MTAP associated autosomal-dominant myopathy diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH), in addition to osteosarcoma is a rare novel disorder. The disease has been previously mapped to chromosomal region 9p21-22 and mutations in the gene encoding methylthioadenosine phosphorylase, MTAP has been implicated. DMS-MFH results from mutations in the most proximal of three previously uncharacterized terminal exons of MTAP a ubiquitously expressed homotrimeric-subunit enzyme critical to polyamine metabolism and adenine and methionine salvage pathways.
Discovery of these three terminal exons has shown that there are six distinct MTAP isoforms naturally occurring within the human body, although the roles of each splice variant, if any, are yet to be determined. The disease-causing mutations results in exon skipping and dysregulated alternative splicing of all MTAP isoforms.
The precise metabolite resulting from disruption of the MTAP metabolic pathway and mechanism that result in this unique disease is still unknown.
On characterizing the histology of the myopathy, varied muscle fiber size, and increased number of centralized nuclei was found. The autophagic pathway is implicated as indicated by increased levels of P62 and LC3 in the muscle fibers.
Characterization of the key metabolic mechanism of bone dysplasia, myopathy, and bone cancer in DMS-MFH offers the potential to uncover key molecular pathways and the promise of novel future treatments.