outcome vs. worse neurologic outcome. RESULTS: Among 100 pediatric patients who had CPR, 56 met inclusion criteria. There were 24 patients who survived and 32 non-survivors. Our study revealed that the incidence of seizure, duration of CPR, and instances of hypothermia were significantly different between survivors and non-survivors. In both survivors and non-survivors, the attenuation of the caudate nucleus, putamen, GWR-basal ganglia, and average GWR were significantly different from controls. In regression analyses, the medial cortex and average GWR were the significant variables to predict survival, and the receiver operating curves revealed areas under curve of 0.733 and 0.666, respectively. Also, the medial cortex 1 was the only variable that predicted the neurologic outcome. CONCLUSIONS: There was some predictive survival value of GWR and medial cortex at the centrum semiovale level in early brain CT within 24 h after cardiac arrest. Although we could not find the predictive value of GWR in the neurologic outcome of pediatric patients, we found that the absolute attenuation of the medial cortex was low in patients with worse neurologic outcomes. Further prospective, multicenter studies are needed to determine the predictive value of GWR and the medial cortex.

Increased expression of L-amino acid transporters in balloon cells of tuberous sclerosis.

OBJECTS: Tuberous sclerosis complex (TSC) is a dysgenetic syndrome involved in multiple organs, and the pathognomonic cortical tuber act as an epileptic substrate. The amino acid transport system L (LAT) is a major nutrient transport system, and LAT1 is highly expressed in malignant tumors to support tumor cell growth. To study the life-long epilepsy from the cortical tuber, the expression of LAT1 in balloon cells and dysplastic neurons of the cortical tuber is investigated. MATERIALS AND METHODS: LAT1 expression was investigated by LAT1 mRNA using reverse transcription-polymerase chain reaction and immunohistochemical staining with anti-human LAT1 antibody in nine patients with TSC and three control brains. CONCLUSION: LAT1 mRNA was detectable only in fresh-frozen tissues of TSC, and it was upregulated in the cortical tuber lesion. While the LAT1 immunopositivity of control brains was limited in the capillary endothelial cells in the gray matter, increased LAT1 immunopositivity was noted in balloon cells of the cortical tubers in addition to the capillary endothelial cells as shown in control brains. Linear and strong immunopositivity along the cell membrane and cytoplasm of the balloon cells, and weakly granular immunopositivity in their cytoplasm were noted. Increased expression of LAT1 in the balloon cells is important for the active transport of large neutral amino acids into the balloon cells, and that the biologic process may play an important role in the active protein synthesis with metabolic maintenance of balloon cells in cortical tubers of patients with TSC.

Influenza-associated Neurologic Complications in Hospitalized Pediatric Patients: A Multicenter Retrospective Study in Republic of Korea.

BACKGROUND: The rates of influenza-associated neurologic complications are variable among studies, and a difference has been observed between the Western and Asian countries. The study aims to evaluate the frequency and characteristics of influenza-associated neurologic complications. METHODS: We performed a retrospective review of hospitalized cases of influenza infection from October 2010 to April 2017 from 3 referral hospitals. RESULTS: A total of 1988 influenza cases were identified. Influenza-associated neurologic complications were 161 cases (8.1%); influenza virus A was detected in 113 (70.2%) cases, B in 47 (29.2%) cases and both A and B in 1 case (0.6%). Twenty-four patients (15%) had underlying neurologic diseases. The most common diagnosis was a simple febrile convulsion (44%), followed by complex febrile convulsion (29%), fever-provoked seizure under pre-existing neurologic disease or afebrile seizure (14%), encephalopathy/encephalitis (8%) and meningitis (5%). Most of the patients fully recovered (96%). Three patients (1.9%) died of myocarditis (n = 1), encephalopathy (n = 1), and simultaneous encephalitis and myocarditis (n = 1). Pre-existing neurologic disease, age groups of 6 months to 6 years and 6-12 years were a risk factor of influenza-associated neurologic complications with an adjusted odds ratio of 5.41 (95% confidence interval [CI] 3.23-9.06, P < 0.001), 12.99 (95% CI 1.77-95.19, P = 0.01) and 8.54 (95% CI 1.14-64.79, P = 0.04), respectively. There was no association between neuropsychiatric adverse events and oseltamivir prescription (P = 0.17). CONCLUSIONS: Influenza-associated neurologic complications are not uncommon, and most patients fully recovered. The frequency of influenza-associated neurologic complications in Korean children was not significantly different from that of children in Western countries.

Neurotoxicity screening in a multipotent neural stem cell line established from the mouse brain.

Neural stem cells (NSCs) have mainly been applied to neurodegeneration in some medically intractable neurologic diseases. In this study, we established a novel NSC line and investigated the cytotoxic responses of NSCs to exogenous neurotoxicants, glutamates and reactive oxygen species (ROS). A multipotent NSC line, B2A1 cells, was established from long-term primary cultures of oligodendrocyte-enriched cells from an adult BALB/c mouse brain. B2A1 cells could be differentiated into neuronal, astrocytic and oligodendroglial lineages. The cells also expressed genotypic mRNA messages for both neural progenitor cells and differentiated neuronoglial cells. B2A1 cells treated with hydrogen peroxide and L-buthionine-(S,R)-sulfoximine underwent 30-40% cell death, while B2A1 cells treated with glutamate and kainate showed 25-35% cell death. Cytopathologic changes consisting of swollen cell bodies, loss of cytoplasmic processes, and nuclear chromatin disintegration, developed after exposure to both ROS and excitotoxic chemicals. These results suggest that B2A1 cells may be useful in the study of NSC biology and may constitute an effective neurotoxicity screening system for ROS and excitotoxic chemicals.

Familial glucocorticoid deficiency with a point mutation in the ACTH receptor: a case report.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by severe glucocorticoid deficiency associated with failure of adrenal responsiveness to ACTH but no mineralocorticoid deficiency. We report a 2 month-old boy of nonconsanguineous parents, presented with hyperpigmentation. Physical examination showed diffuse dark skin of body including, oral mucosa, gum, hands, nails and scrotum. Laboratory evaluation revealed low serum cortisol (0.3 microg/dL), with very high plasma ACTH level (18,000 pg/mL), and serum cortisol level did not increase after ACTH stimulation test. Serum sodium, potassium, plasma renin activity, aldosterone and 17-hydroxyprogesterone were normal. Sequence analysis of the ACTH receptor (MC2R) gene showed a homozygous mutation of D103N. Diagnosis of FGD was made and treatment started with oral hydrocortisone.

Pathophysiologic characteristics of balloon cells in cortical dysplasia.

OBJECTS: Balloon cells are histopathological hallmarks of cortical malformations, i.e., focal cortical dysplasia (FCD) of the Taylor type or the cortical tubers of tuberous sclerosis, and they are believed to be the epileptogenic substrate and cause therapeutic drug resistant epilepsy in man. This study was carried out to investigate the developmental histogenesis and epileptogenesis of balloon cells in FCD. MATERIALS AND METHODS: We used an immunohistochemical approach to examine the expressions of primitive neuroepithelial cell antigens (CD34, nestin, and vimentin), ionotrophic glutamate receptor subunits (NR1, NR2A/B, GluR1, GluR2, GluR3, GluR4, and GluR5/6/7), and P-glycoprotein in balloon cells from FCD and normal cerebral cortex epileptogenic lesions. CONCLUSION: Balloon cells presented in clusters or as scattered cells throughout FCD lesions involving the gray and white matter. We found the balloon cells to be classifiable into three subtypes based on glial fibrillary acidic protein (GFAP) and neurofilament protein (NF-L) immunohistochemistry, i.e., as neuronal, astrocytic, and uncommitted. Immunopositivity for nestin, CD34, and vimentin in balloon cells of FCD suggests that they may be derived from the abnormal development and differentiation of neural stem cells. Moreover, it appears that epileptogenesis in cortical dysplasia is partly caused by the upregulations of some glutamate receptor subunit proteins (NR1, NR2A/B, GluR1, and GluR3) in balloon cells and dysplastic neurons. We speculate that the presence of the drug resistance protein P-glycoprotein in balloon cells might explain medically refractory epilepsy in FCD.

Incidence and characteristics of norovirus-associated benign convulsions with mild gastroenteritis, in comparison with rotavirus ones.

BACKGROUND AND PURPOSE: Rotavirus was detected in 40-50% of patients with benign convulsions with mild gastroenteritis (CwG) before the rotavirus vaccine was introduced in late 2000. However, the rate of rotavirus positivity has decreased since 2010 while the prevalence of norovirus has gradually increased. We investigated the incidence of norovirus-associated CwG during a recent 3-year period and additionally compared the characteristics of norovirus-associated CwG with those of rotavirus-associated CwG. METHODS: The medical records of CwG patients admitted to our hospital between March 2014 and February 2017 were reviewed, including the results of stool virus tests. For comparing norovirus- and rotavirus-associated CwG, data obtained between March 2005 and February 2014 that included sufficient numbers of patients with rotavirus-associated CwG were additionally reviewed. Data were collected on clinical characteristics (age, sex, seasonal distribution, enteric symptoms, and the interval to seizure onset), seizure characteristics (frequency, duration, type, and electroencephalographic findings), and laboratory findings. RESULTS: CwG was diagnosed in 42 patients during the 3-year study period. Stool viruses were checked in 40 (95.2%) patients and were detected in 32 (80.0%) patients. Norovirus genogroup II was detected in 27 (67.5%) of the 40 patients, rotavirus was detected in 3 patients, and adenovirus was detected in 2 patients. In total, 140 CwG patients were enrolled between March 2005 and February 2017. The patients with norovirus-associated CwG (N = 44) and rotavirus-associated CwG (N = 26) were aged 18.66 ±â€¯5.57 and 19.31 ±â€¯7.37 months (mean ±â€¯standard deviation), respectively (P > 0.05). Norovirus-associated CwG was less prevalent than rotavirus-associated CwG during spring (13.6% vs. 34.6%, P = 0.04), while the prevalence of both types of CwG peaked during winter (63.6% and 46.2%, respectively). Vomiting was more prevalent in norovirus- than rotavirus-associated CwG (97.7% vs. 80.8%, P = 0.02) and the interval between enteric symptom onset and seizure onset was shorter in norovirus-associated CwG (2.00 ±â€¯1.06 vs. 2.58 ±â€¯1.21 days, P = 0.04). Most cases in both groups had seizures that lasted for less than 5 min (95.5% vs. 92.3%). Clustered seizures seemed to occur more frequently in the norovirus group (79.5% vs. 57.7%), although with borderline significance (P = 0.05). Posterior slowing was observed more frequently in norovirus-associated CwG (34.9% vs. 11.5%, P = 0.03). CONCLUSION: The most common viral pathogen of CwG was norovirus during the analyzed 3-year period, with an incidence of 67.5%. In comparison with rotavirus-associated CwG, norovirus-associated CwG was less frequent during spring, more frequently seen with vomiting, had a shorter interval from enteric symptom onset to seizure onset, and more frequently showed posterior slowing in electroencephalography.

Moyamoya syndrome in a child with trisomy 12p syndrome.

A female, 2 years and 7 months of age, was admitted to the hospital with stupor and nystagmus following projectile vomiting. She had been prenatally diagnosed with trisomy 12p with a familial pericentric inversion of chromosome 12 originating from her mother. She manifested developmental delay and some dysmorphic features of the face and limbs compatible with the clinical features of trisomy 12p. Four-vessel cerebral angiography revealed severe stenosis and occlusion of the supraclinoid portion of the right and left internal carotid arteries with numerous collateral vessels in the vicinity of the occlusion. These features are consistent with moyamoya syndrome. This report presents the first case of moyamoya syndrome with trisomy 12p with a familial pericentric inversion of chromosome 12.

Single nucleotide polymorphisms in the multidrug resistance 1 gene in Korean epileptics.

PURPOSE: P-glycoprotein 170 encoded by the multidrug resistance 1 (MDR1) gene exports various antiepileptic drugs out of the CNS, which leads to multidrug resistance. This study was performed to elucidate the relationship between single nucleotide polymorphisms (SNPs) in the MDR1 gene and drug resistance in Koreans with epilepsy. SUBJECTS AND METHODS: Three SNPs at nucleotide position 1236 in exon 12, 2677 in exon 21 and 3435 in exon 26 of the MDR1 gene were genotyped in 207 Korean epileptics. Subjects were classified according to whether they had drug-resistant (RS group; N=99) or drug-responsive epilepsy (RP group; N=108). The frequencies of genotype and haplotype were compared between the RS and RP groups. RESULTS: The frequencies of genotype and haplotype in the RS group were not statistically different from those in the RP group. CONCLUSIONS: In Korean epileptics, there was no significant relationship between three known SNPs in MDR1 and drug resistance. And there was no association of MDR1 haplotype based on above three sites with pharmacoresistance.

The relationship between medical students' epistemological beliefs and achievement on a clinical performance examination.

PURPOSE: This study was to explore the relationship between clinical performance examination (CPX) achievement and epistemological beliefs to investigate the potentials of epistemological beliefs in ill-structured medical problem solving tasks. METHODS: We administered the epistemological beliefs questionnaire (EBQ) to fourth-year medical students and correlated the results with their CPX scores. The EBQ comprised 61 items reflecting five belief systems: certainty of knowledge, source of knowledge, rigidity of learning, ability to learn, and speed of knowledge acquisition. The CPX included scores for history taking, physical examination, and patient-physician interaction. RESULTS: The higher epistemological beliefs group obtained significantly higher scores on the CPX with regard to history taking and patient-physician interaction. The epistemological beliefs scores on certainty of knowledge and source of knowledge were significantly positively correlated with patient-physician interaction. The epistemological beliefs scores for ability to learn were significantly positively correlated with those for history taking, physical examination, and patient-physician interaction. CONCLUSION: Students with more sophisticated and advanced epistemological beliefs stances used more comprehensive and varied approaches in the patient-physician interaction. Therefore, educational efforts that encourage discussions pertaining to epistemological views should be considered to improve clinical reasoning and problem-solving competence in the clinic setting.

Familial pachygyria in both genders related to a DCX mutation.

Doublecortin (DCX) and tubulin play critical roles in neuronal migration. DCX mutations usually cause anterior dominant lissencephaly in males and subcortical band heterotopia (SBH) in females. We used whole-exome sequencing to investigate causative gene variants in a large family with late-childhood-onset focal epilepsy and anterior dominant pachygyria without SBH in both genders. Two potential variants were found for the genes encoding DCX and beta tubulin isotype 1 (TUBB1). The novel DCX mutation (p.D90G, NP_000546.2) appeared to be a major causative variant, whereas the novel mutation of TUBB1 (p.R62fsX, NP_110400.1) was found only in patients with more-severe intellectual disability after gender matching. We report an unusual DCX-related disorder exhibiting familial pachygyria without SBH in both genders.

A novel PIGA mutation in a family with X-linked, early-onset epileptic encephalopathy.

Early-onset epileptic encephalopathies (EOEEs) are severe and intractable infantile-onset epilepsies with progressive intellectual disability and other associated neurologic comorbidities. Whole-exome sequencing (WES) was recently used to determine the causative gene mutations in individuals with unclassified EOEEs. The present study used WES to determine the causative variant in a family with X-linked, EOEE. One potential variant (c. 427A>G, NM_002641.3; p.Lys143Glu, NP_002632.1) of the gene encoding phosphatidylinositol glycan biosynthesis class A protein (PIGA; PIGA) was found, which was verified by Sanger sequencing. The functional effect of this PIGA mutation was assessed by the surface expression levels of glycosylphosphatidylinositol-anchored proteins on blood cells: CD16 on red blood cells was significantly decreased in the proband (by 11.0%) and his mother (by 15.6%). This is the second report of a less-severe form of PIGA deficiency.

Characteristics of brain magnetic resonance images at symptom onset in children with moyamoya disease.

OBJECTIVES: To clarify the characteristics of brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at symptom onset in patients with childhood moyamoya disease (MD) according to developmental stage. METHODS: In 26 childhood MD patients who underwent brain MRI and MRA within 3 months from symptom onset, MRA scores and grades and MRI findings from symptomatic hemispheres were summarized according to developmental stage: infancy (0-1 years, three patients), toddlerhood/preschool age (2-5 years, nine patients), school age (6-10 years, seven patients), and adolescence (11-18 years, seven patients). RESULTS: Mean MRA score was 5.6, which was higher in adolescents (6.9). The most common MRA grade was grade 3, particularly in those under 10 years. Acute ischemic infarction presented in 17 patients (65%), was more common in patients below 5 years (83%) and was mainly in a gyral pattern (47%). Most hemorrhagic infarctions occurred in adolescents. Moyamoya vessels in the Sylvian valleys were apparent in 22 patients (85%), which were the most sensitive non-ischemic findings on T2 weighted images. The signal void in the distal internal carotid artery was diminished in 73% and apparent signal voids in basal ganglia were seen in three patients. The ivy sign was positive in 81% on fluid attenuated inversion recovery images and 69% on contrast-enhanced T1-weighted images in 21 and 16 patients, respectively. CONCLUSIONS: Brain MRIs and MRAs at symptom onset in childhood MD have characteristic findings, which differ in different developmental stage.

Incidence of benign convulsions with mild gastroenteritis after introduction of rotavirus vaccine.

BACKGROUND AND PURPOSE: Rotavirus was the most common virus in benign convulsions with mild gastroenteritis (CwG), with an incidence of 40-50%. As rotavirus gastroenteritis has decreased since introduction of rotavirus vaccine, we investigated the incidence of CwG and rotavirus positivity after introduction of the vaccine. METHODS: We retrospectively reviewed the medical records of 987 patients aged between 3months and 3years who were admitted to the Chonnam National University Hospital between March 2005 and February 2014 due to their first seizures and enrolled 102 patients with CwG. The incidences of CwG among seizure patients and stool rotavirus positivity in CwG patients were compared between two periods: period I (March 2005-February 2010) and period II (March 2010-February 2014). Other viruses in stools were also reviewed. RESULTS: The incidence of CwG were 8.47% (45 among 531 patients) in period I and 12.50% (57 among 456 patients) in period II (P=0.018). Stool rotavirus was checked in 85.29% (87 patients): 82.22% (37 patients) in period I and 87.72% (50 patients) in period II (P=0.166). The positivity of rotavirus was 40.54% (15 patients) in period I and 16.00% (8 patients) in period II (P=0.01). In the patients without rotavirus gastroenteritis, 30 patients were test for other viruses. Norovirus was the most common (56.67%, 17 patients) and was more frequent in period II than I (71.43% versus 22.22%, P=0.018). CONCLUSION: After introduction of rotavirus vaccine, rotavirus-associated CwG has decreased but the incidence of CwG has increased due to an increase of norovirus.