Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

Purpose@#Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of disorders characterized by impaired neuromuscular transmission. This study aims to provide the clue for early diagnosis and improved therapeutic strategies in CMS. @*Materials and Methods@#Through the targeted panel sequencing including twenty CMS causative genes, eleven patients were genetically confirmed and enrolled in this study. A retrospective medical record review was carried out for the clinical and laboratory data analysis. @*Results@#The age of patients ranged from 5 to 23 years, with the median age of 16 years. The peak age at onset of symptoms was the neonatal period. Seven out of the eleven patients were symptomatic at birth. The most commonly reported initial finding was generalized hypotonia with poor sucking and crying. Mean time to accurate diagnosis was 9.3±5.0 years. Total fifteen different variants in seven genes associated with CMS (DOK7, AGRN, RAPSN, CHRNE, COLQ, SLC5A7, and GFPT1) were identified. @*Conclusion@#We describe the clinical and genetic characteristics of CMS patients and treatment outcome in a single tertiary center. High clinical suspicion and timely molecular diagnosis is particularly important for the tailored therapy to maximize clinical improvement in CMS.

Wide heterogeneity of congenital myasthenic syndromes: analysis of clinical experience in a tertiary center

Purpose@#Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of disorders characterized by impaired neuromuscular transmission. This study aims to provide the clue for early diagnosis and improved therapeutic strategies in CMS. @*Materials and Methods@#Through the targeted panel sequencing including twenty CMS causative genes, eleven patients were genetically confirmed and enrolled in this study. A retrospective medical record review was carried out for the clinical and laboratory data analysis. @*Results@#The age of patients ranged from 5 to 23 years, with the median age of 16 years. The peak age at onset of symptoms was the neonatal period. Seven out of the eleven patients were symptomatic at birth. The most commonly reported initial finding was generalized hypotonia with poor sucking and crying. Mean time to accurate diagnosis was 9.3±5.0 years. Total fifteen different variants in seven genes associated with CMS (DOK7, AGRN, RAPSN, CHRNE, COLQ, SLC5A7, and GFPT1) were identified. @*Conclusion@#We describe the clinical and genetic characteristics of CMS patients and treatment outcome in a single tertiary center. High clinical suspicion and timely molecular diagnosis is particularly important for the tailored therapy to maximize clinical improvement in CMS.

A Case of Familial Spondyloenchondrodysplasia with Immune Dysregulation Masquerading as Moyamoya Syndrome

No abstract available.

Diagnostic Challenges Associated with GLUT1 Deficiency: Phenotypic Variabilities and Evolving Clinical Features

GLUT1 deficiency is a rare neurometabolic disorder that can be effectively treated with ketogenic diet. However, this condition is underdiagnosed due to its nonspecific, overlapping, and evolving symptoms with age. We retrospectively reviewed the clinical course of nine patients diagnosed with GLUT1 deficiency, based on SLC2A1 mutations and/or glucose concentration in cerebrospinal fluid. The patients included eight boys and one girl who initially presented with seizures (44%, 4/9) or delayed development (44%, 4/9) before 2 years of age, except for one patient who presented with apnea as a neonate. Over the clinical course, all of the children developed seizures of the mixed type, including absence seizures and generalized tonic–clonic seizures. About half (56%, 5/9) showed movement disorders such as ataxia, dystonia, or dyskinesia. We observed an evolution of phenotype over time, although this was not uniform across all patients. Only one child had microcephaly. In five patients, ketogenic diet was effective in reducing seizures and movement symptoms, and the patients exhibited subjective improvement in cognitive function. Diagnosing GLUT1 deficiency can be challenging due to the phenotypic variability and evolution. A high index of clinical suspicion in pediatric and even older patients with epilepsy or movement disorders is key to the early diagnosis and treatment, which can improve the patient's quality of life.

Clinical and genetic characteristics of Korean patients with IARS2-related disorders

PURPOSE@#Genetic defects in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases were first identified as causes of various disorders in 2007. Variants in IARS2, which encodes a mitochondrial isoleucyl-tRNA synthetase, were first reported in 2014. These variants are associated with diverse phenotypes ranging from CAGSSS (CAtaracts, Growth hormone deficiency, Sensory neuropathy, Sensorineural hearing loss, and Skeletal dysplasia) and Leigh syndrome to isolated nonsyndromic cataracts. Here, we describe the phenotypic and genetic spectrum of Korean patients with IARS2-related disorders.@*MATERIALS AND METHODS@#Using whole-exome sequencing followed by Sanger sequencing, we identified five patients with IARS2 mutations. Their medical records and brain magnetic resonance images were reviewed retrospectively.@*RESULTS@#All five patients presented with developmental delay or regression before 18 months of age. Three patients had bilateral cataracts, but none had hearing loss or sensory neuropathy. No evidence of skeletal dysplasia was noted, but two had short stature. One patient had cardiomyopathy and another exhibited renal tubulopathy and hypoparathyroidism. Their brain imaging findings were consistent with Leigh syndrome. Interestingly, we found the recurrent mutations p.R817H and p.V105Dfs*7 in IARS2.@*CONCLUSION@#To our knowledge, this is the first report of Korean patients with IARS2-related disorders. Our findings broaden the phenotypic and genotypic spectrum of IARS2-related disorders in Korea and will help to increase clinical awareness of IARS2-related neurodegenerative diseases.

Chromosomal Microarray With Clinical Diagnostic Utility in Children With Developmental Delay or Intellectual Disability

BACKGROUND: Chromosomal microarray (CMA) testing is a first-tier test for patients with developmental delay, autism, or congenital anomalies. It increases diagnostic yield for patients with developmental delay or intellectual disability. In some countries, including Korea, CMA testing is not yet implemented in clinical practice. We assessed the diagnostic utility of CMA testing in a large cohort of patients with developmental delay or intellectual disability in Korea. METHODS: We conducted a genome-wide microarray analysis of 649 consecutive patients with developmental delay or intellectual disability at the Seoul National University Children's Hospital. Medical records were reviewed retrospectively. Pathogenicity of detected copy number variations (CNVs) was evaluated by referencing previous reports or parental testing using FISH or quantitative PCR. RESULTS: We found 110 patients to have pathogenic CNVs, which included 100 deletions and 31 duplications of 270 kb to 30 Mb. The diagnostic yield was 16.9%, demonstrating the diagnostic utility of CMA testing in clinic. Parental testing was performed in 66 patients, 86.4% of which carried de novo CNVs. In eight patients, pathogenic CNVs were inherited from healthy parents with a balanced translocation, and genetic counseling was provided to these families. We verified five rarely reported deletions on 2p21p16.3, 3p21.31, 10p11.22, 14q24.2, and 21q22.13. CONCLUSIONS: This study demonstrated the clinical utility of CMA testing in the genetic diagnosis of patients with developmental delay or intellectual disability. CMA testing should be included as a clinical diagnostic test for all children with developmental delay or intellectual disability.

Paroxysmal Dyskinesia in Children: from Genes to the Clinic

BACKGROUND AND PURPOSE: Paroxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children. METHODS: Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records. RESULTS: Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups. CONCLUSIONS: This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.

Serrated Adenoma with Adenocarcinoma of Stomach Treated by Endoscopic Submucosal Dissection

Since the first case of gastric serrated adenoma found in 2001, 35 additional cases have been reported. Among these cases, 26 cases were associated with invasive adenocarcinoma within the serrated adenoma. Gastric serrated adenoma when compared with traditional adenoma has close correlation with invasive carcinoma. Serrated colorectal polyps are classified as hyperplastic polyps, sessile serrated adenoma/polyps, and tranditional serrated adenoma (TSA) depending on histological features. Two distinct phenotypes of TSA in the colon and rectum are reported. Those are unlocked serrated crypts (US-TSA) and ectopic crypt formations (ECFs). All gastric serrated adenoma are TSA in historical aspect and ECFs on phenotype. Whereas gastric adenomas are reported with high frequency in the antrum, gastric serrated adenomas are founded in the body and cardia. We report a case of a 60-year-old woman receiving endoscopic submucosal dissection for gastric serrated adenoma with adenocarcinoma discovered during routine screening.

Leigh Syndrome in Childhood: Neurologic Progression and Functional Outcome

BACKGROUND AND PURPOSE: Few studies have analyzed the clinical course and functional outcome in Leigh syndrome (LS). The aim of this study was to determine the clinical, radiological, biochemical, and genetic features of patients with LS, and identify prognostic indicators of the disease progression and neurological outcome. METHODS: Thirty-nine patients who had been diagnosed with LS at the Seoul National University Children's Hospital were included. Their medical records, neuroimaging findings, and histological/biochemical findings of skeletal muscle specimens were reviewed. Targeted sequencing of mitochondrial DNA was performed based on mitochondrial respiratory chain (MRC) enzyme defects. RESULTS: Isolated complex I deficiency was the most frequently observed MRC defect (in 42% of 38 investigated patients). Mitochondrial DNA mutations were identified in 11 patients, of which 81.8% were MT-ND genes. The clinical outcome varied widely, from independent daily activity to severe disability. Poor functional outcomes and neurological deterioration were significantly associated with early onset (before an age of 1 year) and the presence of other lesions additional to basal ganglia involvement in the initial neuroimaging. CONCLUSIONS: The neurological severity and outcome of LS may vary widely and be better than those predicted based on previous studies. We suggest that age at onset and initial neuroimaging findings are prognostic indicators in LS.

Metastatic Spermatic Cord Tumor From Colorectal Cancer

Metastatic tumors of the spermatic cord are extremely rare, and the prognosis for patients is typically poor. In the majority of cases, the primary tumor occurs in the gastrointestinal tract. We report a case of a 62-year-old man with a metastatic spermatic cord tumor. The patient complained of groin discomfort with a tender mass in the right inguinal area. An excisional biopsy was performed, and the pathologic finding was a metastatic mucinous adenocarcinoma. We performed a systemic evaluation including colonoscopy, abdominal computed tomography, and total-body positron emission tomography, and the primary tumor was confirmed to involve the total colon, including the cecum, sigmoid colon, and rectum. The pathologic finding for rectum revealed a mucinous adenocarcinoma compatible with a metastatic spermatic cord tumor.

A Case of Gastric Signet Ring Cell Carcinoma in Young Adult with Nodular Gastritis; On Follow-up without Helicobacter pylori Eradication

A 29-year-old man with nodular gastritis diagnosed by previous gastroscopy was referred to our hospital for an evaluation of laryngeal discomport and soreness. The patient had no previous history of eradication for Helicobacter pylori-associated gastritis. Gastroscopy demonstrated the presence of gooseflesh-like nodularities on antrum and whitish discoloring lesion with depression on lesser curvature of lower body. The whitish discoloring lesion with depression was histologically diagnosed a signet ring cell carcinoma by endoscopic biopsy. We report this case of a patient with nodular gastritis who received no eradication therapy and was diagnosed with signet ring cell carcinoma with a review of the literature.

A Case of Gastric Signet Ring Cell Carcinoma in Young Adult with Nodular Gastritis; On Follow-up without Helicobacter pylori Eradication

A 29-year-old man with nodular gastritis diagnosed by previous gastroscopy was referred to our hospital for an evaluation of laryngeal discomport and soreness. The patient had no previous history of eradication for Helicobacter pylori-associated gastritis. Gastroscopy demonstrated the presence of gooseflesh-like nodularities on antrum and whitish discoloring lesion with depression on lesser curvature of lower body. The whitish discoloring lesion with depression was histologically diagnosed a signet ring cell carcinoma by endoscopic biopsy. We report this case of a patient with nodular gastritis who received no eradication therapy and was diagnosed with signet ring cell carcinoma with a review of the literature.

Case of Malignant Mesothelioma of the Peritoneum and Pleura / 대한내과학회지

Malignant mesothelioma is a rare aggressive tumor and arises from mesothelial cells in the pleural, peritoneal and pericardial cavities. Median survival is -1 year and the incidence is approximately 0.7 per million persons, and is increasing annually in Korea. It is difficult to diagnose malignant mesothelioma because of nonspecific symptoms, signs and laboratory findings. It needs to be confirmed by histological examination and immunohistochemistry. There is no case report of malignant mesothelioma of the peritoneum and pleura in Korea. We report a rare case of malignant mesothelioma with simultaneous involvement of the peritoneum and pleura in a 75-year-old man without evidence of asbestos exposure.

A Case of Ischemic Colitis Presenting as Bloody Diarrhea after Glycerin Enema

Enema has frequently been used for diagnostic or therapeutic purpose. However, cases of colitis from physical, chemical, and thermal injury due to enema have been reported. In severe cases, life threatening complications (perforation, rupture, peritonitis, etc.) may occasionally occur. Reports of ischemic colitis after enema is rare and there have been only 1 case of ischemic colitis after normal saline enema reported in South Korea. Sigmoidoscopy on a 58 year old female, presenting with sudden abdominal pain and hematochezia after glycerin enema, revealed ischemic injury of the rectosigmoid colon, which was improved after using antibiotics and conservative therapy.

Two Cases of Russell Body Gastritis Treated by Helicobacter pylori Eradication

Russell body gastritis was first defined in 1998, but not many cases have been reported since then. The exact causes and process of this condition are unknown yet; however, considering the reported cases, it has been highly suggested to have correlation with Helicobacter pylori infection. Russell body gastritis has a non-specific clinical presentation of gastritis such as gastric mucosal edema in the macroscopic view. It can be mistaken as xanthoma, signet ring cell carcinoma, or a malignant lymphoma including mucosa-associated lymphoid tissue lymphoma and plasmocytoma. Russell body gastritis features polyclonal immunoglobulin and is differentiated from Mott cancer, of which immune globulin has monoclonal aspect. Authors report here two cases of Russell body gastritis with examined endoscopic findings as well as a review of related literature on the association of all reported cases of Russell body gastritis with H. pylori infection.

A Case of Cri du Chat Syndrome with Developmental Delay Misdiagnosed as Fetal Alcohol Syndrome / 대한소아신경학회지

Cri du Chat syndrome (CdCS) is a chromosomal disease resulting from a deletion on the short arm of chromosome 5. Characteristic features include high pitched cat-like cry, distinguishing facial features, and mental retardation. Some cases have been reported in the Korean literature, but no case reports about the concrete aspects of developmental delay in CdCS patients have been published. Therefore, we report a CdCS patient with developmental delay who was misdiagnosed as fetal alcohol syndrome. The result of the Korean-Child Development Review and Sequenced Language Scale for Infants showed severe developmental retardation, especially in expressive language.

A Case of Colonic Collision Tumor (Adenocarcinoma and Neuroendocrine Carcinoma) / 대한소화기학회지

Collision tumors of the colon are rare. A 54-year-old man was referred to our hospital for the evaluation of hematochezia. Colonoscopy demonstrated the presence of about 3 cm sized mass in the rectosigmoid junction. After surgical resection, the colonic lesion was histologically composed of two discrete lesions: adenocarcinoma in the superficial layer and poorly differentiated neuroendocrine carcinoma in the deeper layer. We report this case of colonic collision tumor (adenocarcinoma and neuroendocrine carcinoma) with a review of the literature.

Distribution of Disease Severity and Group A Rotavirus Genotypes (VP7 & VP4) in Children with Acute Rotavirus Gastroenteritis / 대한소아소화기영양학회지

PURPOSE: We aimed to study the distribution of rotavirus genotypes (VP7 and VP4) and disease severity of rotavirus gastroenteritis prevalent in our community. METHODS: Stool samples were collected from 156 children who were hospitalized with rotavirus gastroenteritis from December 2007 to June 2008. The disease severity of all patients was scored using the Vesikari scale. After extraction of ds-RNA of the rotavirus, cDNA synthesis using reverse transcription and polymerase chain reaction (RT-PCR) and multiplex PCR was performed. Following this, the final identification of genotypes was performed. RESULTS: Of the 156 samples, VP7(G) and VP4(P) genotypes were identified in 147 (94.2%) and 140 (89.7%) samples, respectively. G1 (116 of 147 samples; 78.9%) and P[8] (137 of 140 samples; 97.9%) were the most prevalent, respectively. Of the 138 samples identified of combination types of VP7 and VP4, G1P[8] (111 samples; 80.4%) was the most prevalent. Other combination types varied with very low distribution rates. 9.4% of genotypes were not included in the new vaccines. The disease severity score was 11.8+/-3.3 (mean+/-2SD). The distribution of disease severity was mild or moderate in 37.8% and severe in 62.2% of patients. CONCLUSION: The most prevalent genotype combination of rotavirus was G1P[8] and genotypes not included in the vaccines represented 9.4% in our community. Disease severity distribution of hospitalized children with rotavirus gastroenteritis was higher in the severe than in the mild and moderate categories.

Co-localization of activating transcription factor 3 and phosphorylated c-Jun in axotomized facial motoneurons / 대한해부학회지

Activating transcription factor 3 (ATF3) and c-Jun play key roles in either cell death or cell survival, depending on the cellular background. To evaluate the functional significance of ATF3/c-Jun in the peripheral nervous system, we examined neuronal cell death, activation of ATF3/c-Jun, and microglial responses in facial motor nuclei up to 24 weeks after an extracranial facial nerve axotomy in adult rats. Following the axotomy, neuronal survival rate was progressively but significantly reduced to 79.1% at 16 weeks post-lesion (wpl) and to 65.2% at 24 wpl. ATF3 and phosphorylated c-Jun (pc-Jun) were detected in the majority of ipsilateral facial motoneurons with normal size and morphology during the early stage of degeneration (1-2 wpl). Thereafter, the number of facial motoneurons decreased gradually, and both ATF3 and pc-Jun were identified in degenerating neurons only. ATF3 and pc-Jun were co-localized in most cases. Additionally, a large number of activated microglia, recognized by OX6 (rat MHC II marker) and ED1 (phagocytic marker), gathered in the ipsilateral facial motor nuclei. Importantly, numerous OX6- and ED1-positive, phagocytic microglia closely surrounded and ingested pc-Jun-positive, degenerating neurons. Taken together, our results indicate that long-lasting co-localization of ATF3 and pc-Jun in axotomized facial motoneurons may be related to degenerative cascades provoked by an extracranial facial nerve axotomy.

A Case of Thyrotoxicosis Manifesting With Coma / 대한소아신경학회지

Thyrotoxicosis is a rare, but life-threatening condition in children. The diagnosis of Graves' thyrotoxicosis is more complicated in children than adults because associated clinical features may be atypical. Moreover, severe thyrotoxicosis may cause symptoms of CNS dysfunction, including seizures, chorea, psychosis, fluctuating confusion, and coma. We report on a case of thyrotoxicosis with coma in a 13-year-old girl. This is the first such report in the Korean pediatric population. During 2 episodes the patient presented with coma, fever without definite focus, intermittent hypertension, and sinus tachycardia. A diagnosis of Graves' thyrotoxicosis with developing thyroid storm was made. Following improvement in her condition, she was discharged on methimazole and propranolol. Thyroid dysfunction should be considered whenever unexplained coma or psychosis is encountered in children.