SELENON-Congenital Myopathy (SELENON-CM), defined on the basis of recessive SELENON gene mutations, is characterized by spinal and axial muscle weakness with progressive respiratory insufficiency. There are no effective treatments for SELENON-CM. Natural history studies in SELENON-CM patients report insulin-resistance as well as altered body mass index, both of which correlate with disease severity. The SELENON gene encodes selenoprotein N, a reductase enzyme involved in redox reactions located at the sarcoplasmic/endoplasmic reticulum membrane. The molecular mechanism(s) by which selenoprotein N deficiency causes SELENON-CM are undetermined. The most common histopathological features in muscle biopsies are multiminicores (areas of mitochondrial depletion) or a dystrophic presentation. However, there are no studies defining the cellular composition of these biopsies. In this project, we used spatial transcriptomics (ST) and single nuclei RNA sequencing (snRNAseq) to discover the cellular composition and generate pathway analyses of patient biopsies with SELENON-CM. Our ST study consisted of two quadricep patient biopsies that were age-matched and compared to non-disease quadricep muscles. We found that all samples were mostly composed of fast-twitch fibers with fewer slow-twitch fibers. In addition, differential expression (DE) analysis identified overexpression of KEGG pathway “Diabetic Cardiomyopathy”, “AMPK Signaling”, transcripts, among others, in patient samples. To validate these data and increase sensitivity, we performed snRNAseq in three patient samples and four non-disease controls. These studies identified significant increase in immune, fibroblast, adipocyte, and fibroadipogenic cell populations in our patient samples when compared to healthy controls. DE analysis of all myofibers subgroups also identified increased expression of genes from a number of metabolic pathways, most notably “Diabetic Cardiomyopathy” and “AMPK Signaling”. Together, these data can help us understand the pathology of SELENON-CM as well as elucidate pathways that may lead to identification of therapeutic targets for the treatment of this disease.