Myofibrillar myopathies (MFMs) are a heterogeneous group of neuromuscular disorders characterized by disintegration of myofibrils. The inheritance pattern in MFMs is commonly autosomal dominant, but there has been a striking absence of secondary cases noted in a BAG3-associated subtype. We studied three families with BAG3 p.Pro209Leu mutation showing a severe phenotype of myofibrillar myopathy and axonal neuropathy with giant axons. In one family, transmission to a pair of siblings has occurred from their asymptomatic father who showed somatic mosaicism. In two other families, neither of the parents was affected or showed detectable level of somatic mosaicism. These observations suggest that the BAG3 variant of MFM may result from a spontaneous mutation at an early point of embryonic development and that transmission from a mosaic parent may occur more than once. The study underlines the importance of parental evaluation as it may have implications for genetic counseling.

Policy and practice aspirations for care leavers recommend gradual change but transfer rather than transition continues to be described by care leavers. Our data support the need for transition as a long-term process, with children and young people having early opportunities to prepare for citizenship.

Objective The objective of this study was to evaluate the presenting features of bone and joint infections with a view to identify distinguishing trends that will be useful for pediatric emergency departments. Methods We performed a retrospective review of patient records over a 12-year period in the pediatric emergency department of a large regional pediatric teaching center serving a diverse population. Results There were 88 cases of osteoarticular infections during the study period. Pain, fever, and impaired function were commonly reported, but overall, there was inconsistency in the presenting features. Inflammatory makers were sensitive tools, particularly in combination. When C-reactive protein, total white cell count, and erythrocyte sedimentation rate were all abnormal, 98% of bone and joint infections were identified. Causative organisms were identified in only 38% of cases, mostly from cultures of synovial fluid and bone. Streptococcal organisms were significantly more likely to be isolated in children under 5 years than in children over 5 years (P = <0.014). Staphylococcal organisms were significantly more likely to be isolated in children over 5 years than in children under 5 years (P = <0.001). Identification of virulent organisms such as Panton-Valentine leukocidin Staphylococcus aureus and methicillin-resistant S. aureus in our study should prompt review of diagnostic techniques and antibiotic choices. Conclusions Overall, children under 5 years were significantly more likely to be diagnosed with septic arthritis than osteomyelitis (P = 0. 006). Children over 12 years were significantly more likely to be diagnosed with osteomyelitis than septic arthritis (P = 0. 019). These trends are useful to consider at presentation and in cases of diagnostic uncertainty.

Purpose Lamins are the major component of nuclear lamina, maintaining structural integrity of the nucleus. Lamin A/C variants are well established to cause a spectrum of disorders ranging from myopathies to progeria, termed laminopathies. Phenotypes resulting from variants in LMNB1 and LMNB2 have been much less clearly defined. Methods We investigated exome and genome sequencing from the Deciphering Developmental Disorders Study and the 100,000 Genomes Project to identify novel microcephaly genes. Results Starting from a cohort of patients with extreme microcephaly, 13 individuals with heterozygous variants in the two human B-type lamins were identified. Recurrent variants were established to be de novo in nine cases and shown to affect highly conserved residues within the lamin ɑ-helical rod domain, likely disrupting interactions required for higher-order assembly of lamin filaments. Conclusion We identify dominant pathogenic variants in LMNB1 and LMNB2 as a genetic cause of primary microcephaly, implicating a major structural component of the nuclear envelope in its etiology and defining a new form of laminopathy. The distinct nature of this lamin B–associated phenotype highlights the strikingly different developmental requirements for lamin paralogs and suggests a novel mechanism for primary microcephaly warranting future investigation.

Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.