Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.

Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies.

BACKGROUND: Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. METHOD: We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. RESULTS: Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. CONCLUSION: Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.

Gastric ulceration and perforation secondary to large trichobezoar - A case report describing the role of magnetic resonance imaging in diagnosis.

INTRODUCTION: Trichotillomania and trichotillophagia can result in huge intraluminal coagulations of hair. Rarely, these can present with gastric perforation. This work has been reported in line with the SCARE criteria (Agha et al., 2016) [1]. PRESENTATION OF CASE: We report the case of a 15 year old girl who attended the emergency department with abdominal pain and vomiting. Ultrasound abdomen and pelvis identified free fluid within the pelvis concerning for inflammatory bowel disease. A subsequent magnetic resonance enterography (MRE) demonstrated a giant gastric trichobezoar which resulted in gastric perforation necessitating laparotomy and gastrotomy. The patient recovered well from the surgery and was reviewed by the psychiatry service prior to discharge. DISCUSSION: Trichobezoar is a challenging diagnosis and as clinician, we must always include it in our differential diagnosis. The clinical presentation, signs and symptoms depend on the size of the trichobezoar and the presence of complications. Management is almost always surgical. CONCLUSION: This case illustrates the infrequent perforation risk of gastric bezoars and the important role of magnetic resonance imaging in diagnosis, particularly in a population who must not be exposed to excessive radiation.

[Sepsis--current aspects].

Sepsis is defined as a clinical syndrome of systemic response to infections. With progression of the disease develop organ failure (i.e. severe sepsis) and hypotension (i.e. septic shock) and mortality increases significantly. Sepsis is an interdisciplinary problem, cause significant morbidity and mortality and higher hospital costs. Deepening ofinflammation, immunity distortions, coagulation and oxygen perfusion have a major role in organ dysfunction and death. Proper diagnosis of sepsis requires an understanding of risk factors, a high index of suspicion and anatomic approach to the localization of the infectious focus. Early detection of septic patients is crucial for the outcome of disease in the application of reasoned therapy. Future treatment of sepsis associated with a better understanding of the molecular bases of pathological process.

[Improved technique for internal biliary-digestive drainage during conventional palliative procedure of nonresectable tumors of periampullary region].

AIM: We represent variation of bilio-digestive stomy with "lost" protecting drainage during conventional palliative procedure of nonresectable tumors of periampullary region. MATERIALS AND METHODS: During the period 01.01.2008 -31.05.2008 in the Clinic of general and liver-pancreatic surgery-"Aleksandrovska" Hospital, Sofia, we applied modified technique for internal bilio-digestive prosthetic drain with "lost" drainage, protecting choledocho-duodenostomy in 12 patients with nonresectable tumors of periampullary region. Eight of them are males and 4--females, with age between 60-82 (average 64,5). In 8 patients we found nonresectable malignancy of the head of pancreas and in 4 nonresectable malignancy of distal part of the common bile duct. RESULTS: We follow the early postoperative results and postoperative period during tree months. We did not have insufficiency of the choledocho-duodenostomy and that afford early discharge of the patients. At the end of third month we haven't observed jaundice or other complications cause of obstruction of protecting drainage. CONCLUSION: We consider that the technique is useful and appropriate when doing choledocho-duodenostomy cause of nonresectable periampullary neoplasms. The using of this technique don't increase the postoperative morbidity and improve early postoperative results.