Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations.

Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem disorder caused by compound heterozygous or homozygous variants in the gene OTUD6B. Herein, we describe novel pathogenic compound heterozygous variants in OTUD6B identified via whole-exome sequencing in an index case exhibited the severe IDDFSDA phenotype. The potential pathogenicity of the novel frameshift and missense variants in the index case was investigated using in silico tools. The truncating frameshift variant in one allele was predicted to undergo degradation via nonsense-mediated decay of the mRNA molecule. To predict the severity of the damage to the protein caused by the missense variant in the other allele and its effects on phenotypic severity was further investigated together with a previously reported first homozygous missense variant in the same domain in another patient with a less severe IDDFSDA phenotype using structural modeling and molecular dynamics (MD) simulations for the first time. Based on these analyzes, it is anticipated that Tyr216Cys in the earlier reported case with less severe IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the presented index case with the severe IDDFSDA phenotype will lead to significant distortion in the overall fold of OTUD6B. Our findings suggest that compound LOF and ultrarare missense variants may be contribute to the underlying variability expressivity associated with this disorder. In conclusion, our findings support that the clinical severity could be related with the predicted functional severity of the variations in OTUD6B. However, additional functional studies are required.

Evaluation of the Efficacy and Safety of 3 Different Management Protocols in Pediatric Diabetic Ketoacidosis.

OBJECTIVE: Management protocols for pediatric diabetic ketoacidosis (DKA) vary considerably among medical centers. The aim of this study was to investigate the efficacy and safety of 3 different fluid protocols in the management of DKA. METHODS: Fluid management protocols with sodium contents of 75, 100, and 154 mEq/L NaCl were compared. In all groups, after the initial rehydration, the protocols differed from each other in terms of the maintenance fluid, which had different rates of infusion and sodium contents. Clinical status and blood glucose levels were checked every hour during the first 12 hours. Biochemical tests were repeated at 2, 6, 12, 24, and 36 hours. RESULTS: The medical records of 144 patients were evaluated. Cerebral edema developed in 18% of the patients. The incidence of cerebral edema was lowest in the group that received fluid therapy with a sodium content of 154 mEq/L NaCl at least 4 to 6 hours and had a constant rate of infusion for 48 hours. The patients with cerebral edema had lower initial pH and HCO3 and severe dehydration with higher initial plasma osmolality. There was no significant difference between the groups in terms of the recovery times of blood glucose, pH, HCO3, and the time of transition to subcutaneous insulin therapy. CONCLUSIONS: Severity of acidosis and dehydration are associated with the development of cerebral edema. It can be concluded that fluid therapy with higher Na content and a constant maintenance rate may present less risk for the patient with DKA.