A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome.

KCNB1 encodes the α-subunit of Kv2.1, the main contributor to neuronal delayed rectifier potassium currents. The subunit consists of six transmembrane α helices (S1-S6), comprising the voltage-sensing domain (S1-S4) and the pore domain (S5-P-S6). Heterozygous KCNB1 pathogenic variants are associated with developmental and epileptic encephalopathy. Here we report an individual who shows the milder phenotype compared to the previously reported cases, including delayed language development, mild intellectual disability, attention deficit hyperactivity disorder, late-onset epilepsy responsive to an antiepileptic drug, elevation of serum creatine kinase, and peripheral axonal neuropathy. On the other hand, his brain MRI showed characteristic findings including periventricular heterotopia, polymicrogyria, and abnormal corpus callosum. Exome sequencing identified a novel de novo KCNB1 variant c.574G>A, p.(Ala192Thr) located in the S1 segment of the voltage-sensing domain. Functional analysis using the whole-cell patch-clamp technique in Neuro2a cells showed that the Ala192Thr mutant reduces both activation and inactivation of the channel at membrane voltages in the range of -50 to -30 mV. Our case could expand the phenotypic spectrum of patients with KCNB1 variants, and suggested that variants located in the S1 segment might be associated with a milder outcome of seizures.

Prediction and assessment of acute encephalopathy syndromes immediately after febrile status epilepticus.

OBJECTIVE: This study aimed to predict occurrence of acute encephalopathy syndromes (AES) immediately after febrile status epilepticus in children and to explore the usefulness of electroencephalogram (EEG) in the early diagnosis of AES. METHODS: We reviewed data from 120 children who had febrile status epilepticus lasting >30 min and were admitted to our hospital between 2012 and 2019. AES with reduced diffusion on brain magnetic resonance imaging was diagnosed in 11 of these patients. EEG and serum cytokines were analyzed in AES patients. Clinical symptoms and laboratory data were compared between AES and non-AES patients. Logistic regression analysis was used to identify early predictors of AES. RESULTS: Multivariate logistic regression identified serum creatinine as a risk factor for developing AES. A scoring model to predict AES in the post-ictal phase that included serum creatinine, sodium, aspartate aminotransferase, and glucose was developed, and a score of 2 or more predicted AES with sensitivity of 90.9% and specificity of 71.6%. Post-ictus EEG revealed non-convulsive status epilepticus in four of the seven AES patients. CONCLUSION: Children with febrile status epilepticus may be at risk of developing severe AES with reduced diffusion. Post-ictus EEG and laboratory data can predict the occurrence of severe AES.

Immunodeficiency in a patient with microcephalic osteodysplastic primordial dwarfism type I as compared to Roifman syndrome.

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.

TUBB3 E410K syndrome with osteoporosis and cough syncope in a patient previously diagnosed with atypical Moebius syndrome.

BACKGROUND: A heterozygous c.1228G > A p.E410K mutation in TUBB3 encoding neuronal-specific ß-tubulin isotype 3 causes TUBB3 E410K syndrome, which exhibits a wide range of neurological and endocrinological abnormalities. CASE DESCRIPTION: The patient is a 31-year-old Japanese woman who was diagnosed with atypical Moebius syndrome because of congenital facial weakness and extraocular ophthalmoplegia sparing abduction. She suffered a femoral neck fracture at 23 years of age, and radiological and endocrinological studies revealed osteoporosis because of hypogonadotropic hypogonadism. She also had borderline intellectual disability, cyclic vomiting, syncope with cough, and decreased sense of smell since childhood. Brain magnetic resonance imaging revealed abnormal morphology of the corpus callosum and pontine. Hypoplastic bilateral oculomotor and facial nerves were evident. Based on these symptoms, we analyzed the TUBB3 gene and identified a heterozygous c.1228G > A (p.E410K) mutation that confirmed the diagnosis of TUBB3 E410K syndrome. CONCLUSION: TUBB3 E410K syndrome may be diagnosed as atypical Moebius syndrome because of overlapping clinical symptoms. Genetic analysis of c.1228G > A in TUBB3 is useful to differentiate TUBB3 E410K syndrome from other disorders presenting congenital external ophthalmoplegia and facial nerve palsy.

Glucose-regulated protein 78 expression in urothelial carcinoma of the upper urinary tract.

OBJECTIVE: To examine glucose-regulated protein 78 (GRP78; a major molecular chaperone at the endoplasmic reticulum, strongly expressed in several tumours) expression in urothelial carcinoma (UC) of the upper urinary tract (UUT) and to evaluate the diagnostic and progressive importance of GRP78 expression in UC-UUT. PATIENTS AND METHODS: We investigated GRP78 expression (using immunohistochemistry) in 126 UC-UUTs to assess its relevance to progression. GRP78 overexpression was recognised in 23 (18.3%) of tumour samples. RESULTS: There was no association between GRP78 overexpression and clinicopathological findings, except for an association with low grade in invasive tumours. GRP78 overexpression significantly improved the disease-free survival rate in all patients (according to univariate and multivariate analyses), but did not alter the overall survival rate. CONCLUSION: The detection of GRP78 overexpression would appear to provide valuable information for the prognosis of UC-UUT.