Molecular 400px As of 2020, there seems to be a consensus that aberrant expression of DUX4 in muscle is the cause of<unk> . DUX4 is expressed in extremely small amounts, detectable in 1 out of every 1000 immature muscle cells (myoblast), which appears to increase after myoblast maturation, in part because the cells fuse as they mature, and a single nucleus expressing DUX4 can provide DUX4 protein to neighboring nuclei from fused cells. It remains an area of active research how DUX4 protein causes muscle damage. DUX4 protein is a transcription factor that regulates many other genes. Some of these genes are involved in apoptosis, such as p53, p21, MYC, and β-catenin, and indeed it seems that DUX4 protein makes muscle cells more prone to apoptosis. Other DUX4 protein-regulated genes are involved in oxidative stress, and indeed it seems that DUX4 expression lowers muscle cell tolerance of oxidative stress. Variation in the ability of individual muscles to handle oxidative stress could partially explain the muscle involvement patterns of<unk> . DUX4 protein downregulates many genes involved in muscle development, including MyoD, myogenin, desmin, and PAX7, and indeed DUX4 expression has shown to reduce muscle cell proliferation, differentiation, and fusion. DUX4 protein regulates a few genes that are involved in RNA quality control, and indeed DUX4 expression has been shown to cause accumulation of RNA with subsequent apoptosis. Estrogen seems to play a role in modifying DUX4 protein effects on muscle differentiation, which could explain why females are lesser affected than males. The cellular hypoxia response has been reported in a single study to be the main driver of DUX4 protein-induced muscle cell death. The hypoxia-inducible factors (HIFs) are upregulated by DUX4 protein, possibly causing pathologic signaling leading to cell death. Another study found that DUX4 expression in muscle cells led to the recruitment and alteration of fibrous/fat progenitor cells, which helps explain why muscles become replaced by fat and fibrous tissue. A single study implicated RIPK3 in DUX4-mediated cell death. Muscle histology Microscopic cross-sectional views of<unk> -affected muscle fibers. Visible is inflammation and fibrosis, as well as muscle fiber shape change, death, and regeneration. Unlike other muscular dystrophies, early muscle biopsies show only mild degrees of fibrosis, muscle fiber hypertrophy, and displacement of nuclei from myofiber peripheries (central nucleation). More often found is inflammation. There can be endomysial inflammation, primarily composed of CD8+ T-cells, although these cells do not seem to directly cause muscle fiber death. Endomysial blood vessels can be surrounded by inflammation, which is relatively unique to<unk> , and this inflammation contains CD4+ T-cells. Inflammation is succeeded by deposition of fat (fatty infiltration), then fibrosis. Individual muscle fibers can appear whorled, moth-eaten, and, especially, lobulated. Muscle involvement pattern Why certain muscles are preferentially affected in<unk>  remains unknown. There are multiple trends of involvement seen in<unk> , possibly hinting at underlying pathophysiology. Individual muscles can weaken while adjacent muscles remain healthy. The right shoulder and arm muscles are more often affected than the left upper extremity muscles, a pattern also seen in Poland syndrome and hereditary neuralgic amyotrophy; this could reflect a genetic, developmental/anatomic, or functional-related mechanism. The deltoid is often spared, which is not seen in any other condition that affects the muscles around the scapula. Medical imaging (CT and MRI) have shown muscle involvement not readily apparent otherwise * A single MRI study shows the teres major muscle to be commonly affected. * The semimembranosus muscle, part of the hamstrings, is commonly affected, deemed by one author to be "the most frequently and severely affected muscle." * Of the quadricep muscles, the rectus femoris is preferentially affected * Of the gastrocnemius, the medial section is preferentially affected; * The iliopsoas, a hip flexor muscle, is very often spared. Retinopathy Tortuosity of the retinal arterioles, and less often microaneurysms and telangiectasia, are commonly found in<unk> . Abnormalities of the capillaries and venules are not observed. One theory for why the arterioles are selectively affected is that they contain smooth muscle. The degree of D4Z4 contraction correlates to the severity of tortuosity of arterioles. It has been hypothesized that retinopathy is due to DUX4-protein-induced modulation of the CXCR4–SDF1 axis, which has a role in endothelial tip cell morphology and vascular branching.
Facioscapulohumeral muscular dystrophy
Limb–girdle muscular dystrophy
Becker muscular dystrophy
Ullrich congenital muscular dystrophy
Fukuyama congenital muscular dystrophy
Spinal muscular atrophy
Duchenne muscular dystrophy
Jokela type spinal muscular atrophy