UC Irvine

Autosomal‐dominant myopathic disorder associated with diaphyseal medullary stenosis with malignant fibrous his􀆟ocytoma (DMS‐MFH) is characterized by myopathy, bone fragility, and osteosarcoma. DMS‐MFH was recently associated with muta􀆟ons in the methylthioadenosine phosphorylase gene (MTAP). MTAP is a ubiquitously expressed enzyme crucial for polyamine biosynthesis. Two disease‐causing muta􀆟ons have been iden􀆟fied in MTAP: c.813‐2A>G and c.885A>G, both of which result in dysregulated alterna􀆟ve splicing of MTAP isoforms. Here, we report on myopathy in two cousins with the c.813‐2A>G muta􀆟on. Both developed a progressive limb‐girdle type myopathy at age 30 years. To our knowledge, we are the first group to characterize the myopathy associated with DMS‐MFH, discovering varied muscle fiber size, degenera􀆟on, and increased centralized nuclei. In this report, expression levels of transac􀆟ve response DNA‐binding protein (TDP)‐43, light chain (LC)3‐I/II, and p62/sequestome 1 (SQSTM1) in the muscle fibers were increased, sugges􀆟ng a possible dysregula􀆟on of autophagy. Elucida􀆟on of the pathologic mechanism(s) in DMS‐MFH offers the poten􀆟al to uncover key molecular signaling pathways and the promise of novel future treatments.