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.