Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.

Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.

Adequate surgical treatment of periprosthetic femoral fractures following hip arthroplasty does not correlate with functional outcome and quality of life.

PURPOSE: This study aimed to analyse functional outcome and quality of life (QoL) after surgical treatment of periprosthetic femoral fractures (PPF) following total hip arthroplasty (THA). METHODS: This retrospective study assessed 67 patients from 2005 to 2012. Epidemiologic data, surgical details, comorbidities, deaths and postoperative complications were recorded. Functional assessment included Harris Hip Score (HHS) and range of motion (ROM); QoL was assessed using the Short-Form Health Survey of 36 questions (SF-36) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. RESULTS: Mean HHS was 69 ± 21 and ROM 96° ± 17°. Mean SF-36 and WOMAC scores revealed 44 ± 7.2 and 18.9 ± 19.6, respectively. The complication rate was 25.4%; 23.7% of patients died. Analysis revealed no statistical influence on final outcome as a function of fracture type or treatment strategy. Comorbidities seem to influence functional outcome. CONCLUSION: PPF following THA are accompanied by a perceptible decline of function and remarkably high complication rates. In contrast to fracture classification and treatment type, American Society of Anesthesiologists (ASA) score predicts outcome.