| Pathogenic mechanism | Evidence source/type | Key molecular players/pathways | Cellular processes affected | GO/CL term suggestions | Supporting references |
|---|---|---|---|---|---|
| Noncoding CGG/GGC repeat expansion as initiating mutation | Human genetic studies; long-read sequencing; clinicogenetic cohorts | Expanded CGG/GGC repeats in **LRP12, GIPC1, NOTCH2NLC, RILPL1, LOC642361/NUTM2B-AS1, ABCD3**; repeat length, flanking sequence context, and CpG methylation modulate phenotype | Repeat instability, altered transcriptional/epigenetic state, genotype-phenotype correlation | GO:0006351 transcription, DNA-templated; GO:0006306 DNA methylation; GO:0006996 organelle organization; CL:0000187 muscle cell | (pqac-00000005, pqac-00000013, pqac-00000014) |
| RAN / non-AUG-associated translation into toxic polyglycine proteins | Cell models; human muscle pathology; mouse and fly models | **uGIPpolyG, uN2CpolyG, asRILpolyG, LOC6polyG, LRP12-associated polyG**; initiation from upstream AUG/near-cognate codons or noncanonical mechanisms; repeat translated predominantly in glycine frame | Aberrant translation of repeat-containing transcripts; production of aggregation-prone polyglycine proteins | GO:0006412 translation; GO:0034059 response to unfolded protein; GO:0017148 negative regulation of translation; CL:0000187 muscle cell, CL:0000540 neuron | (pqac-00000007, pqac-00000009, pqac-00000015, pqac-00000018) |
| Polyglycine protein toxicity | Cell models; iPSC-derived myotubes; mouse skeletal muscle and CNS models | PolyG proteins derived from expanded repeats; cytotoxicity correlates with inclusion formation and subtype-specific flanking sequences | Cell death, myofiber atrophy, locomotor deficits, neurodegeneration, shortened lifespan | GO:0008219 cell death; GO:0016043 cellular component organization; GO:0048856 anatomical structure development; CL:0000187 muscle cell, CL:0002319 myotube, CL:0000540 neuron | (pqac-00000015, pqac-00000016, pqac-00000017) |
| Protein aggregation and p62/ubiquitin-positive intranuclear inclusions | Human muscle biopsy; cell models; mouse models | **SQSTM1/p62, ubiquitin, SUMO1**, poly-ubiquitinated proteins; eosinophilic intranuclear inclusions and rimmed vacuoles | Protein quality control failure, aggregate sequestration, inclusion formation in myonuclei and non-muscle cells | GO:0061684 chaperone-mediated autophagy; GO:0016567 protein ubiquitination; GO:0097352 autophagosome organization; CL:0000187 muscle cell, CL:0000359 skeletal muscle fiber | (pqac-00000001, pqac-00000006, pqac-00000015, pqac-00000016, pqac-00000017) |
| RNA toxicity / RNA gain-of-function | Human muscle studies; mechanistic reviews; immunofluorescence-based studies | Expanded CGG-repeat RNAs; **RNA foci**, RNA-binding proteins including **hnRNP A/B** and **MBNL1** discussed/assessed; disruption of RNA metabolism proposed | RNA sequestration, impaired RNA processing, altered RNA metabolism | GO:0008380 RNA splicing; GO:0016071 mRNA metabolic process; GO:0003723 RNA binding; CL:0000187 muscle cell, CL:0000540 neuron | (pqac-00000003, pqac-00000005, pqac-00000007, pqac-00000014) |
| Nuclear architecture disruption | Cell models; transfected skeletal muscle cells | LRP12-associated polyG inclusions alter **Lamin B1 / nuclear lamina** architecture; nuclear rather than cytosolic localization in muscle | Nuclear envelope stress, altered nuclear organization, impaired nucleo-cytoplasmic homeostasis | GO:0005635 nuclear envelope; GO:0006998 nuclear envelope organization; GO:0051290 protein heterooligomerization; CL:0000187 muscle cell | (pqac-00000007, pqac-00000015) |
| Mitochondrial dysfunction and oxidative phosphorylation defects | Drosophila model; human NIID/NOTCH2NLC-related muscle samples; cellular studies | **uN2CpolyG**, **LRPPRC**, oxidative phosphorylation genes/pathways; idebenone-responsive mitochondrial dysfunction | Mitochondrial swelling, impaired oxidative phosphorylation, energy failure, progressive neurodegeneration | GO:0005739 mitochondrion; GO:0006119 oxidative phosphorylation; GO:0007005 mitochondrion organization; CL:0000540 neuron, CL:0000187 muscle cell | (pqac-00000019) |
| Disturbance of proteostasis / ubiquitin-proteasome and autophagy-related pathways | Human RNA-seq; cell and animal models | **Ubiquitin-mediated proteolysis**, **p53 signaling**, ribosome pathways; p62-positive inclusions; altered protein turnover | Proteostasis imbalance, stress signaling, impaired degradation of toxic species | GO:0010498 proteasomal protein catabolic process; GO:0006914 autophagy; GO:0006977 DNA damage response; CL:0000187 muscle cell | (pqac-00000000, pqac-00000010, pqac-00000016) |
| Gene-specific epigenetic modulation and incomplete penetrance | Human long-read methylation studies; family-based analyses | Upstream-region **CpG methylation**, especially in **LRP12** and **NOTCH2NLC**; hypermethylation associated with delayed onset or asymptomatic carriers | Epigenetic silencing/modulation of toxic repeat effects; age-at-onset modification | GO:0006306 DNA methylation; GO:0040029 regulation of gene expression, epigenetic; CL:0000000 cell | (pqac-00000005, pqac-00000013, pqac-00000014) |
| Somatic repeat-size variability and repeat instability | Human nanopore/long-read sequencing | Intra-patient variability of expanded repeats, especially in **LRP12** and **NOTCH2NLC**; structural variation in expanded alleles | Somatic mosaicism, dynamic mutation behavior, tissue-level heterogeneity | GO:0006310 DNA recombination; GO:0006281 DNA repair; CL:0000000 cell | (pqac-00000005, pqac-00000013) |
| Multisystem overlap with NIID/FNOP spectrum | Human clinical-pathologic studies; review synthesis | **NOTCH2NLC** links OPDM to **NIID**; shared inclusions and overlapping CNS/PNS manifestations support common disease biology | Shared neuromyodegenerative processes across muscle, peripheral nerve, retina, and CNS | GO:0048856 anatomical structure development; GO:0007268 synaptic transmission; CL:0000540 neuron, CL:0000187 muscle cell, CL:0000125 glial cell | (pqac-00000001, pqac-00000004, pqac-00000011, pqac-00000014) |
| Therapeutic mechanism-of-action leads under investigation | Animal models; cell models | **Idebenone** improved mitochondrial dysfunction in NOTCH2NLC fly model; **TMPyP4** reduced polyglycine abundance/toxicity and appears to act mainly on translation | Rescue of mitochondrial function; reduction of toxic protein expression/aggregation | GO:1902600 proton transmembrane transport; GO:0017148 negative regulation of translation; CL:0000540 neuron, CL:0000187 muscle cell | (pqac-00000017, pqac-00000019) |


*Table: This table summarizes the main pathogenic mechanisms proposed for oculopharyngodistal myopathy and links each mechanism to the evidence type, molecular players, affected cellular processes, and ontology suggestions. It is useful for curating pathophysiology across OPDM subtypes and distinguishing well-supported mechanisms from emerging ones.*