| domain | key entities/findings | suggested ontology terms/IDs | evidence notes |
|---|---|---|---|
| disease definition | Inherited protein-aggregate myopathy characterized by myofibrillar dissolution beginning at the Z-disc, accumulation of desmin/myotilin/\u03b1B-crystallin and other proteins, and progressive skeletal \u00b1 cardiac/respiratory involvement | MONDO: myofibrillar myopathy **[suggested; validate]**; MeSH: Myopathies **[broader; validate]**; GO: sarcomere organization (GO:0045214), protein-containing complex assembly (GO:0065003) | Workshop and reviews describe MFM as Z-disc-initiated myofibrillar degradation with pleomorphic aggregates and multisystem muscle involvement (pqac-00000004, pqac-00000001) |
| core causal genes | **DES**, **CRYAB**, **MYOT**, **LDB3**/**ZASP**, **FLNC**, **BAG3** | HGNC gene symbols; OMIM-linked disease subtypes **[suggested; validate exact IDs]** | Recurrent/core MFM genes consistently listed across reviews and workshop synthesis (pqac-00000001, pqac-00000004) |
| expanded/associated genes | **FHL1, TTN, DNAJB6, PLEC, ACTA1, HSPB8, PYROXD1, SQSTM1/TIA1**; additional overlap genes reported in MFM/protein aggregate myopathy spectrum | HGNC symbols; MONDO disease links **[suggested; validate]** | Expanded genetic heterogeneity emphasized in genomic-context review and ENMC workshop; Japanese screening found a molecular diagnosis in 34% of 297 cases, with **TTN** most common among solved cases (pqac-00000000, pqac-00000004) |
| inheritance | Predominantly autosomal dominant; variable penetrance/expressivity; some recessive, X-linked, and digenic examples reported in expanded spectrum | HP: Family history (HP:0032316) **[suggested]**; inheritance terms from HPO/GENO **[suggested; validate]** | Autosomal dominant inheritance is typical for classic forms, but broader genomic studies show heterogeneous inheritance patterns (pqac-00000001, pqac-00000000) |
| phenotype: muscle weakness | Slowly progressive proximal, distal, scapuloperoneal, or limb-girdle weakness; axial/facial weakness can occur | HP: Muscle weakness (HP:0001324), Proximal muscle weakness (HP:0003701), Distal muscle weakness (HP:0002460), Axial muscle weakness (HP:0003323), Facial weakness (HP:0000204) | Major phenotype across cohorts and reviews; onset and distribution are genotype-dependent (pqac-00000004, pqac-00000002, pqac-00000003) |
| phenotype: progression/onset | Usually chronic progressive disease; many classic forms adult-onset, but BAG3 and some TTN-related forms can begin in childhood or earlier | HP: Progressive muscle weakness (HP:0003323 **[broader/validate]**), Adult onset (HP:0003581), Childhood onset (HP:0011463) | Mayo/French cohorts summarized by ENMC showed mean onset ages ~52 and ~42 years; genotype-specific childhood onset noted for BAG3opathy (pqac-00000004, pqac-00000002) |
| phenotype: cardiac | Cardiomyopathy, conduction disease, arrhythmia; some patients require pacemaker/defibrillator or transplantation | HP: Cardiomyopathy (HP:0001638), Arrhythmia (HP:0011675), Cardiac conduction abnormality (HP:0000076), Pacemaker implantation **[procedure term, validate]** | Cardiac involvement is a major morbidity driver; reviews cite frequent cardiac disease and intervention needs, especially in DES/BAG3-related disease (pqac-00000001, pqac-00000002) |
| phenotype: respiratory | Respiratory insufficiency/restrictive respiratory involvement; early respiratory failure in some genotypes; ventilatory support may be required | HP: Respiratory insufficiency (HP:0002093), Restrictive ventilatory defect (HP:0002091), Sleep-disordered breathing (HP:0002360) **[suggested]** | Respiratory dysfunction occurs in a substantial subset; one review notes ~one-third with respiratory insufficiency/dysphagia, with severe BAG3 cases showing high respiratory burden (pqac-00000001, pqac-00000002) |
| phenotype: neuropathy | Peripheral neuropathy may accompany myopathy, often axonal/sensorimotor; can complicate phenotypic classification | HP: Peripheral neuropathy (HP:0009830), Axonal neuropathy (HP:0003447), Sensorimotor neuropathy (HP:0007141) | ENMC and cohort data note peripheral neuropathy in subsets; Chinese series reported motor/sensorimotor axonopathy predominance (pqac-00000000, pqac-00000002) |
| phenotype: bulbar/other | Dysphagia, dysphonia, stiffness, myalgia, ophthalmoparesis, contractures/spine deformity in some subtypes | HP: Dysphagia (HP:0002015), Dysphonia (HP:0001618), Myalgia (HP:0003326), Ophthalmoparesis (HP:0000602), Joint contracture (HP:0001371), Scoliosis (HP:0002650) | Recognized but variably frequent features in workshop and gene-specific series (pqac-00000004, pqac-00000002, pqac-00000003) |
| pathology/histology | Myofibrillar dissolution starts at Z-disc; protein aggregates; hyaline/eosinophilic inclusions; rimmed vacuoles; desmin/myotilin/\u03b1B-crystallin accumulation; Z-line streaming on EM | GO CC: Z disc (GO:0030018), myofibril (GO:0030016), sarcomere (GO:0030017); HP: Rimmed vacuoles (HP:0003795), Myofibrillar disorganization **[suggested]** | Defining pathologic pattern across MFM subtypes and myotilinopathy/filaminopathy literature (pqac-00000004, pqac-00000003, pqac-00000005) |
| molecular mechanism: Z-disc failure | Disease proteins cluster at/around the Z-disc, disrupting force transmission and sarcomere integrity | GO: sarcomere organization (GO:0045214), actin filament organization (GO:0007015), muscle filament sliding (GO:0030049) | Z-disc proteins such as FLNC, MYOT, ZASP/LDB3, DES are central to MFM pathogenesis (pqac-00000005, pqac-00000001) |
| molecular mechanism: proteostasis/CASA | Misfolding/aggregation with impaired chaperone-assisted selective autophagy (CASA), aggrephagy, UPS/autophagy stress responses; BAG3/HSPB8/DNAJB6 network implicated | GO: autophagy (GO:0006914), selective autophagy (GO:0061919), protein folding (GO:0006457), response to unfolded protein (GO:0006986), ubiquitin-dependent protein catabolic process (GO:0006511) | Reviews connect MFM to defective protein quality control near the sarcomere; BAG3 and DNAJB6 are highlighted in protein aggregate myopathy biology (pqac-00000000, pqac-00000001) |
| molecular mechanism: aggregate toxicity | Aggregates contain Z-disc and stress-response proteins and likely contribute to myofiber dysfunction rather than being purely epiphenomenal | GO: protein-containing complex disassembly (GO:0043624), aggrephagy **[GO mapping validate]** | Protein aggregation is a defining lesion in MFM and broader protein aggregate myopathies (pqac-00000004, pqac-00000005) |
| molecular mechanism: mitochondria/metabolism | Especially in desmin-related disease, mitochondrial architecture, respiration, and metabolic activity can be impaired, contributing to cardiomyopathy | GO: mitochondrial organization (GO:0007005), oxidative phosphorylation (GO:0006119), ATP metabolic process (GO:0046034) | 2024 hiPSC-cardiomyocyte study of **DES E439K** linked mutant desmin to mitochondrial defects and contractile dysfunction (pqac-00000007) |
| anatomy: primary organs | Skeletal muscle is primary; heart and respiratory musculature are frequent secondary/parallel targets | UBERON: skeletal muscle tissue (UBERON:0001134), heart (UBERON:0000948), diaphragm (UBERON:0001103), respiratory system (UBERON:0001004) | Clinical burden spans neuromuscular, cardiac, and respiratory systems (pqac-00000001, pqac-00000004) |
| anatomy: tissue/cell types | Striated muscle fibers/myofibers; cardiomyocytes; peripheral nerve involvement in subsets | CL: skeletal muscle fiber (CL:0000188), cardiomyocyte (CL:0000746), neuron (CL:0000540), Schwann cell (CL:0002573) **[suggested]** | Reviews and cohorts support primary involvement of skeletal/cardiac muscle with occasional neuropathic features (pqac-00000002, pqac-00000005) |
| subcellular localization | Z-disc, sarcomere, myofibril, intermediate filament network, protein aggregates, mitochondria | GO CC: Z disc (GO:0030018), sarcomere (GO:0030017), myofibril (GO:0030016), intermediate filament (GO:0005882), mitochondrion (GO:0005739), protein-containing aggregate (GO:0061702) | Subcellular sites align with pathology and mechanism across major MFM genes (pqac-00000001, pqac-00000005, pqac-00000007) |
| diagnostics: biopsy | Muscle biopsy remains key: modified Gomori trichrome, immunohistochemistry for desmin/myotilin/\u03b1B-crystallin/BAG3, EM for Z-line streaming/disarray | NCIT: Muscle Biopsy (C51895) **[suggested]**; HP pathology terms above | Biopsy defines the MFM pattern and helps triage genetic testing (pqac-00000004, pqac-00000002, pqac-00000003) |
| diagnostics: electrophysiology | EMG usually myopathic with abnormal electrical irritability; NCS may reveal axonal or sensorimotor neuropathy in mixed phenotypes | NCIT: Electromyography (C38054) **[suggested]**; nerve conduction study **[suggested]** | ENMC notes myopathic EMG patterns; cohort data show neuropathy in subsets (pqac-00000000, pqac-00000002) |
| diagnostics: imaging | Muscle MRI can show characteristic distribution patterns aiding subtype recognition and differential diagnosis | NCIT: Magnetic Resonance Imaging (C16809) **[suggested]** | Reviews note MRI utility as part of diagnostic work-up in hereditary myopathies including MFM (pqac-00000001) |
| diagnostics: cardiac/respiratory assessment | ECG, echocardiography, Holter, pulmonary function testing, sleep/ventilation assessment according to symptoms/genotype | NCIT: Electrocardiography (C38053), Echocardiography (C16550), Pulmonary Function Test (C38036) **[suggested]** | Cardiac and respiratory complications are common enough to justify systematic surveillance in many patients (pqac-00000001, pqac-00000002) |
| diagnostics: genomics | NGS gene panels, WES/WGS increasingly used because phenotype overlaps with muscular dystrophies/distal myopathies; genomics expanded solved gene list | NCIT: Next Generation Sequencing (C126060), Whole Exome Sequencing (C101294), Whole Genome Sequencing (C150810) **[suggested]** | Genomic-context review and ENMC workshop emphasize heterogeneous genetics and value of NGS; 2024 neuromuscular gene table reflects updated gene-disease curation (pqac-00000000, pqac-00000001) |
| differential diagnosis | Distal myopathies, limb-girdle muscular dystrophies, hereditary myopathy with early respiratory failure, inclusion body myositis, congenital myopathies with aggregates, neuropathy-plus-myopathy syndromes | MONDO/HPO differential terms **[suggested; validate]** | Consider broad overlap because MFM pathology and genetics intersect multiple inherited myopathy groups (pqac-00000000, pqac-00000004) |
| prognosis | Variable but chronic progressive; morbidity driven by loss of ambulation, cardiomyopathy/arrhythmia, respiratory failure, and occasionally sudden death or transplant need | HP: Reduced mobility (HP:0002374) **[suggested]**, Sudden cardiac death (HP:0001645) | Severity depends strongly on genotype; BAG3 and some DES forms can be particularly aggressive (pqac-00000001, pqac-00000002) |
| treatment/supportive care | No approved disease-modifying therapy established; multidisciplinary supportive care includes physiotherapy, orthotics, respiratory support, cardiac rhythm management, heart failure therapy, pacemaker/ICD, transplantation in selected cases | NCIT: Physical Therapy (C15313), Orthotic Device Use **[suggested]**, Ventilatory Support (C15785), Cardiac Pacing (C99532), Implantable Cardioverter Defibrillator Placement (C99925), Heart Transplantation (C15239) **[all suggested; validate]** | Reviews emphasize supportive management and organ-specific interventions; no definitive pharmacologic cure cited (pqac-00000001, pqac-00000000) |
| prevention/genetic counseling | Cascade testing, reproductive counseling, and early cardiac/respiratory surveillance in at-risk relatives are pragmatic secondary/tertiary prevention strategies | NCIT: Genetic Counseling (C15271); cascade screening **[suggested]** | Given inherited and variably penetrant nature, family-based testing and surveillance are clinically relevant (pqac-00000001, pqac-00000000) |
| model systems | Animal and cellular models include mouse, zebrafish, Drosophila, and patient-derived/iPSC systems for DES/CRYAB/FLNC/BAG3 and related genes | NCBITaxon: Mus musculus (10090), Danio rerio (7955), Drosophila melanogaster (7227); Cell line/iPSC model terms **[suggested]** | Animal-model review highlights broad model ecosystem; 2024 desmin cardiomyopathy work used patient-derived/gene-edited hiPSC cardiomyocytes (pqac-00000001, pqac-00000007) |
| evidence gaps | Exact MONDO/Orphanet/HPO mappings for all subtypes, population prevalence/incidence, penetrance, and modifier genes often require source-by-source validation | Ontology IDs in this table are **suggestions requiring database validation where uncertain** | MFM remains genetically and phenotypically heterogeneous, and many summary statistics come from specialized cohorts rather than population registries (pqac-00000000, pqac-00000001, pqac-00000004) |


*Table: This compact table organizes key disease, gene, phenotype, mechanism, anatomy, diagnostic, and intervention facts for myofibrillar myopathy into a knowledge-base-friendly format. Suggested ontology mappings are included for rapid curation, but uncertain IDs should be validated against source ontologies before ingestion.*