A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk insT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits

A Randomized, Prospective Study of Pediatric Patients With Community-acquired Pneumonia Treated With Ceftaroline Versus Ceftriaxone

Background: Community-acquired bacterial pneumonia (CABP) remains a major infection among children, despite the use of pneumococcal vaccination. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic with activity against many bacteria, including Streptococcus pneumoniae (both penicillin-nonsusceptible and multidrug-resistant strains) and Staphylococcus aureus (including methicillin-resistant S. aureus). This article describes the safety, tolerability, and effectiveness of ceftaroline fosamil in the treatment of pediatric patients hospitalized with CABP, from a randomized, active-controlled, observer-blinded clinical study (registration number NCT01530763). Methods: Pediatric patients were stratified into 4 age cohorts and randomized (3:1) to receive either intravenous ceftaroline fosamil or ceftriaxone, with optional oral switch for a total treatment duration of 5-14 days. Enrollment was planned for 160 patients. Data collected included demographics, infection characteristics and pathogens. Treatment-emergent adverse events, clinical outcomes, and microbiologic responses were assessed. Results: Ceftaroline fosamil was well tolerated. Similar percentages of patients in the ceftaroline fosamil (55/121; 45%) and ceftriaxone (18/39; 46%) groups reported treatment-emergent adverse events. Coombs seroconversion was observed in 17% of patients in the ceftaroline fosamil group; however, no evidence of hemolytic anemia or hemolysis was found. No deaths were reported during the study. Ceftaroline fosamil had similar effectiveness to ceftriaxone, with high clinical cure rates at test-of-cure in the modified intent-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus. Conclusions: The results of this study suggest that ceftaroline fosamil may be an important treatment option for pediatric patients hospitalized with CABP