MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy

UNLABELLED Infantile movement disorders are rare and genetically heterogeneous. We set out to identify the disease-causing mutation in siblings with a novel recessive neurodegenerative movement disorder. Genetic linkage analysis and whole-exome sequencing were performed in the original family. A cohort of six unrelated patients were sequenced for further mutations in the identified candidate gene. Pathogenicity of the mutation was evaluated by in silico analyses and by structural modeling. We identified the first and homozygous mutation (p.Gly114Ala) in the Mediator subunit 20 gene (MED20) in siblings presenting with infantile-onset spasticity and childhood-onset dystonia, progressive basal ganglia degeneration, and brain atrophy. Mediator refers to an evolutionarily conserved multi-subunit RNA polymerase II co-regulatory complex. Pathogenicity of the identified missense mutation is suggested by in silico analyses, by structural modeling, and by previous reporting of mutations in four distinct Mediator subunits causing neurodegenerative phenotypes. No further MED20 mutations were detected in this study. CONCLUSION We delineate a novel infantile-onset neurodegenerative movement disorder and emphasize the Mediator complex as critical for normal neuronal function. Definitive proof of pathogenicity of the identified MED20 mutation will require confirmation in unrelated patients

Hand MRI and the Greulich-Pyle atlas in skeletal age estimation in adolescents

Objective To evaluate the feasibility of hand MRI in age assessment in adolescents using the Greulich-Pyle (GP) atlas criteria. Materials and methods Two radiologists, who were blinded to the study subjects chronologic ages, semi-objectively evaluated 1.5-T MRIs of the left hands of ten patients (13.52.6 years) who had left-hand radiographs and 50 healthy volunteers (152 years). Results A coronal T1-weighted, volumetric, interpolated, breath-hold examination with water excitation (T1 VIBE-3D-WE) achieved the best image quality. The correlation between estimated patients ages on radiographs and MRI was high. The average estimated age difference between the MRIs and radiographs was 0.05 years for reader 1 and 0.175 years for reader 2. The interclass coefficients (ICCs) showed high interobserver agreement (radiographs: ICC=0.95, MRI: ICC=0.97). The ICC, calculated separately for the male and female volunteers estimated ages by MRI, also showed a high agreement between the two readers (male: ICC=0.97, female: ICC=0.95). Reader 1 estimated 94% of volunteers within 2 standard deviations (SD) and 62% within 1 SD. The results for reader 2 were 92% and 54%, respectively. Thirty-nine percent of girls and 27% of boys were estimated to be older using 1 SD. Conclusion MRI of the left hand is a feasible alternative to hand radiographs for skeletal age estimation in adolescents using the GP criteria with 2 SD. Using 1 SD, the age of healthy volunteers tended to be estimated as higher than the chronologic age. Future studies should evaluate the results in a larger number of participants.(VLID)358223

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies

A Novel Transdermal Delivery System for the Anti-Inflammatory Lumiracoxib: Influence of Oleic Acid on In Vitro Percutaneous Absorption and In Vivo Potential Cutaneous Irritation

Transdermal delivery of non-steroidal anti-inflammatory drugs may be an interesting strategy for delivering these drugs to the diseased site, but it would be ineffective due to low skin permeability. We investigated whether oleic acid (OA), a lipid penetration enhancer in poloxamer gels named poloxamer-based delivery systems (PBDS), can improve lumiracoxib (LM) delivery to/through the skin. The LM partition coefficient (K) studies were carried out in order to evaluate the drug lipophilicity grade (Koctanol/buffer), showing values >1 which demonstrated its high lipophilicity. Both in vitro percutaneous absorption and skin retention studies of LM were measured in the presence or absence of OA (in different concentrations) in PBDS using porcine ear skin. The flux of in vitro percutaneous absorption and in vitro retention of LM in viable epidermis increased in the presence of 10.0% (w/w) OA in 25.0% (w/w) poloxamer gel. In vivo cutaneous irritation potential was carried out in rabbits showing that this formulation did not provide primary or cumulative cutaneous irritability in animal model. The results showed that 25.0% poloxamer gel containing 10.0% OA is potential transdermal delivery system for LM