SLC9A6 -related developmental and epileptic encephalopathy with spike-and-wave activation in sleep: A case report

The gene encoding solute carrier family 9 member 6 (SLC9A6) on Xq26.3 is associated with Christianson syndrome (CS) mimicking Angelman syndrome. In CS, developmental and epileptic encephalopathy (DEE) appears in about 20%, and DEE with spike-and-wave activation in sleep (SWAS) is reported only in several cases. A 10-year-old boy with DEE showed multidrug resistant focal seizures from 6 months of age. He had progressive microcephaly, regression, global developmental delay without speech, hyperkinesia, and truncal ataxia; he had a long thin face, esotropia, and happy demeanor. Brain magnetic resonance imaging demonstrated cerebellar atrophy. Electroencephalogram at 7.5 years of age showed nearly continuous diffuse paroxysms in slow wave sleep. The seizures were responsive to corticosteroids for a while. Trio whole exome sequencing exhibited a likely pathogenic variant of SLC9A6 in the proband and his asymptomatic mother: c.1194dup (p.Leu399AlafsTer12).This is a rare case report of CS with DEE-SWAS in a Korean patient.

Effective ketogenic diet in CACNA1A-related ‘epilepsy of infancy with migrating focal seizures’

Genetic causes of developmental and epileptic encephalopathy (DEE) have been rapidly uncovered from mid-2010s. The mutations of gene enconding calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) are recently detected in DEE, which gene is already known well in familial hemiplegic migrine type 1 or episodic ataxia type 2. Ketogenic diet therapy (KDT) is effective in some DEE, which data is short in CACNA1A encephalopathy. A 3-month-old male with global developmental delay and multidrug-resistant focal seizures was diagnosed as epilepsy of infancy with migrating focal seizures (EIMFS). Brain magnetic resonance imaging and metabolic screening were all normal. Whole exome sequencing revealed two variants of CACNA1A : c.899A>C, and c.2808del that is from his mother. His seizures disappeared within 3 days whenever on KDT, which recurred without it. To our knowledge, this rare case of EIMFS with novel mutations of CACNA1A, is the first report in CACNA1A encephalopathy becoming seizure-free on KDT.

A Rare Case of Pulmonary Arteriovenous Malformation Caused by Hereditary Hemorrhagic Telangiectasia in a Hemodialysis Patient / 대한내과학회지

Hereditary hemorrhagic telangiectasia (HHT) is an uncommon autosomal dominant disorder resulting in vascular malformation, such as pulmonary arteriovenous malformation (PAVM). Here, we report a rare case of pulmonary arteriovenous malformation caused by HHT in a hemodialysis (HD) patient. A 34-year-old man receiving maintenance HD via radiocephalic arteriovenous fistula developed progressive dyspnea without definite pulmonary edema. His mother had been diagnosed with HHT. He had experienced multiple episodes of epistaxis and had been intermittently treated with blood transfusions because of severe anemia. Blood gas analysis showed hypoxia. Chest computed tomography revealed multiple dilated vessels of variable sizes, continuous with the pulmonary artery throughout both lung fields, consistent with PAVM. After treating pulmonary artery embolization at the largest PAVM, he recovered from his dyspnea symptoms and hypoxia.

A Case of Laryngeal Lymphoepithelial Carcinoma

Laryngeal lymphoepithelial carcinoma (LEC) is a rare tumor with only 34 cases in the published literature. Epidemiologically, laryngeal LEC is extremely rare in Asian. Originally, LEC is a common type of carcinoma in nasopharynx. Laryngeal LEC resembles nasopharyngeal LEC, except that most cases of laryngeal LEC are not associated with Epstein-Barr virus. We present a case of laryngeal LEC which developed at the left false cord extending to true vocal cord, para-glottic space and pre-epiglottic space. Total laryngectomy with bilateral neck dissection was performed. LEC was reported as biopsy confirmation result. The patient underwent postoperative radiotherapy and showed no evidence of recurrence during follow-up period of 42 months. In consideration that LEC in larynx have not been reported in South Korea yet, we introduce the clinical features and treatment outcomes of laryngeal LEC with literature review.

West syndrome with hyperkinesia and cortical visual impairment: A case report of GRIN1 encephalopathy

West syndrome (WS) presenting with infantile spasms, developmental delay, and hypsarrhythmia has genetic etiology in some patients. Movement disorders or visual impairment that share genetic underpinnings with infantile spasms can provide diagnostic clues for specific genetic mutations. Mutations of the GRIN1 gene encoding the glutamate receptor inotropic Nmethyl-D-aspartate subunit can result in WS with hyperkinetic movements, cortical visual impairment, autistic features, and bilateral polymicrogyria. An 11-month-old boy with WS showed hyperkinetic movements and visual impairment. Brain magnetic resonance imaging and metabolic investigations revealed no abnormalities. Whole-exome sequencing revealed a novel likely pathogenic variant (c.1561_1563del; p.Asn521del) of GRIN1 (NM_007327.3). The proband was treated with vigabatrin and became seizure-free within one week. Notably, the cortical blindness improved within 3 months and the hyperkinetic movements resolved one year after the proband became seizure-free. To the best of our knowledge, this is the first report of GRIN1 encephalopathy in Koreans.

Cohen–Gibson syndrome in a family: The first familial case report

Cohen–Gibson syndrome (CGS) was first reported by Cohen et al., who identified the mutation of the gene encoding the embryonic ectoderm development (EED) in a patient with phenotypes similar to Weaver syndrome. CGS manifests as an overgrowth and intellectual disability, in addition to the characteristic facial features and organ anomalies. CGS has been reported in only 11 unrelated patients since 2015. A girl aged 6 years and 3 months presented with seizures. She had macrosomia, a dysmorphic face, and intellectual disability. Her mother and younger sister and brother also had macrosomia, intellectual disability, and similar facial features; additionally, her mother experienced seizures and had an arachnoid cyst, while her siblings had valvar pulmonary stenosis. Whole-exome sequencing for the proband revealed a mutation of EED (c.581A>G, p.Asn194Ser), which was also verified in the mother and both siblings using Sanger sequencing. This is the first report of familial CGS.

A Rare Case of Pulmonary Arteriovenous Malformation Caused by Hereditary Hemorrhagic Telangiectasia in a Hemodialysis Patient / 대한내과학회지

Hereditary hemorrhagic telangiectasia (HHT) is an uncommon autosomal dominant disorder resulting in vascular malformation, such as pulmonary arteriovenous malformation (PAVM). Here, we report a rare case of pulmonary arteriovenous malformation caused by HHT in a hemodialysis (HD) patient. A 34-year-old man receiving maintenance HD via radiocephalic arteriovenous fistula developed progressive dyspnea without definite pulmonary edema. His mother had been diagnosed with HHT. He had experienced multiple episodes of epistaxis and had been intermittently treated with blood transfusions because of severe anemia. Blood gas analysis showed hypoxia. Chest computed tomography revealed multiple dilated vessels of variable sizes, continuous with the pulmonary artery throughout both lung fields, consistent with PAVM. After treating pulmonary artery embolization at the largest PAVM, he recovered from his dyspnea symptoms and hypoxia.

A Case of Laryngeal Lymphoepithelial Carcinoma

Laryngeal lymphoepithelial carcinoma (LEC) is a rare tumor with only 34 cases in the published literature. Epidemiologically, laryngeal LEC is extremely rare in Asian. Originally, LEC is a common type of carcinoma in nasopharynx. Laryngeal LEC resembles nasopharyngeal LEC, except that most cases of laryngeal LEC are not associated with Epstein-Barr virus. We present a case of laryngeal LEC which developed at the left false cord extending to true vocal cord, para-glottic space and pre-epiglottic space. Total laryngectomy with bilateral neck dissection was performed. LEC was reported as biopsy confirmation result. The patient underwent postoperative radiotherapy and showed no evidence of recurrence during follow-up period of 42 months. In consideration that LEC in larynx have not been reported in South Korea yet, we introduce the clinical features and treatment outcomes of laryngeal LEC with literature review.

West syndrome with hyperkinesia and cortical visual impairment: A case report of GRIN1 encephalopathy

West syndrome (WS) presenting with infantile spasms, developmental delay, and hypsarrhythmia has genetic etiology in some patients. Movement disorders or visual impairment that share genetic underpinnings with infantile spasms can provide diagnostic clues for specific genetic mutations. Mutations of the GRIN1 gene encoding the glutamate receptor inotropic Nmethyl-D-aspartate subunit can result in WS with hyperkinetic movements, cortical visual impairment, autistic features, and bilateral polymicrogyria. An 11-month-old boy with WS showed hyperkinetic movements and visual impairment. Brain magnetic resonance imaging and metabolic investigations revealed no abnormalities. Whole-exome sequencing revealed a novel likely pathogenic variant (c.1561_1563del; p.Asn521del) of GRIN1 (NM_007327.3). The proband was treated with vigabatrin and became seizure-free within one week. Notably, the cortical blindness improved within 3 months and the hyperkinetic movements resolved one year after the proband became seizure-free. To the best of our knowledge, this is the first report of GRIN1 encephalopathy in Koreans.

Cohen–Gibson syndrome in a family: The first familial case report

Cohen–Gibson syndrome (CGS) was first reported by Cohen et al., who identified the mutation of the gene encoding the embryonic ectoderm development (EED) in a patient with phenotypes similar to Weaver syndrome. CGS manifests as an overgrowth and intellectual disability, in addition to the characteristic facial features and organ anomalies. CGS has been reported in only 11 unrelated patients since 2015. A girl aged 6 years and 3 months presented with seizures. She had macrosomia, a dysmorphic face, and intellectual disability. Her mother and younger sister and brother also had macrosomia, intellectual disability, and similar facial features; additionally, her mother experienced seizures and had an arachnoid cyst, while her siblings had valvar pulmonary stenosis. Whole-exome sequencing for the proband revealed a mutation of EED (c.581A>G, p.Asn194Ser), which was also verified in the mother and both siblings using Sanger sequencing. This is the first report of familial CGS.

A Rare Case of Fibromuscular Dysplasia with Postpartum Renal Artery Rupture in a Non-Hypertensive Woman / 대한내과학회지

Fibromuscular dysplasia (FMD) of the renal artery is a non-atherosclerotic, non-inflammatory vascular disease that causes stenosis, aneurysm, dissection, and occlusion of the vessel. We report a rare case of a postpartum FMD patient who presented with spontaneous acute perirenal hematoma due to renal artery aneurysm rupture after cesarean section. The 40-year-old patient presented with sudden onset of abdominal pain 2 days after an elective cesarean section performed at full gestational term. A computed tomography scan of the abdomen revealed perirenal hematomas with signs of FMD in both renal arteries. The bleeding was successfully controlled by transcatheter arterial embolization. Short-term continuous renal replacement therapy was performed until her renal function recovered. FMD of the renal artery is rare in pregnant patients. Additionally, aneurysm rupture can be life threatening and requires immediate medical attention and prompt management.

Renal Artery Stenosis Presenting at Sudden Flash Pulmonary Edema in a Patient with Solitary Kidney / 대한내과학회지

Flash pulmonary edema is characterized by a sudden episode of dyspnea resulting from acute pulmonary venous congestion, which resolves rapidly. We report a case of renal artery stenosis presenting as flash pulmonary edema in a patient with solitary kidney treated by angioplasty with stent implantation. A 75-year-old man with solitary kidney visited the emergency room with acute shortness of breath. His blood pressure had risen to 206/90 mmHg and a chest radiograph revealed pulmonary edema. Echocardiography and coronary arteriography showed no clear abnormalities, but abdominal computed tomography revealed severe focal stenosis in the left proximal renal artery. A captopril renal scan found that the time to peak and half-time of radioactivity were delayed in the left kidney. Percutaneous transluminal angioplasty was performed, followed by stent implantation. After this procedure, the stenotic segment was completely dilated and blood pressure returned to the normal range.

Association between Blood Pressure and Renal Progression in Korean Adults with Normal Renal Function

Background@#Although hypertension (HTN) is a well-established major risk factor for renal progression in patients with chronic kidney disease (CKD), few studies investigating its role in renal deterioration in the general population with normal renal function (NRF) have been published. Here, we analyzed the correlation between blood pressure (BP) and impaired renal function (IRF) in Korean adults with NRF. @*Methods@#Data for the study were collected from the national health screening database of the Korean National Health Insurance Service. Patients whose baseline estimated glomerular filtration rate (eGFR) was less than 60 mL/min/1.73 m 2 or whose baseline urinalysis showed evidence of proteinuria were excluded. IRF was defined as an eGFR below 60 mL/min/1.73 m 2 . We performed follow up for eGFR for 6 years from 2009 to 2015 and investigated IRF incidence according to baseline BP status. We categorized our study population into two groups of IRF and NRF according to eGFR level in 2015. @*Results@#During 6 years of follow-up examinations, IRF developed in 161,044 (2.86%) of 5,638,320 subjects. The IRF group was largely older, and the incidence was higher in females and patients with low income, HTN, diabetes mellitus, dyslipidemia, and obesity compared with the NRF group. Subjects whose systolic BP was more than 120 mmHg or whose diastolic BP was more than 70 mmHg had an increased risk of developing IRF compared with subjects with lower BP (odds ratio [OR], 1.037; 95% confidence interval [CI], 1.014–1.061 vs. OR, 1.021; 95% CI, 1.004–1.038). @*Conclusion@#BP played a major role in renal progression in the general population with NRF.Strict BP control may help prevent CKD in the general population.

Periventricular nodular heterotopia in a child with a mild Mowat–Wilson phenotype caused by a novel missense mutation of ZEB2

Periventricular nodular heterotopia (PNH) is a malformation of cortical development in which normal neurons inappropriately cluster in periventricular areas. Patients with Mowat–Wilson syndrome (MWS) typically present with facial gestalt, complex neurologic problems (e.g., severe developmental delay with marked speech impairment and epilepsy), and multiple anomalies (e.g., Hirschsprung disease, urogenital anomalies, congenital heart defects, eye anomalies, and agenesis of the corpus callosum [CC]). MWS is mostly caused by haploinsufficiency of the gene encoding zinc-finger E-box-binding homeobox 2 (ZEB2) due to premature stops or large deletions. We present a case report of a 9-year-old girl with PNH, drug-responsive epilepsy, severe intellectual disability, and facial dysmorphisms only in whom we performed whole-exome sequencing and found a de novo heterozygous missense mutation (c.3134A>C; p.His1045Pro) of ZEB2 (NM_014795.3; NP_055610.1). This mild case of MWS caused by a rare novel missense mutation of ZEB2 represents the first report of MWS with isolated PNH.

A novel frameshift mutation of PRRT2 in a family with infantile convulsions and choreoathetosis syndrome: c.640delinsCC (p.Ala214ProfsTer11)

The infantile convulsions and choreoathetosis (ICCA) syndrome is defined when two overlapping clinical features of benign familial infantile epilepsy (BFIE) and paroxysmal kinesigenic dyskinesia (PKD) are present in an individual or a family. Since the gene encoding proline-rich transmembrane protein 2 (PRRT2) was first identified in Han Chinese families with PKD, mutations of PRRT2 have additionally been reported in patients with BFIE and ICCA. We attempted to identify the genetic etiology in an ICCA family where the proband, her elder sister, and a maternal male cousin had BFIE, and her mother had PKD. Whole-exome sequencing performed in the proband and her sister and mother identified a novel pathogenic mutation of PRRT2 (c.640delinsCC; p.Ala214ProfsTer11), which was verified by Sanger sequencing. This frameshift PRRT2 mutation located near the genetic hot spot of base 649_650 results in the premature termination of the protein, as do most previously reported mutations in BFIE, ICCA, and PKD.

Primary Cutaneous Mucinous Carcinoma with Extramammary Paget’s Disease: Eccrine or Apocrine?

Primary cutaneous mucinous carcinoma (PCMC) is an uncommon tumor of the sweat gland origin. The occurrence of PCMC is mostly in middle-aged and older patients, with a slight male predominance. Most cases of PCMC arise on the head, with a preference for eyelids. The histogenesis of PCMC, whether eccrine or apocrine, remains controversial. We report a rare case of PCMC with secondary extramammary Paget’s disease in the groin of a 75-year-old man, which favored an apocrine origin. Furthermore, based on a review of the literature, we provide several histologic clues that can be used to differentiate PCMC from metastatic mucinous carcinoma.

CLN6 Mutation in a Patient with Progressive Myoclonus Epilepsy / 대한소아신경학회지

Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders, which are caused by the accumulation of lipopigment in lysosomes. Variant forms of late infantile NCLs (vLINCLs) characterized by a later onset of seizures and visual impairment (3–8 years) than in the classic form (2–4 years) are caused by mutations of the gene encoding ceroid lipofuscinosis neuronal protein 6 (CLN6). In a girl with progressive myoclonus epilepsy, we found heterozygous variants of CLN6 (NM_017882.2; NP_060352.1): c.296A>G (p.Lys99Arg) and c.307C>T (p.Arg103Trp). They were identified with whole-exome sequencing and verified with Sanger sequencing. At 7 years and 9 months, our patient had developed multiple types of seizures, prominent myoclonus with photosensitivity, regression in motor and language skills, pyramidal and extrapyramidal signs, and brain atrophy in brain images, all of which were progressive and were compatible with vLINCLs. However, this first Korean report shows no visual impairment, which resembles the previously reported Japanese case.

Neurological Outcome of Ischemic Stroke in Children: a Single Center Study / 대한소아신경학회지

PURPOSE: Ischemic stroke is rarely seen in children, but it could cause mortality and result in developmental disabilities such as motor paralysis, cognitive dysfunction, and epilepsy. In this study, the neurological outcomes of ischemic stroke in children were reviewed and the factors associated with the neurological outcomes were to be analyzed. METHODS: Medical records of patients younger than 15 years of age who were newly diagnosed with ischemic stroke between January 2006 and December 2016 in Chonnam National University Hospital were reviewed. RESULTS: This study consisted of 38 patients with ischemic stroke (male/female= 18/20, mean age=6 years 1 month±4 years 8 months). Neurological outcomes assessment was done at least 1 year after the onset of ischemic stroke. 10 patients (26.3%) had no neurological impairments. Motor paralysis was noted in 22 (57.9%), cognitive dysfunction was in 9 (23.7%), and epilepsy in 20 (52.6%). Among the possible risk factors for neurological impairments (age, sex, early seizures, characteristics of the infarcted lesions, abnormal electroencephalogram (EEG) findings), abnormalities on EEG findings were significantly associated with cognitive dysfunction (P=0.026) and the occurrence of early seizures with epilepsy (P=0.000). CONCLUSION: Neurological impairments were remained in 73.7% of children one year after ischemic stroke. Cognitive dysfunction was associated with abnormalities on EEG findings within 2 weeks after the onset of ischemic stroke and epilepsy with the occurrence of early seizures.

Acute Childhood Encephalitis and Encephalopathy following Infectious Symptoms: a Single Center Study / 대한소아신경학회지

PURPOSE: Acute encephalitis and encephalopathy are preceded by respiratory or enteric infection, whose pathogens can be detected more easily with advanced tools. However, studies for pathogens in Korea remain scarce. We investigated the clinical characteristics and pathogens in childhood encephalitis and encephalopathy. METHODS: We retrospectively reviewed the records of children with acute encephalitis and encephalopathy admitted to our hospital between March 2013 and February 2017. RESULTS: The 51 included patients were aged 5.8±4.4 years (mean±standard deviation), comprising 36 with encephalitis (70.6%) and 15 with encephalopathy (29.4%). Respiratory symptoms (62.7%) were more common than enteric symptoms (45.1%). Brain MRI was abnormal in 54.9%, and leu-kocytosis in the cerebrospinal fluid was noted in 41.2%. The prevalence of diseases was highest in winter (29.4%). In encephalitis, eight patients had infective encephalitis (15.7%), comprising enterovirus (N=4), Epstein-Barr virus (N=3; one with HHV6 coinfection), and tsutsugamushi in-fection (N=1). The 11 patients with ADEM included 1each with adenovirus, influenza A, and mycoplasmal infection. One patient with Bickerstaff-brainstem encephalitis had mycoplasmal pneumonia. In the 15 patients with encephalitis of unknown etiology, rhinovirus (N=3), influenza A (N=2), adenovirus (N=1), and mycoplasmal infection (N=6) were found. In the encephalopa-thy group, three patients had abnormal brain MRI: ANE with influenza A, AESD with exanthem subitum, and norovirus-associated MERS. In the remaining 12 patients, influenza A (N=2), ade-novirus, rhinovirus, enterovirus, norovirus (N=1 for each virus), and mycoplasmal infection (N=4) were found. CONCLUSION: Acute childhood encephalitis and encephalopathy were the most prevalent in winter and were fre-quently associated with respiratory infections.

The impact of high serum bicarbonate levels on mortality in hemodialysis patients

BACKGROUND/AIMS: The optimal serum bicarbonate level is controversial for patients who are undergoing hemodialysis (HD). In this study, we analyzed the impact of serum bicarbonate levels on mortality among HD patients. METHODS: Prevalent HD patients were selected from the Clinical Research Center registry for End Stage Renal Disease cohort in Korea. Patients were categorized into quartiles according to their total carbon dioxide (tCO₂) levels: quartile 1, a tCO₂ of < 19.4 mEq/L; quartile 2, a tCO₂ of 19.4 to 21.5 mEq/L; quartile 3, a tCO₂ of 21.6 to 23.9 mEq/L; and quartile 4, a tCO₂ of ≥ 24 mEq/L. Cox regression analysis was used to calculate the adjusted hazard ratio (HR) and confidence interval (CI) for mortality. RESULTS: We included 1,159 prevalent HD patients, with a median follow-up period of 37 months. Kaplan-Meier analysis revealed that the all-cause mortality was significantly higher in patients from quartile 4, compared to those from the other quartiles (p = 0.009, log-rank test). The multivariate Cox proportional hazard model revealed that patients from quartile 4 had significantly higher risk of mortality than those from quartile 1, 2 and 3, after adjusting for the clinical variables in model 1 (HR, 1.99; 95% CI, 1.15 to 3.45; p = 0.01) and model 2 (HR, 1.82; 95% CI, 1.03 to 3.22; p = 0.04). CONCLUSIONS: Our data indicate that high serum bicarbonate levels (a tCO₂ of ≥ 24 mEq/L) were associated with increased mortality among prevalent HD patients. Further effort might be necessary in finding the cause and correcting metabolic alkalosis in the chronic HD patients with high serum bicarbonate levels.