No abstract

Background POLG pathogenic variants are the commonest single-gene cause of inherited mitochondrial disease. However, the data on clinicogenetic associations in POLG-related disorders are sparse. This study maps the clinicogenetic spectrum of POLG-related disorders in the pediatric population. Methods Individuals were recruited across 6 centers in India. Children diagnosed between January 2015 and August 2020 with pathogenic or likely pathogenic POLG variants and age of onset <15 years were eligible. Phenotypically, patients were categorized into Alpers-Huttenlocher syndrome; myocerebrohepatopathy syndrome; myoclonic epilepsy, myopathy, and sensory ataxia; ataxia-neuropathy spectrum; Leigh disease; and autosomal dominant / recessive progressive external ophthalmoplegia. Results A total of 3729 genetic reports and 4256 hospital records were screened. Twenty-two patients with pathogenic variants were included. Phenotypically, patients were classifiable into Alpers-Huttenlocher syndrome (8/22; 36.4%), progressive external ophthalmoplegia (8/22; 36.4%), Leigh disease (2/22; 9.1%), ataxia-neuropathy spectrum (2/22; 9.1%), and unclassified (2/22; 9.1%). The prominent clinical manifestations included developmental delay (n = 14; 63.7%), neuroregression (n = 14; 63.7%), encephalopathy (n = 11; 50%), epilepsy (n = 11; 50%), ophthalmoplegia (n = 8; 36.4%), and liver dysfunction (n = 8; 36.4%). Forty-four pathogenic variants were identified at 13 loci, and these were clustered at exonuclease (18/44; 40.9%), linker (13/44; 29.5%), polymerase (10/44; 22.7%), and N-terminal domains (3/44; 6.8%). Genotype-phenotype analysis suggested that serious outcomes including neuroregression (odds ratio [OR] 11, 95% CI 2.5, 41), epilepsy (OR 9, 95% CI 2.4, 39), encephalopathy (OR 5.7, 95% CI 1.4, 19), and hepatic dysfunction (OR 4.6, 95% CI 21.3, 15) were associated with at least 1 variant involving linker or polymerase domain. Conclusions We describe the clinical subgroups and their associations with different POLG domains. These can aid in the development of follow-up and management strategies of presymptomatic individuals.

Temporal Knowledge Graphs (Temporal KGs) extend regular Knowledge Graphs by providing temporal scopes (e.g., start and end times) on each edge in the KG. While Question Answering over KG (KGQA) has received some attention from the research community, QA over Temporal KGs (Temporal KGQA) is a relatively unexplored area. Lack of broadcoverage datasets has been another factor limiting progress in this area. We address this challenge by presenting CRONQUESTIONS, the largest known Temporal KGQA dataset, clearly stratified into buckets of structural complexity. CRONQUESTIONS expands the only known previous dataset by a factor of 340×. We find that various state-of-the-art KGQA methods fall far short of the desired performance on this new dataset. In response, we also propose CRONKGQA, a transformerbased solution that exploits recent advances in Temporal KG embeddings, and achieves performance superior to all baselines, with an increase of 120% in accuracy over the next best performing method. Through extensive experiments, we give detailed insights into the workings of CRONKGQA, as well as situations where significant further improvements appear possible. In addition to the dataset, we have released our code as well.1. The underlying KG is a Temporal KG.2. The answer is either an entity or time duration. 3. Complex temporal reasoning might be needed. KG Embeddings are low-dimensional dense vector representations of entities and relations in a KG. Several methods have been proposed in the literature to embed KGs (Bordes et al. 2013, Trouillon et al. 2016, Vashishth et al. 2020). These embeddings were originally proposed for the task of KG completion i.e., predicting missing edges in the KG, since most real world KGs are incomplete. Recently, however, they have also been applied to the task of KGQA where they have been shown to increase performance the settings of both of complete and incomplete KGs (Saxena et al. 2020;).

Background: Hypernatremic dehydration is an uncommon but a serious cause of readmission in neonates especially in the ones on exclusive breast-feeding. The management of such neonates is challenging as serious complications can occur both because of hypernatremic dehydration and its rapid correction. The aim was to study the clinical profile of neonates with hypernatremic dehydration and determine the outcome of these neonates after appropriate management.Methods: This is a prospective cross-sectional observational study of neonates readmitted with hypernatremic dehydration in a tertiary care hospital in a 12-month period from March 2017 to February 2018. The inclusion criterion was as follows: all neonates with serum sodium >145 mEq/l. The exclusion criteria were as follows: neonates with hypoglycemia, positive sepsis screen and any other congenital diseases. Neonates with serum sodium between 145 and 160 mEq/l were treated with supervised quantified oral feeds at 150 ml/kg/day, unless they had features of shock. Neonates who had serum sodium !160 mEq/l were given intravenous (IV) fluids initially.Results: A total of 2412 deliveries took place during the study period. Hypernatremic dehydration was reported in 46 (1.9%) of them, which required admission. We found that all these neonates were exclusively breast-fed, with 81.3% neonates born to primigravidae.One neonate presented with seizures, and one, with metabolic acidosis. More than 50% neonates had acute kidney injury (AKI) on admission. No neonates in our study developed central nervous system (CNS) complications such as cerebral venous thrombosis, convulsions or intracranial haemorrhage, and complete recovery from AKI was documented in all neonates.

BackgroundAicardi-Goutières syndrome (AGS) is a genetic inflammatory disorder that presents with early infantile encephalopathy. We report the clinical and molecular details of multiple members of a family with AGS secondary to a novel RNASEH2C mutation, highlighting the evolution of phenotypic abnormalities in AGS.MethodsBetween February 2018 and June 2019, a pedigree tree was constructed for 141 members of a family. The clinical and radiological details of 14 symptomatic children were chronicled and compared with the asymptomatic family members. Genetic analysis was performed on 23 individuals (six symptomatic). This involved whole exome sequencing for one patient and confirmation of the identified indel variant in other family members.ResultsThe symptomatic children were diagnosed as AGS secondary to a novel indel variation in exon 2 of the RNASEH2C gene (chr11:65487843_65487846delinsGCCA). Clinically, between the ages of 2 and 6 months, the symptomatic children developed irritability (14/14), unexplained fever (9/14), chill blains (12/14), sleep irregularities (14/14) and developmental delay (14/14), with deterioration to vegetative state at a median (IQR) age of 10.5 months (9.25–11). In addition, chill blains were observed in 5/17 (29.4%) carrier individuals. Neuroimaging demonstrated a gradual progression of calcification involving basal ganglia, periventricular white matter and dentate nucleus. Three patients also demonstrated presence of subependymal germinolytic cysts.ConclusionThis report highlights a novel founder RNASEH2C mutation and the phenotypic evolution of AGS. In addition, we report chill blains in one-third of RNASEH2C mutation carriers. Neuroradiologically, the report illustrates novel MRI findings and demonstrates a progression pattern of disease. These findings will aid in earlier suspicion and diagnosis of AGS.