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Mappings

MONDO

MONDO:0018943 myofibrillar myopathy

Primary MONDO identifier for the myofibrillar myopathy disease group.

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Inheritance

3

Autosomal Dominant HP:0000006

Most myofibrillar myopathy is inherited in an autosomal dominant manner. Heterozygous missense and truncating variants in DES, CRYAB, MYOT, LDB3/ZASP, FLNC and BAG3 each act dominantly (the prototypical FLNC allele is the nonsense p.Trp2710Ter), and dominant transmission was apparent in the original gene-discovery cohorts.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"Myofibrillar myopathy is most commonly inherited in an autosomal dominant manner."

GeneReviews states dominant inheritance is the usual mode.

Autosomal Recessive HP:0000007

A recessive route exists for CRYAB, where biallelic frameshift variants that lead to premature termination and loss of the alphaB-crystallin protein cause disease. Recessive variants have also been reported for PYROXD1, KY and SVIL.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"autosomal recessive inheritance of CRYAB pathogenic frameshift variants that lead to premature termination of the translational chain resulting in non-transcription of the mutated protein"

GeneReviews documents the recessive CRYAB exception.

X-Linked HP:0001417

FHL1-related muscular dystrophy, which can display full myofibrillar myopathy pathology (with or without reducing bodies), is X-linked.

X-linked inheritance

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"X-linked inheritance of FHL1 pathogenic variants"

GeneReviews documents X-linked FHL1 as an inheritance exception within MFM.

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Subtypes

13

Myofibrillar myopathy 1 (desminopathy, DES) MONDO:0011076

DES hgnc:2770

Desminopathy, caused by variants in DES encoding the muscle intermediate filament protein desmin. The most common genetically defined MFM and the one with the earliest and most frequent cardiac involvement: distal-onset leg weakness spreading proximally, with conduction block, arrhythmia and heart failure, and frequent respiratory muscle involvement. Gene assignment verified against OMIM 601419 / NCBI GeneID 1674.

Show evidence (1 reference)

PMID:41183253 SUPPORT Human Clinical

"Patients with desminopathy exhibited earlier and higher rates of cardiac involvement (p < 0.001), more frequent respiratory involvement (p = 0.029), earlier gait aid dependence (p = 0.018)"

Mayo natural-history cohort identifies desminopathy as the most cardiopulmonary-severe MFM subtype.

Myofibrillar myopathy 2 (alphaB-crystallinopathy, CRYAB) MONDO:0012130

CRYAB hgnc:2389

AlphaB-crystallinopathy, caused by variants in CRYAB encoding the small heat-shock protein / molecular chaperone alphaB-crystallin. The classic adult-onset form (MFM2A, OMIM 608810) arises from the dominant p.Arg120Gly variant and can be accompanied by cataract; recessive CRYAB frameshift alleles cause a distinct fatal infantile hypertonic form (MFM2B, OMIM 613869, MONDO:0013472). CRYAB is a component of the chaperone/proteostasis axis shared with BAG3. Gene assignment verified against the MONDO:0012130 definition ("mutation in the CRYAB gene"), its xref OMIM 608810 (the dominant adult-onset arm) and NCBI GeneID 1410; the recessive infantile arm carries a separate OMIM (613869) and MONDO class (MONDO:0013472), so the bound subtype term strictly covers only the dominant arm while this subtype entry describes both.

Show evidence (1 reference)

PMID:9731540 SUPPORT Human Clinical

"We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family."

Original identification of CRYAB p.Arg120Gly as a cause of desmin-related (myofibrillar) myopathy.

Myofibrillar myopathy 3 (myotilinopathy, MYOT) MONDO:0012215

MYOT hgnc:12399

Myotilinopathy, caused by variants in MYOT encoding myotilin, a key Z-disc component. Mutations cluster in the serine-rich exon 2 hotspot, the same region harbouring the LGMD1A variants. Onset at 42-77 years with weakness starting in distal or proximal leg muscles and spreading; cardiomyopathy, respiratory failure and peripheral neuropathy occur in a fraction of patients. Gene assignment verified against OMIM 609200 / NCBI GeneID 9499.

Show evidence (2 references)

PMID:15111675 SUPPORT Human Clinical

"The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located."

Establishes MYOT exon 2 as an MFM mutation hotspot.

PMID:15947064 SUPPORT Human Clinical

"The disease is characterized by the onset at the age of 42-77 years with muscle weakness initially in distal or proximal leg muscles, eventually spreading to other muscle groups of the lower and upper extremities."

Defines the age-at-onset range and weakness distribution of myotilinopathy.

Myofibrillar myopathy 4 (zaspopathy, LDB3/ZASP) MONDO:0012277

LDB3 hgnc:15710

Zaspopathy, caused by variants in LDB3 encoding ZASP (Z-band alternatively spliced PDZ motif-containing protein). Late-adult onset (44-73 years in the original series) with distal-predominant weakness in a subset; also known as Markesbery-Griggs late-onset distal myopathy. Cardiac involvement and neuropathy occur in a minority. Gene assignment verified against OMIM 609452 / NCBI GeneID 11155.

Show evidence (1 reference)

PMID:15668942 SUPPORT Human Clinical

"We therefore searched for mutations in ZASP in 54 MFM patients and detected 3 heterozygous missense mutations in 11. Their age at onset was 44 to 73 years."

Original description of ZASP/LDB3 mutations as a cause of MFM with late-adult onset.

Myofibrillar myopathy 5 (filaminopathy, FLNC) MONDO:0012289

FLNC hgnc:3756

Filaminopathy, caused by variants in FLNC encoding filamin C. The prototypical variant (p.Trp2710Ter) lies in the dimerization domain and abolishes proper dimerization, producing massive cytoplasmic filamin C-containing aggregates. Clinically limb-girdle (proximal-predominant), with common respiratory muscle weakness and reported cardiac conduction and structural abnormalities. Gene assignment verified against OMIM 609524 / NCBI GeneID 2318.

Show evidence (1 reference)

PMID:15929027 SUPPORT Human Clinical

"we identified a co-segregating, heterozygous nonsense mutation (8130G-->A; W2710X) in the filamin c gene (FLNC) on chromosome 7q32.1"

Original FLNC MFM family with the dimerization-domain nonsense variant.

Myofibrillar myopathy 6 (BAG3-opathy, BAG3) MONDO:0013061

BAG3 hgnc:939

BAG3-related MFM, caused almost invariably by the recurrent de novo heterozygous BAG3 p.Pro209Leu variant. Distinct from other MFM subtypes in its childhood onset, rapid progression, severe early cardiomyopathy (which may precede weakness and require transplantation), severe axonal sensorimotor neuropathy, rigid spine and adolescent respiratory failure. BAG3 is the mammalian orthologue of Drosophila Starvin and the organising co-chaperone of chaperone-assisted selective autophagy (CASA). Gene assignment verified against OMIM 612954 / NCBI GeneID 9531.

Show evidence (1 reference)

PMID:19085932 SUPPORT Human Clinical

"We identified a heterozygous p.Pro209Leu mutation in three patients. All presented in childhood, had progressive limb and axial muscle weakness, and experienced development of cardiomyopathy and severe respiratory insufficiency in their teens"

Defines the BAG3 p.Pro209Leu childhood-onset severe MFM subtype.

Myofibrillar myopathy 7 (KY) MONDO:0014922

KY hgnc:26576

KY-related myopathy, caused by biallelic variants in KY encoding kyphoscoliosis peptidase, a Z-disc-associated protein. Presents as a congenital myopathy with core targetoid defects, kyphoscoliosis and tongue atrophy. Gene assignment verified against OMIM 617114 / NCBI GeneID 339855 and the MONDO:0014922 definition.

Show evidence (1 reference)

PMID:27484770 SUPPORT Human Clinical

"Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."

Original report assigning KY as a myopathy gene. PubMed provides only the title for this short Acta Neuropathologica communication (no abstract body), so the quoted snippet is the article title itself.

Myofibrillar myopathy 8 (PYROXD1) MONDO:0014993

PYROXD1 hgnc:26162

PYROXD1-related myopathy, caused by biallelic variants in PYROXD1, a pyridine nucleotide-disulphide oxidoreductase. Early-onset myopathy with internalized nuclei and myofibrillar disorganization; slowly progressive, with facial weakness, nasal speech and swallowing difficulties. Gene assignment verified against OMIM 617258 / NCBI GeneID 79912 and the MONDO:0014993 definition.

Show evidence (2 references)

PMID:27745833 SUPPORT Human Clinical

"Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands."

Original gene-discovery report for PYROXD1 myopathy (MFM8); the quoted histopathology is the myofibrillar-pattern lesion that places it in this group.

PMID:27745833 SUPPORT Human Clinical

"facial weakness, nasal speech, swallowing difficulties"

Documents the facial and bulbar involvement characteristic of MFM8.

Myofibrillar myopathy 9 / hereditary myopathy with early respiratory failure (TTN)

TTN hgnc:12403

Hereditary myopathy with early respiratory failure, caused by heterozygous variants in the region of TTN encoding the 119th fibronectin-3 domain of titin. Third-to-fifth-decade onset with distal leg weakness and, distinctively, early nocturnal respiratory symptoms out of proportion to limb weakness. MONDO does not currently expose a `myofibrillar myopathy 9` class under MONDO:0018943; the OMIM designation MFM9 corresponds to OMIM 603689 (verified via NCBI `mim2gene_medgen` → GeneID 7273, TTN). HMERF is included here because contemporary MFM reviews explicitly place it inside the group.

Show evidence (2 references)

PMID:24575448 SUPPORT Human Clinical

"The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin on molecular genetic testing."

GeneReviews defines the TTN A-band FN3-119 domain as the HMERF locus.

PMID:26342832 SUPPORT Human Clinical

"other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group"

Justifies including HMERF/TTN within the MFM group.

FHL1 muscular dystrophy with myofibrillar myopathy pathology

FHL1 hgnc:3702

X-linked FHL1-related muscular dystrophy. LIM2-domain variants produce menadione-NBT-positive reducing bodies composed of 13-nm tubulofilaments that emanate from Z-discs; a variant outside the LIM domains produced a mild late-onset phenotype with MFM pathology and no reducing bodies. Features include muscle hypertrophy, rigid spine and joint contractures.

Show evidence (1 reference)

PMID:22094483 SUPPORT Human Clinical

"FHL1 dystrophies can be associated with MFM pathology. Mutations in the LIM2 domain are associated with reducing bodies composed of distinct tubulofilaments."

Establishes FHL1 as a cause of MFM-pattern pathology.

DNAJB6 limb-girdle muscular dystrophy (LGMD1D) with myofibrillar pathology

DNAJB6 hgnc:14888

Dominant DNAJB6 G/F-domain variants (p.Phe89Ile, p.Phe93Leu) cause LGMD1D with Z-disc myofibrillar disintegration, rimmed vacuoles and accumulation of myotilin, desmin and alphaB-crystallin. DNAJB6 interacts with the CASA complex including BAG3, placing it mechanistically inside the MFM proteostasis group.

Show evidence (1 reference)

PMID:22366786 SUPPORT Human Clinical

"we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3"

Links DNAJB6 disease to the BAG3/CASA proteostasis axis of MFM.

Myofibrillar myopathy 10 (supervillin, SVIL) MONDO:0033620

SVIL hgnc:11480

Biallelic loss-of-function variants in SVIL encoding supervillin cause a childhood/adolescence-onset myopathy with myofibrillar disorganization and autophagic vacuoles. Supervillin is a sarcolemmal myosin II- and F-actin-binding protein that potentially attaches the sarcolemma to myofibrillar Z-lines — a costameric rather than strictly Z-disc location. Note that the reported patients had no or only minor muscle weakness and only mild cardiac manifestations, so this is a mild outlier within the group. Gene assignment verified against OMIM 619040 / NCBI GeneID 6840.

Show evidence (2 references)

PMID:32779703 SUPPORT Human Clinical

"We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL."

Original SVIL gene-discovery report establishing recessive loss of function as the mechanism.

PMID:32779703 SUPPORT Human Clinical

"Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines."

Places supervillin at the costamere-to-Z-line link rather than within the Z-disc proper, which is why this subtype extends the group beyond the classic Z-disc proteins.

Myofibrillar myopathy 11 (myosin chaperone UNC-45B) MONDO:0030927

UNC45B hgnc:14304

Bi-allelic variants in UNC45B, encoding the myosin-directed chaperone UNC-45B, cause childhood-onset progressive muscle weakness, extending the MFM group beyond Z-disc structural proteins into the sarcomeric chaperone machinery. Mutant UNC-45B is reduced in muscle and mislocalized away from the A-band towards the Z-disc. Gene assignment verified against OMIM 619178 / NCBI GeneID 146862. Two further numbered members of the OMIM MFM series are not separately modelled here: MFM12 (MYL2, OMIM 619424, MONDO:0859168) and MFM13 (HSPB8, OMIM 621078, MONDO:0976133); HSPB8 is of particular mechanistic interest because it is the small heat-shock protein partner of BAG3 in the CASA complex. Also out of scope for this release, but reported in the wider protein-aggregate myopathy spectrum and worth a future look: PLEC, ACTA1 (a patient with an ACTA1 variant appears in the Mayo cohort cited under `genetic[DES]`), VCP, and the digenic SQSTM1-TIA1 combination.

Show evidence (2 references)

PMID:33217308 SUPPORT Human Clinical

"We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness."

Original UNC45B gene-discovery report establishing the recessive childhood-onset phenotype.

PMID:33217308 SUPPORT Human Clinical

"In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere."

Documents the mislocalization toward the Z-disc that connects this chaperonopathy to the Z-disc-centred MFM group.

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Discussions and Knowledge Gaps

2

What causes myofibrillar myopathy in the roughly half of patients in whom no pathogenic variant is found in any known MFM gene?

KNOWLEDGE GAP OPEN gap_mfm_unsolved_genetic_basis

Attached to

pathophysiology#Z-Disc and Chaperone Protein Variant

Despite the addition of KY, PYROXD1, TTN, FHL1, DNAJB6, SVIL, UNC45B, MYL2 and HSPB8 to the original six genes, a large fraction of pathologically confirmed MFM remains genetically unsolved. In the 21-patient Verona cohort the genetic basis was established in only 28% of cases; GeneReviews puts the historical figure at about 50%, and even the contemporary Mayo cohort left 24 of 80 patients uncharacterized. Whether the remainder reflects additional Z-disc/proteostasis genes, non-coding or structural variation in known genes, or a non-Mendelian route is unresolved, and it directly limits both prognosis and family counseling.

Proposed experiments

Genome sequencing of biopsy-confirmed, panel-negative MFM

exp_mfm_genome_sequencing_panel_negative

Apply short- and long-read genome sequencing with structural- and non-coding-variant analysis to biopsy-confirmed MFM cohorts that are negative on a comprehensive MFM gene panel, to test whether the missing heritability lies in undetected variation within known genes.

Muscle RNA sequencing for aberrant splicing and allelic imbalance

exp_mfm_muscle_rnaseq

Sequence RNA from patient muscle to detect aberrant splicing events and allele-specific expression at known MFM loci that escape DNA-level panels.

Proteomic profiling of laser-captured aggregates

exp_mfm_aggregate_proteomics

Laser-capture microdissect the protein aggregates from genetically unsolved MFM biopsies and characterise their constituents by mass spectrometry to nominate novel candidate genes.

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases."

Quantifies the diagnostic gap that motivates this knowledge gap.

PMID:22106715 SUPPORT Human Clinical

"Therefore, the genetic basis of MFM was established in only 28% of our cases and these data are consistent with those reported in other studies."

Independent cohort quantification of the unsolved fraction.

Is protein aggregation in myofibrillar myopathy the cause of muscle fibre degeneration, or a downstream marker of a more proximal stress-induced pathway?

KNOWLEDGE GAP OPEN gap_mfm_aggregate_causality

Attached to

pathophysiology#Ectopic Protein Aggregate Accumulation

The mechanisms leading to protein aggregation are not fully understood, and it has been proposed that the fibre abnormalities in MFM represent a common step of a stress-induced pathway that can be triggered by different stimuli — which would make the aggregates a consequence rather than the primary toxic species. This distinction determines whether therapeutic strategies should target aggregate clearance (for example by augmenting chaperone-assisted selective autophagy) or the upstream stress response, and it is the reason the aggregate-to-degeneration edge in this entry is typed INDIRECT_UNKNOWN_INTERMEDIATES.

Proposed experiments

Time-resolved aggregate formation versus fibre dysfunction

exp_mfm_temporal_aggregate_vs_dysfunction

Use inducible MFM models to establish whether measurable contractile dysfunction precedes, coincides with, or follows detectable aggregate formation.

CASA augmentation rescue experiment

exp_mfm_casa_augmentation_rescue

Test whether pharmacological or genetic augmentation of chaperone-assisted selective autophagy rescues muscle function, and whether any rescue tracks with reduction in aggregate burden.

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"To date, the mechanisms leading to protein aggregation are not fully understood and recent studies proposed that the fiber abnormalities in MFM probably are a common step of a stress-induced pathway, triggered by different stimuli"

States the unresolved causal direction between aggregation and fibre injury.

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Pathophysiology

8

Z-Disc and Chaperone Protein Variant

The initiating lesion is a pathogenic variant in a Z-disc structural protein (desmin, myotilin, ZASP/LDB3, filamin C) or in a Z-disc-associated molecular chaperone or co-chaperone (alphaB-crystallin, BAG3, DNAJB6, UNC45B). Each of the six classical MFM gene products (desmin, alphaB-crystallin, myotilin, ZASP, filamin C, Bag3) is an integral part of the Z-disc or is closely associated with it, which is why the pathology converges on that structure regardless of which of them is mutated. The expanded gene set reaches the same Z-disc lesion from other compartments rather than by being Z-disc structural proteins: TTN through its A-band FN3-119 domain, UNC45B as a myosin-directed chaperone that mislocalizes from the A-band toward the Z-disc, SVIL from the costamere-to-Z-line link, and PYROXD1 as a nuclear-cytoplasmic oxidoreductase. Mutant proteins misfold or lose their normal binding capacity — for example the FLNC p.Trp2710Ter truncation disrupts the dimerization domain so that filamin C can no longer dimerize.

Skeletal muscle cell CL:0000188

DES hgnc:2770 CRYAB hgnc:2389 MYOT hgnc:12399 LDB3 hgnc:15710 FLNC hgnc:3756 BAG3 hgnc:939 KY hgnc:26576 PYROXD1 hgnc:26162 TTN hgnc:12403 FHL1 hgnc:3702 DNAJB6 hgnc:14888 SVIL hgnc:11480 UNC45B hgnc:14304

Protein Folding GO:0006457 ⚠ ABNORMAL

Skeletal muscle tissue UBERON:0001134

Downstream

Chaperone-Assisted Selective Autophagy Failure Variants in BAG3, CRYAB and DNAJB6 directly impair the CASA machinery; variants in structural clients such as filamin C increase the substrate load on it.

Desmin Intermediate Filament Network Disruption Mutant desmin, or loss of its alphaB-crystallin chaperone, destabilises the intermediate filament network directly.

Peripheral Neuropathy Peripheral nerve involvement accompanies several MFM genotypes (notably BAG3 and MYOT) but the mechanism by which the Z-disc protein defect injures peripheral axons has not been established.

Sensorimotor Neuropathy Severe axonal sensorimotor neuropathy in BAG3 disease; the mechanism in nerve is unestablished.

Cataract AlphaB-crystallin is abundant in the lens as well as in muscle, so a CRYAB chaperone defect can also produce lens opacification.

Show evidence (3 references)

PMID:21496631 SUPPORT Human Clinical

"To date, all MFM mutations have appeared in Z-disk-associated proteins: namely, desmin, αB-crystallin, myotilin, ZASP, filamin C, and Bag3."

Establishes that the causative lesion is uniformly in a Z-disc-associated protein.

PMID:28269794 SUPPORT Other

"Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc in the muscular fibers."

States the dual structural / protein-quality-control character of the MFM gene set that this trigger node encodes. evidence_source is OTHER because this is a narrative review (primarily of animal models) rather than a primary human study.

PMID:15929027 SUPPORT In Vitro

"Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly."

Worked molecular example of how an MFM variant destroys the normal protein function.

Chaperone-Assisted Selective Autophagy Failure

The Z-disc is under continuous mechanical, thermal and oxidative stress during contraction, and its damaged components are disposed of by chaperone-assisted selective autophagy (CASA). In this pathway BAG3 (mammalian orthologue of Drosophila Starvin) coordinates the activity of the constitutive chaperone Hsc70/HSPA8 and the small heat-shock protein HspB8; disposal is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62. Damaged filamin is a canonical CASA client. CASA is mechanistically distinct from chaperone-mediated autophagy — it proceeds through macroautophagy of ubiquitinated aggregates (aggrephagy) rather than direct lysosomal translocation of the client. This node explains why CRYAB and BAG3, which are chaperones rather than structural Z-disc proteins, produce the identical Z-disc lesion, and DNAJB6 disease joins the same axis through its interaction with the CASA complex. Impaired CASA results in Z-disc disintegration and progressive muscle weakness in flies, mice and humans.

Skeletal muscle cell CL:0000188

Aggrephagy GO:0035973 ↓ DECREASED Protein Quality Control for Misfolded Proteins GO:0006515 ↓ DECREASED

Hsc70/HSPA8 chaperone activity within the CASA complex GO:0140662 ↓ DECREASED

Downstream

Ectopic Protein Aggregate Accumulation Failure to clear damaged Z-disc components leaves them to aggregate.

Myofibrillar Disintegration Beginning at the Z-Disc Loss of CASA-mediated turnover of damaged Z-disc components causes Z-disc disintegration directly, as shown in Drosophila, mouse and human muscle.

Show evidence (3 references)

PMID:20060297 SUPPORT Model Organism

"Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62."

Defines the molecular composition of the CASA machinery centred on BAG3.

PMID:20060297 SUPPORT Model Organism

"Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."

Directly connects CASA failure to the defining Z-disc lesion of MFM.

PMID:22366786 SUPPORT In Vitro

"In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect."

Shows loss of anti-aggregation chaperone capacity as the mechanism in a CASA-complex partner.

Desmin Intermediate Filament Network Disruption

Desmin is the principal intermediate filament protein of cardiac, skeletal and smooth muscle, forming a continuous cytoskeletal network that links adjacent Z-discs to each other and to the sarcolemma, nucleus and mitochondria. Mutant desmin — or loss of its dedicated chaperone alphaB-crystallin — destabilises this network so that it can no longer maintain the spatial organisation of the contractile apparatus. Muscle cell lines transfected with mutant CRYAB reproduce intracellular aggregates containing both desmin and alphaB-crystallin, identical to those seen in patient muscle fibres.

Skeletal muscle cell CL:0000188 Cardiomyocyte CL:0000746

Intermediate Filament Cytoskeleton Organization GO:0045104 ⚠ ABNORMAL

Downstream

Myofibrillar Disintegration Beginning at the Z-Disc Loss of the desmin network that mechanically couples adjacent Z-discs permits their disintegration under contractile load.

Show evidence (2 references)

PMID:19587455 SUPPORT Human Clinical

"desminopathy, a disease caused by dysfunctional mutations in desmin, a type III intermediate filament protein, or alphaB-crystallin, a chaperone for desmin"

Establishes the desmin/alphaB-crystallin chaperone-client relationship underlying this node.

PMID:9731540 SUPPORT In Vitro

"Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin as observed in muscle fibers from DRM patients."

In vitro reconstitution of desmin network aggregation by a chaperone mutation.

Myofibrillar Disintegration Beginning at the Z-Disc

The defining, gene-agnostic lesion of the group. Ultrastructural studies implicate the Z-disc as the site of the initial pathological change: Z-disc streaming and breakdown is followed by disintegration of the myofibrils themselves and accumulation of granular and filamentous (granulofilamentous) material that on longitudinal sections appears to derive from the Z-disc. This node is the central effector to which every genetic route converges, and it is why MFM is a pathologically rather than genetically defined entity.

Skeletal muscle cell CL:0000188

Sarcomere Organization GO:0045214 ⚠ ABNORMAL Myofibril Assembly GO:0030239 ⚠ ABNORMAL

Skeletal muscle tissue UBERON:0001134

Downstream

Ectopic Protein Aggregate Accumulation Degraded myofibrillar filaments aggregate into pleomorphic inclusions.

Progressive Skeletal Muscle Fiber Degeneration Loss of contractile-apparatus integrity leads to fibre degeneration and weakness.

Cardiomyocyte Z-Disc Aggregate Pathology The same lesion occurs in cardiomyocytes, which express the MFM proteins at comparable levels to skeletal muscle.

Myotonic Discharges on EMG Abnormal electrical irritability with myotonic discharges accompanies the structural lesion; the membrane mechanism is not established.

Show evidence (2 references)

PMID:21496631 SUPPORT Human Clinical

"The MFMs are characterized by a distinct pathological pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins"

Canonical statement of the defining lesion.

PMID:22106715 SUPPORT Human Clinical

"Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments."

Ultrastructural confirmation that disintegration begins at the Z-disc.

Ectopic Protein Aggregate Accumulation

Degraded myofibrillar filaments aggregate into pleomorphic granular or hyaline inclusions in which multiple proteins are ectopically expressed: desmin, alphaB-crystallin, myotilin, dystrophin, sarcoglycans, NCAM, plectin, gelsolin, ubiquitin, filamin C and sometimes congophilic amyloid material. Immunohistochemically these focal accumulations affect 2-15% of muscle fibres and correspond to the fibre regions with lost ATPase and oxidative enzyme activity. Importantly, immunoblotting shows no change in total protein content, indicating mislocalisation and aggregation rather than overexpression — which is why immunohistochemistry, not immunoblot, is the diagnostic tool.

Skeletal muscle cell CL:0000188

Response to Unfolded Protein GO:0006986 ↑ INCREASED

Downstream

Progressive Skeletal Muscle Fiber Degeneration Whether aggregates are directly cytotoxic or a marker of a more proximal stress pathway is unresolved (see the corresponding knowledge gap).

Show evidence (2 references)

PMID:22106715 SUPPORT Human Clinical

"Immunohistochemical studies demonstrate focal accumulation of desmin, alphaB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins"

Documents aggregation without increased total protein, defining the ectopic-accumulation mechanism.

PMID:19085932 SUPPORT In Vitro

"expression of FLAG-labeled mutant and wild-type Bag3 in COS cells showed abnormal aggregation of the mutant protein"

Demonstrates that the mutant MFM protein itself aggregates in a cellular model.

Progressive Skeletal Muscle Fiber Degeneration

Aggregate-laden fibres lose oxidative and ATPase enzyme activity in the affected regions, degenerate, and are progressively replaced by endomysial connective tissue and fat. Apoptotic nuclear loss is a documented additional mechanism in BAG3 disease, where 8% of nuclei were apoptotic on electron microscopy — consistent with BAG3's antiapoptotic function. Clinically this produces the slowly progressive proximal and distal weakness that defines MFM, with distal predominance in the majority, together with axial, bulbar and spinal manifestations.

Skeletal muscle cell CL:0000188

Apoptotic Process GO:0006915 ↑ INCREASED

Skeletal muscle tissue UBERON:0001134

Downstream

Respiratory Muscle Involvement Involvement of diaphragm and intercostal muscles by the same degenerative process.

Distal Muscle Weakness

Proximal Muscle Weakness

Dysphagia Bulbar muscle involvement.

Muscle Stiffness

Muscle Cramps

Joint Contractures Secondary to chronic weakness and axial rigidity, prominent in FHL1 disease.

Skeletal Muscle Hypertrophy FHL1-related disease produces hypertrophied rather than wasted muscle; the mechanism of this divergence is not established.

Myalgia

Spinal Rigidity Axial and paraspinal muscle involvement, prominent in BAG3 and FHL1 disease.

Elevated Serum Creatine Kinase Sarcolemmal leak of creatine kinase from degenerating fibres.

Show evidence (2 references)

PMID:19085932 SUPPORT Human Clinical

"Electron microscopy showed disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of 8% of the nuclei."

Quantifies myonuclear apoptosis as a degeneration mechanism in BAG3 MFM.

PMID:20301672 SUPPORT Human Clinical

"Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles."

Links fibre degeneration to the clinical weakness phenotype.

Cardiomyocyte Z-Disc Aggregate Pathology

Desmin and the other MFM proteins are as highly expressed in cardiac as in skeletal muscle, so the same Z-disc aggregate pathology occurs in cardiomyocytes. The resulting cardiomyocyte insult drives two clinically distinct arms: a conduction/arrhythmia arm (atrioventricular and bundle branch block, atrial and ventricular tachyarrhythmia, syncope, sudden cardiac death) and a structural arm (dilated, hypertrophic or restrictive cardiomyopathy progressing to congestive heart failure). This is the main driver of mortality in MFM and the reason cardiac surveillance is the dominant management concern. In BAG3 disease the cardiomyopathy can be the presenting feature and precede neuromuscular weakness by years, requiring transplantation in childhood. The node is declared conformant to the `Primary Cardiomyocyte Insult` trigger of the `cardiomyopathy_maladaptive_remodeling` module, whose definition explicitly covers "a variant in a sarcomeric or cytoskeletal protein gene that perturbs sarcomere assembly and force generation" — the situation here — and it carries both biological processes that module trigger expects (sarcomere organization and muscle contraction, both ABNORMAL). Scope note: only **trigger-level** conformance is asserted. The module's downstream neurohormonal-activation, ventricular-remodeling and heart-failure nodes are not duplicated here because MFM-specific evidence for them was not identified, and the module is explicitly kept distinct from the electrical mechanism modelled by `cardiac_ion_channel_repolarization`; the conduction/arrhythmia manifestations below are therefore attached as phenotypic outputs of this cardiomyocyte insult, not as a claim that this entry instantiates the module's electrical arm.

Cardiomyocyte CL:0000746

Sarcomere Organization GO:0045214 ⚠ ABNORMAL Muscle Contraction GO:0006936 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Cardiomyopathy

Cardiac Conduction Disease and Arrhythmia

Atrioventricular Block

Sudden Cardiac Death Via malignant ventricular arrhythmia or high-grade conduction block.

Show evidence (3 references)

PMID:33802723 PARTIAL Other

"Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle."

Establishes that the Z-disc machinery disrupted in MFM operates in cardiomyocytes as well as skeletal myofibres, which is the basis for cardiac involvement and for conformance to the cardiomyopathy module's cytoskeletal-variant trigger. Marked PARTIAL because this is a generic statement of Z-disc biology rather than a direct observation of MFM aggregate pathology in cardiomyocytes; evidence_source is OTHER because the paper is a narrative review.

PMID:25728519 SUPPORT Human Clinical

"we describe the first case in which cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years (age 12)"

Shows the cardiac arm can be the presenting and dominant manifestation.

PMID:22106715 SUPPORT Human Clinical

"Among 10 patients who underwent to heart assessment, seven had cardiac involvement. Two of these patients had signs of congestive heart failure and arrhythmia; two had signs of congestive heart failure without arrhythmia; and three had arrhythmia without congestive failure."

Documents both the structural (heart failure) and electrical (arrhythmia) arms in a clinical cohort.

Respiratory Muscle Involvement

The mechanism-level node: the same aggregate-driven fibre degeneration involves the diaphragm and intercostal muscles, so the respiratory pump loses capacity. Pump failure declares itself first during sleep, when accessory muscle recruitment falls away. In HMERF/TTN disease this arm is characteristically early and out of proportion to limb weakness, and in BAG3 disease it reaches severity in the teens. Together with the cardiac arm it is the principal cause of death in MFM. The measured clinical consequence is modelled separately as the `Respiratory Insufficiency due to Muscle Weakness` phenotype.

Skeletal muscle cell CL:0000188

Downstream

Respiratory Insufficiency due to Muscle Weakness

Show evidence (2 references)

PMID:24575448 SUPPORT Human Clinical

"The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness."

Documents the ventilatory-failure route in the TTN/HMERF form.

PMID:41183253 SUPPORT Human Clinical

"Seven patients (2 with DES, 1 with ACTA1, 4 genetically uncharacterized) died, mainly due to cardiopulmonary complications."

Establishes cardiopulmonary failure as the dominant cause of death.

✶

Histopathology

5

Myofibrillar dissolution with Z-disc disintegration

The defining biopsy lesion: foci of myofibrillar dissolution associated with disintegration of the Z-disc and accumulation of myofibrillar degradation products, visible on Engel-Gomori trichrome as amorphous dark blue material (eosinophilic on H&E).

Show evidence (1 reference)

PMID:21496631 SUPPORT Human Clinical

"The MFMs are characterized by a distinct pathological pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins that include desmin, αB-crystallin, dystrophin, and sometimes..."

Canonical description of the diagnostic biopsy lesion.

Granulofilamentous material on electron microscopy

Ultrastructurally, focal areas of myofibrillar disruption with Z-disc streaming and abundant granular and filamentous material that on longitudinal section appears to derive from the Z-disc, either interspersed among myofibrils or subsarcolemmal.

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"Ultrastructural examination showed single or multiple focal areas of different size with myofibrillar disruption, streaming of Z-disk, and abundant granulofilamentous material which was either diffusely interspersed among the myofibrils or located under the sarcolemma"

Ultrastructural signature of MFM.

Focal loss of oxidative and ATPase enzyme activity

Histochemistry shows focal intrafibre areas with reduction or loss of ATPase and oxidative enzyme (NADH, SDH, COX) activity, corresponding to the regions occupied by protein aggregates.

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"Muscle biopsies from all MFM patients showed areas with a loss or reduction of ATPase and oxidative enzyme activity (COX, SDH and NADH)"

Documents the histochemical hallmark present in all cohort biopsies.

Rimmed and non-rimmed vacuoles FREQUENT

Sparse small vacuoles, rimmed or not, appear in roughly half of MFM biopsies; they contain cytoplasmic degradation products and reflect the autophagic arm of the disease. Their presence contributes to diagnostic confusion with inclusion body myositis.

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"rimmed and non-rimmed vacuoles observed in 45% of cases and cytoplasmic bodies in only 10%"

Quantifies rimmed/non-rimmed vacuoles at 45% of biopsies, mapping to the FREQUENT band (30-79%).

Ectopic desmin, alphaB-crystallin and myotilin immunoreactivity

Immunohistochemistry shows focal accumulation of desmin, alphaB-crystallin and myotilin in 2-15% of muscle fibres regardless of the underlying gene. AlphaB-crystallin deposits are typically the most numerous. Immunoblotting is uninformative because total protein content is unchanged.

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"In all muscle biopsies from patients with MFM, abnormal fibers with focal areas of increased reactivity for desmin, αB-crystallin and myotilin were observed"

Documents the immunohistochemical diagnostic pattern.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

19

Cardiovascular 4

Cardiomyopathy OCCASIONAL Cardiomyopathy HP:0001638

Course: PROGRESSIVE

Banded on the only source that quantifies *overt structural cardiomyopathy* specifically. The Mayo cohort's 31/80 (39%) figure is for "cardiac involvement", a composite that also includes conduction disease and arrhythmia — modelled here as a separate phenotype — so it is not used to band this structural phenotype.

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"Overt cardiomyopathy is present in 15%-30%."

GeneReviews quantifies overt cardiomyopathy at 15%-30%, which falls in the OCCASIONAL band (5-29%) at all but the extreme upper bound.

PMID:22106715 SUPPORT Human Clinical

"Congestive heart failure is not uncommon; in our series it was documented in 4 of 21 patients."

Independent cohort: overt heart failure in 4 of 21 (19%), consistent with the OCCASIONAL band.

Cardiac Conduction Disease and Arrhythmia FREQUENT Arrhythmia HP:0011675

Banded from the composite "cardiac involvement" figure, which chiefly comprises conduction and rhythm abnormalities: 31 of 80 (39%) in the Mayo cohort and 7 of 10 assessed in the Verona cohort.

Show evidence (2 references)

PMID:22106715 SUPPORT Human Clinical

"Arrhythmias included paroxysmal supraventricular tachycardia in three patients, left bundle branch block in two affected brothers with desmin mutation, and sinus block in one patient. Two patients with arrhythmias underwent pacemaker implantation."

Documents the specific arrhythmia spectrum and its device consequence.

PMID:41183253 SUPPORT Human Clinical

"Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."

31 of 80 patients (39%) had cardiac involvement — a composite dominated by conduction and rhythm disease — supporting the FREQUENT band here.

Atrioventricular Block Atrioventricular block HP:0001678

Show evidence (1 reference)

PMID:19587455 SUPPORT Human Clinical

"patients experience dizziness and syncopal and fainting episodes associated with conduction blocks and require insertion of a permanent pacemaker"

Documents conduction block with syncope in desminopathy.

Sudden Cardiac Death Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:19587455 PARTIAL Human Clinical

"this would ensure prevention of sudden death from cardiac arrhythmias and other complications"

Identifies sudden arrhythmic death as an outcome that diagnosis is intended to prevent; the review does not quantify its occurrence, hence PARTIAL.

Digestive 1

Dysphagia OCCASIONAL Dysphagia HP:0002015

Show evidence (1 reference)

PMID:41183253 SUPPORT Human Clinical

"Dysphagia occurred in 16 patients, with 4 requiring feeding tubes."

16 of 80 patients (20%) had dysphagia, mapping to the OCCASIONAL band (5-29%).

Eye 1

Cataract Cataract HP:0000518

Show evidence (2 references)

PMID:38212463 SUPPORT Human Clinical

"Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype."

Directly documents cataract as part of the clinical spectrum of CRYAB (alpha-B crystallinopathy) disease alongside desmin-related myopathy.

PMID:9731540 PARTIAL Human Clinical

"This region contains the alphaB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle."

Supports the biological basis for lens involvement in CRYAB disease (the protein is abundant in lens); this abstract does not itself enumerate cataract as a clinical finding, hence PARTIAL.

Metabolism 1

Elevated Serum Creatine Kinase Elevated circulating creatine kinase concentration HP:0003236

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"Serum CK was determined in 12 patients and the mean level was found to be 4-fold above the upper normal limit (range, from normal to 9-fold)."

Quantifies the degree of CK elevation in MFM.

Musculoskeletal 7

Distal Muscle Weakness VERY_FREQUENT Distal muscle weakness HP:0002460

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%."

GeneReviews quantifies distal weakness at about 80%, mapping to the VERY_FREQUENT band (80-99%).

Proximal Muscle Weakness FREQUENT Proximal muscle weakness HP:0003701

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:41183253 SUPPORT Human Clinical

"all patients had weakness, commonly distal-predominant (n = 34), followed by proximal-predominant (n = 24) and diffuse (n = 11) weakness"

24 of 69 patients with a described pattern (~35%) were proximal-predominant and a further 11 diffuse, supporting the FREQUENT band (30-79%).

Respiratory Insufficiency due to Muscle Weakness FREQUENT Respiratory insufficiency due to muscle weakness HP:0002747

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:41183253 SUPPORT Human Clinical

"Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."

33 of 80 patients (41%) had respiratory involvement, supporting the FREQUENT band.

Muscle Cramps Muscle spasm HP:0003394

`frequency` intentionally omitted: GeneReviews says only "a minority of individuals", which does not pin an HPO band.

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps."

GeneReviews lists cramps among the minority symptoms; the phrase "a minority" is not band-determining, so no frequency is asserted.

Muscle Stiffness Muscle stiffness HP:0003552

`frequency` intentionally omitted: GeneReviews says only "a minority of individuals", which does not pin an HPO band.

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps."

GeneReviews documents the association; it says only "a minority", which is not band-determining, so no frequency is asserted.

Spinal Rigidity Spinal rigidity HP:0003306

Show evidence (1 reference)

PMID:19085932 SUPPORT Human Clinical

"two had rigid spines, and one a peripheral neuropathy"

Documents rigid spine in BAG3-related MFM.

Joint Contractures Flexion contracture HP:0001371

Show evidence (1 reference)

PMID:22094483 SUPPORT Human Clinical

"The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures"

Documents joint contractures in the FHL1 arm of the MFM spectrum.

Nervous System 1

Peripheral Neuropathy OCCASIONAL Peripheral neuropathy HP:0009830

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"Peripheral neuropathy is present in about 20% of affected individuals."

GeneReviews quantifies peripheral neuropathy at about 20%, mapping to the OCCASIONAL band (5-29%).

PMID:41183253 SUPPORT Human Clinical

"Peripheral neuropathy was found in 21 patients (13 with axonal large fiber neuropathy and 8 with small fiber neuropathy), mostly mild in severity."

Characterizes the neuropathy subtypes and their mild severity.

Constitutional 1

Myalgia Myalgia HP:0003326

Show evidence (1 reference)

PMID:22106715 SUPPORT Human Clinical

"the remaining four patients complained of myalgias associated with elevated serum CK (three patients) or had similarly affected family members (one patient)"

Documents myalgia as a presenting complaint in MFM.

Other 3

Sensorimotor Neuropathy Sensorimotor neuropathy HP:0007141

Show evidence (1 reference)

PMID:25728519 SUPPORT Human Clinical

"The phenotype comprised distal weakness and severe sensorimotor neuropathy."

Documents severe sensorimotor neuropathy in BAG3-related MFM.

Skeletal Muscle Hypertrophy Skeletal muscle hypertrophy HP:0003712

Show evidence (1 reference)

PMID:22094483 SUPPORT Human Clinical

"The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures"

Documents muscle hypertrophy in the FHL1 arm of the MFM spectrum.

Myotonic Discharges on EMG EMG: myotonic discharges HP:0100284

Show evidence (1 reference)

PMID:21496631 SUPPORT Human Clinical

"Electromyography of the affected muscles reveals myopathic motor unit potentials and abnormal irritability, often with myotonic discharges."

Documents the characteristic EMG finding.

🧬

Genetic Associations

13

DES

Gene: DES hgnc:2770 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:41183253 SUPPORT Human Clinical

"Eighty patients were identified; 56 were genetically characterized (23 with DES, 10 with MYOT, 9 with LDB3, 2 with FLNC, 2 with BAG3, 2 with CRYAB, 1 with FHL1, and 7 others)."

Quantifies DES as the most frequent MFM gene in a large referral cohort.

CRYAB

Gene: CRYAB hgnc:2389 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:9731540 SUPPORT Human Clinical

"These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder."

Establishes CRYAB as the first chaperone gene implicated in inherited human muscle disease.

MYOT

Gene: MYOT hgnc:12399 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15111675 SUPPORT Human Clinical

"1) Mutations in myotilin cause MFM; 2) exon 2 of MYOT is a hotspot for mutations; 3) peripheral neuropathy, cardiomyopathy, and distal weakness greater than proximal weakness are part of the spectrum of myotilinopathy"

Establishes MYOT causality and the exon 2 hotspot.

LDB3

Gene: LDB3 hgnc:15710 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15668942 SUPPORT Human Clinical

"Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk; one carried a missense mutation in exon 9 (R268C)."

Localizes the ZASP variants to the Z-disc-linking motif.

FLNC

Gene: FLNC hgnc:3756 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:15929027 SUPPORT Human Clinical

"As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins."

Links the FLNC dimerization defect to the aggregate phenotype.

BAG3

Gene: BAG3 hgnc:939 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (1 reference)

PMID:19085932 SUPPORT Human Clinical

"The mutation is not present in 400 alleles of 200 unrelated controls, in unaffected parents of Patients 1 and 2, and in the unaffected sibling of Patient 2."

Establishes the de novo dominant nature of the recurrent BAG3 p.Pro209Leu variant.

KY

Gene: KY hgnc:26576 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27484770 SUPPORT Human Clinical

"Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."

Original KY myopathy report; the cached PubMed record for this short communication carries no abstract body, so the snippet is the article title.

PYROXD1

Gene: PYROXD1 hgnc:26162 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:27745833 SUPPORT Human Clinical

"Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization."

Original PYROXD1 gene-discovery report; the cached PubMed record carries no abstract body, so the snippet is the article title.

TTN

Gene: TTN hgnc:12403 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:24575448 SUPPORT Human Clinical

"a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin"

Defines the specific TTN domain implicated in HMERF.

FHL1

Gene: FHL1 hgnc:3702 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:22094483 SUPPORT Human Clinical

"Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM."

Documents the discovery route of FHL1 within an MFM cohort.

DNAJB6

Gene: DNAJB6 hgnc:14888 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:22366786 SUPPORT Human Clinical

"we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6"

Establishes the DNAJB6 variants and their dominant inheritance.

SVIL

Gene: SVIL hgnc:11480 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:32779703 SUPPORT Human Clinical

"Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles."

Original SVIL myopathy report; the cached PubMed record carries no abstract body, so the snippet is the article title.

UNC45B

Gene: UNC45B hgnc:14304 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:33217308 SUPPORT Human Clinical

"Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores."

Original UNC45B myopathy report; the cached PubMed record carries no abstract body, so the snippet is the article title.

💊

Medical Actions

6

Cardiac Pacemaker or Implantable Cardioverter Defibrillator

Category: Therapeutic Action: pacemaker or implantable cardioverter-defibrillator placement Ontology label: Pacemaker Placement NCIT:C80434

Device therapy for arrhythmia and cardiac conduction defects. Because conduction block and ventricular arrhythmia in MFM (especially desminopathy) can cause syncope and sudden death, pacemaker or ICD implantation is a central and potentially life-saving intervention.

Mechanism Target:

MODULATES Cardiomyocyte Z-Disc Aggregate Pathology — Does not modify the underlying aggregate pathology; it substitutes for or terminates the arrhythmic consequence of it.

Target Phenotypes: Arrhythmia HP:0011675 Sudden cardiac death HP:0001645

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"Consider pacemaker and implantable cardioverter defibrillator (ICD) in individuals with arrhythmia and/or cardiac conduction defects"

GeneReviews management recommendation for the arrhythmia arm.

PMID:22106715 SUPPORT Human Clinical

"Two patients with arrhythmias underwent pacemaker implantation."

Documents real-world pacemaker use in an MFM cohort.

Cardiac Transplantation

Category: Therapeutic Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Considered for progressive or life-threatening cardiomyopathy. In BAG3 disease transplantation has been required as early as age eight, before neuromuscular weakness became apparent.

Mechanism Target:

BYPASSES Cardiomyocyte Z-Disc Aggregate Pathology — Replaces the diseased myocardium rather than correcting the aggregate pathology.

Target Phenotypes: Cardiomyopathy HP:0001638

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"consider cardiac transplantation in individuals with progressive or life-threatening cardiomyopathy"

GeneReviews management recommendation for advanced cardiomyopathy.

PMID:25728519 SUPPORT Human Clinical

"cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years"

Worked example of paediatric cardiac transplantation in BAG3-related MFM.

Noninvasive Ventilatory Support

Category: Therapeutic Action: continuous or bilevel positive airway pressure ventilation Ontology label: Continuous Positive Airway Pressure NCIT:C124040

Continuous or bilevel positive airway pressure, initially nocturnal for hypoventilation and later extended into the daytime, with progression to mechanical ventilation as needed.

Mechanism Target:

MODULATES Respiratory Muscle Involvement — Mechanically supplements the failing respiratory pump.

Target Phenotypes: Respiratory insufficiency due to muscle weakness HP:0002747

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"respiratory support (continuous or bilevel positive airway pressure), initially at night and later in the daytime, in individuals with hypercapnea and other signs of incipient respiratory failure"

GeneReviews management recommendation for ventilatory failure.

PMID:24575448 SUPPORT Human Clinical

"Noninvasive ventilation with bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) may be indicated for nocturnal hypoventilation initially, followed by mechanical ventilatory support as needed."

GeneReviews HMERF management recommendation confirming the ventilatory escalation pathway.

Physical Therapy and Assistive Devices

Category: Therapeutic Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Range-of-motion physical therapy and assistive devices for advanced muscle weakness. Ankle-foot orthoses optimise independent ambulation early in the course of distal leg weakness; canes, walkers and wheelchairs follow. Note the explicit GeneReviews caveat that the role of strengthening exercise has not been defined — this is the closest thing MFM has to an "agents/circumstances to avoid" statement, and strengthening programmes should not be assumed beneficial.

Mechanism Target:

MODULATES Progressive Skeletal Muscle Fiber Degeneration — Mitigates contracture and functional loss; does not modify fibre degeneration.

Target Phenotypes: Distal muscle weakness HP:0002460

Show evidence (2 references)

PMID:20301672 SUPPORT Human Clinical

"range-of-motion physical therapy and assistive devices for those with advanced muscle weakness. Other: The role of strengthening exercises has not been defined."

GeneReviews management recommendation, including the explicit caveat that strengthening exercise is of undefined benefit.

PMID:24575448 SUPPORT Human Clinical

"For distal leg weakness, use of ankle-foot orthoses can optimize independent ambulation early in the disease course; later in the disease course other mobility aids (canes, walkers, or wheelchairs) may be required."

Specifies the orthotic and mobility-aid escalation for distal leg weakness.

Genetic Counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling must accommodate the mixed inheritance of the group: usually autosomal dominant, but X-linked for FHL1 and autosomal recessive for CRYAB frameshift alleles, PYROXD1, KY and SVIL. When the familial variant is known, carrier testing and prenatal testing are possible.

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"When the pathogenic variant(s) in the family are known, carrier testing and prenatal testing for pregnancies at increased risk is possible."

GeneReviews genetic counseling recommendation.

Cardiac and Respiratory Surveillance

Category: Monitoring Action: supportive care Ontology label: Supportive Care NCIT:C15747

Systematic surveillance is the key management lever in MFM because there is no disease-modifying therapy and because cardiac and respiratory involvement typically emerge years after myopathy onset and are the main causes of death. Annual reassessment of muscle strength and clinical status by a neurologist and pulmonary function testing every six to twelve months are recommended, alongside cardiac assessment.

Show evidence (3 references)

PMID:24575448 SUPPORT Human Clinical

"Reassessment of muscle strength and clinical status annually by a neurologist; pulmonary function testing every six to 12 months, or guided by individual findings."

GeneReviews surveillance schedule.

PMID:28269794 SUPPORT Other

"MFMs share common histological characteristics including progressive disorganization of the interfibrillar network and protein aggregation. Currently no treatment is available."

Establishes the absence of disease-modifying therapy, which is why surveillance and organ-specific intervention constitute the management strategy.

PMID:41183253 SUPPORT Human Clinical

"Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."

Establishes the multi-year latency that makes ongoing surveillance, rather than a single baseline assessment, necessary.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Myofibrillar Myopathy:

Limb-girdle muscular dystrophy Not Yet Curated MONDO:0016971

Overlapping Features MFM with proximal-predominant weakness — particularly filaminopathy (FLNC) and myotilinopathy — is clinically indistinguishable from limb-girdle muscular dystrophy at the bedside. The boundary is genuinely blurred: MYOT is the LGMD1A gene and myotilinopathy forms a phenotypic continuum spanning LGMD1A and MFM; the original FLNC MFM pedigree was described as having clinical features of a limb-girdle myopathy; and DNAJB6-related LGMD1D shows myofibrillar pathology.

Distinguishing Features

Muscle biopsy showing myofibrillar dissolution with Z-disc disintegration and ectopic desmin/alphaB-crystallin/myotilin aggregates favors MFM
Concomitant cardiomyopathy, cardiac conduction disease and peripheral neuropathy point toward MFM
Several genes (MYOT/LGMD1A, DNAJB6/LGMD1D, FLNC) span both diagnostic labels, so genetic testing may not fully resolve the boundary

Show evidence (2 references)

PMID:15929027 SUPPORT Human Clinical

"In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM"

Documents the clinical overlap of MFM with limb-girdle myopathy and its resolution by morphology.

PMID:15947064 SUPPORT Human Clinical

"The Spanish cohort, the largest group of patients studied so far, shares phenotypic features with both LGMD1A and MFM/MYOT variants thus establishing a continuum of phenotypic manifestations characteristic of myotilinopathy"

Establishes that MFM and LGMD1A are a continuum for MYOT, not cleanly separable diagnoses.

Inclusion body myositis MONDO:0007827

Overlapping Features Sporadic inclusion body myositis shares rimmed vacuoles, protein aggregation including congophilic material, late-adult onset and slowly progressive weakness with MFM, and an endomysial inflammatory infiltrate can be present in MFM biopsies.

Distinguishing Features

IBM shows characteristic asymmetric quadriceps and finger-flexor weakness, whereas MFM weakness is more often symmetric with distal leg predominance
MFM biopsies show Z-disc-origin granulofilamentous material on electron microscopy and focal desmin/alphaB-crystallin/myotilin immunoreactivity
Cardiomyopathy and cardiac conduction disease are features of MFM but not of IBM
A pathogenic variant in an MFM gene establishes MFM

Show evidence (2 references)

PMID:22106715 PARTIAL Human Clinical

"Sparse small vacuoles, rimmed or not, appeared in half of the specimens"

Documents the rimmed-vacuolar pathology in MFM that creates the diagnostic overlap with inclusion body myositis; the source does not itself discuss IBM, hence PARTIAL.

PMID:22106715 PARTIAL Human Clinical

"In one biopsy specimen there was an endomysial inflammatory infiltrate."

Documents that an inflammatory infiltrate — the histological hallmark used to suspect myositis — can occur in genuine MFM.

Distal myopathy Not Yet Curated MONDO:0018949

Overlapping Features Because distal weakness is present in about 80% of MFM patients, MFM enters the differential of every hereditary distal myopathy. Indeed several eponymous distal myopathies have turned out to be MFM subtypes: Markesbery-Griggs late-onset distal myopathy is LDB3/ZASP-related MFM4.

Distinguishing Features

Myofibrillar pathology on biopsy distinguishes MFM from non-aggregating distal myopathies such as Welander or Laing distal myopathy
Associated cardiomyopathy and peripheral neuropathy favor MFM
Some historical distal myopathy eponyms (Markesbery-Griggs) are now classified as MFM subtypes

Show evidence (1 reference)

PMID:20301672 SUPPORT Human Clinical

"Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%."

Establishes why MFM must be considered in any distal myopathy presentation.

VCP-related multisystem proteinopathy MONDO:0000507

Overlapping Features VCP (valosin-containing protein) disease is the closest molecular near-neighbour outside the modelled gene set: VCP is a proteostasis ATPase, its muscle pathology is rimmed-vacuolar with p62/TDP-43 and desmin/myotilin inclusions that overlap the MFM immunohistochemical panel, and in the Japanese 297-case protein-aggregate-myopathy screen VCP was the second most frequent gene among solved cases. It is included as a differential rather than a subtype because its defining multisystem phenotype (Paget disease of bone and frontotemporal dementia) is outside the MFM concept.

Distinguishing Features

Paget disease of bone and frontotemporal dementia in the proband or family point to VCP rather than MFM
VCP inclusions are p62- and TDP-43-positive; TDP-43 is not part of the MFM aggregate signature
A purely myopathic VCP presentation without CNS or bone involvement is well described and is the hardest case to separate clinically

Show evidence (2 references)

PMID:37091525 SUPPORT Human Clinical

"we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43"

Shows that VCP myopathy is worked up with the same desmin/myotilin panel used for MFM, plus p62 and TDP-43 — the overlap that makes it a differential and the markers that separate it.

PMID:37091525 SUPPORT Human Clinical

"Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement"

Documents the purely myopathic VCP presentation, which is the presentation that is genuinely hard to distinguish from MFM.

Pompe disease (glycogen storage disease II) MONDO:0009290

Overlapping Features Late-onset Pompe disease presents with slowly progressive proximal and axial weakness plus early diaphragmatic weakness and respiratory failure — the same combination that characterizes MFM, and particularly HMERF. It is the single most important treatable mimic, since enzyme replacement therapy is available.

Distinguishing Features

Pompe disease is diagnosed by deficient acid alpha-glucosidase activity on dried blood spot and biallelic GAA variants
Pompe muscle biopsy shows PAS-positive glycogen-filled lysosomal vacuoles with acid phosphatase reactivity, not Z-disc granulofilamentous material
Muscle glycogen content is normal in MFM
Pompe disease has a licensed disease-modifying enzyme replacement therapy; MFM management is supportive

Show evidence (1 reference)

PMID:22106715 PARTIAL Human Clinical

"The muscle fiber lipid and glycogen content was normal."

Documents normal muscle glycogen in MFM, one of the morphological features that separates it from the glycogen-storage mimic. Marked PARTIAL because it supports a single distinguishing feature from the MFM side only; no Pompe-side source is cited here.

{ }

Source YAML

click to show

name: Myofibrillar Myopathy
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
description: >
  Myofibrillar myopathy (MFM) is a genetically heterogeneous but morphologically
  stereotyped group of protein-aggregation myopathies. The unifying lesion is
  disintegration of the myofibril that begins at the Z-disc, followed by
  accumulation of myofibrillar degradation products and ectopic accumulation of
  desmin, alphaB-crystallin, myotilin, dystrophin and other proteins into
  intracellular inclusions — the "myofibrillar" pattern seen on Engel-Gomori
  trichrome and electron microscopy. Nearly all of the causative genes encode
  Z-disc or Z-disc-associated proteins (DES, CRYAB, MYOT, LDB3/ZASP, FLNC, BAG3,
  KY) or components of the muscle protein-quality-control machinery (CRYAB, BAG3,
  DNAJB6, HSPB8, UNC45B); the more recently added members (TTN, SVIL, PYROXD1)
  converge on the same Z-disc lesion from the A-band, the costamere and redox
  metabolism respectively rather than by being Z-disc structural proteins.
  Clinically MFM causes slowly progressive skeletal muscle weakness involving
  both proximal and distal muscles — distal weakness is present in about 80% of
  affected individuals — with peripheral neuropathy in a substantial minority
  (about a fifth to a quarter). Cardiomyopathy and cardiac conduction disease occur in a
  substantial minority and, together with respiratory muscle weakness, are the
  principal drivers of morbidity and mortality; there is no disease-modifying
  therapy, so cardiac and respiratory surveillance with timely device or
  transplant therapy is the main management lever.
disease_term:
  preferred_term: myofibrillar myopathy
  term:
    id: MONDO:0018943
    label: myofibrillar myopathy
synonyms:
- myofibrillar myopathies
- desminopathy
- desmin-related myopathy
- protein surplus myopathy
- protein aggregate myopathy
- myotilinopathy
- zaspopathy
- filaminopathy
- alphaB-crystallinopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018943
      label: myofibrillar myopathy
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for the myofibrillar myopathy disease group.
notes: >-
  MONDO:0018943 carries `subset: disease_grouping` / `ordo_group_of_disorders`.
  It is curated here as an umbrella `Disease` (not a `Grouping`) because the
  entity is defined by a single conserved pathological process — Z-disc-initiated
  myofibrillar disintegration with ectopic protein aggregation — that can be
  modelled as one pathograph with gene-specific substitutions in `has_subtypes`,
  rather than as a curated union over independently modelled member diseases.
  Every gene-to-MFM-number assignment in this entry was verified independently
  against the MONDO term definition, the OMIM phenotype MIM number and the NCBI
  `mim2gene_medgen` gene mapping rather than taken from secondary review text.
  The `histopathology` findings deliberately carry no `finding_term`: the
  `HistopathologyFindingTerm` dynamic enum is rooted in the NCIT Histopathology
  Result branch, which has no term for myofibrillar dissolution,
  granulofilamentous material or rimmed vacuoles, and forcing an approximate
  binding would be less accurate than leaving the finding unbound (the same
  convention used in `Nemaline_Myopathy`).
references:
- reference: PMID:20301672
  title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
- reference: PMID:24575448
  title: "Hereditary Myopathy with Early Respiratory Failure."
  tags:
  - GeneReviews
parents:
- Congenital Structural Myopathy
- Protein Aggregation Myopathy
inheritance:
- name: Autosomal Dominant
  description: >
    Most myofibrillar myopathy is inherited in an autosomal dominant manner.
    Heterozygous missense and truncating variants in DES, CRYAB, MYOT, LDB3/ZASP,
    FLNC and BAG3 each act dominantly (the prototypical FLNC allele is the
    nonsense p.Trp2710Ter), and dominant transmission was apparent in the original
    gene-discovery cohorts.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myofibrillar myopathy is most commonly inherited in an autosomal dominant manner."
    explanation: GeneReviews states dominant inheritance is the usual mode.
- name: Autosomal Recessive
  description: >
    A recessive route exists for CRYAB, where biallelic frameshift variants that
    lead to premature termination and loss of the alphaB-crystallin protein cause
    disease. Recessive variants have also been reported for PYROXD1, KY and SVIL.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "autosomal recessive inheritance of CRYAB pathogenic frameshift variants that lead to premature termination of the translational chain resulting in non-transcription of the mutated protein"
    explanation: GeneReviews documents the recessive CRYAB exception.
- name: X-Linked
  description: >
    FHL1-related muscular dystrophy, which can display full myofibrillar
    myopathy pathology (with or without reducing bodies), is X-linked.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked inheritance of FHL1 pathogenic variants"
    explanation: GeneReviews documents X-linked FHL1 as an inheritance exception within MFM.

has_subtypes:
- name: MFM1
  display_name: Myofibrillar myopathy 1 (desminopathy, DES)
  description: >
    Desminopathy, caused by variants in DES encoding the muscle intermediate
    filament protein desmin. The most common genetically defined MFM and the one
    with the earliest and most frequent cardiac involvement: distal-onset leg
    weakness spreading proximally, with conduction block, arrhythmia and heart
    failure, and frequent respiratory muscle involvement. Gene assignment
    verified against OMIM 601419 / NCBI GeneID 1674.
  subtype_term:
    preferred_term: myofibrillar myopathy 1
    term:
      id: MONDO:0011076
      label: myofibrillar myopathy 1
  genes:
  - preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with desminopathy exhibited earlier and higher rates of cardiac involvement (p < 0.001), more frequent respiratory involvement (p = 0.029), earlier gait aid dependence (p = 0.018)"
    explanation: Mayo natural-history cohort identifies desminopathy as the most cardiopulmonary-severe MFM subtype.
- name: MFM2
  display_name: Myofibrillar myopathy 2 (alphaB-crystallinopathy, CRYAB)
  description: >
    AlphaB-crystallinopathy, caused by variants in CRYAB encoding the small
    heat-shock protein / molecular chaperone alphaB-crystallin. The classic
    adult-onset form (MFM2A, OMIM 608810) arises from the dominant p.Arg120Gly
    variant and can be accompanied by cataract; recessive CRYAB frameshift
    alleles cause a distinct fatal infantile hypertonic form (MFM2B, OMIM 613869,
    MONDO:0013472). CRYAB is a component of the chaperone/proteostasis axis
    shared with BAG3. Gene assignment verified against the MONDO:0012130
    definition ("mutation in the CRYAB gene"), its xref OMIM 608810 (the
    dominant adult-onset arm) and NCBI GeneID 1410; the recessive infantile arm
    carries a separate OMIM (613869) and MONDO class (MONDO:0013472), so the
    bound subtype term strictly covers only the dominant arm while this subtype
    entry describes both.
  subtype_term:
    preferred_term: myofibrillar myopathy 2
    term:
      id: MONDO:0012130
      label: myofibrillar myopathy 2
  genes:
  - preferred_term: CRYAB
    term:
      id: hgnc:2389
      label: CRYAB
  evidence:
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified an R120G missense mutation in CRYAB that co-segregates with the disease phenotype in this family."
    explanation: Original identification of CRYAB p.Arg120Gly as a cause of desmin-related (myofibrillar) myopathy.
- name: MFM3
  display_name: Myofibrillar myopathy 3 (myotilinopathy, MYOT)
  description: >
    Myotilinopathy, caused by variants in MYOT encoding myotilin, a key Z-disc
    component. Mutations cluster in the serine-rich exon 2 hotspot, the same
    region harbouring the LGMD1A variants. Onset at 42-77 years with weakness
    starting in distal or proximal leg muscles and spreading; cardiomyopathy,
    respiratory failure and peripheral neuropathy occur in a fraction of
    patients. Gene assignment verified against OMIM 609200 / NCBI GeneID 9499.
  subtype_term:
    preferred_term: myofibrillar myopathy 3
    term:
      id: MONDO:0012215
      label: myofibrillar myopathy 3
  genes:
  - preferred_term: MYOT
    term:
      id: hgnc:12399
      label: MYOT
  evidence:
  - reference: PMID:15111675
    reference_title: "Mutations in myotilin cause myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors detected four missense mutations in 6 of 57 patients with MFM in the serine-rich exon 2 of MYOT, where the two previously identified LGMD1A mutations are located."
    explanation: Establishes MYOT exon 2 as an MFM mutation hotspot.
  - reference: PMID:15947064
    reference_title: "Myotilinopathy: refining the clinical and myopathological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease is characterized by the onset at the age of 42-77 years with muscle weakness initially in distal or proximal leg muscles, eventually spreading to other muscle groups of the lower and upper extremities."
    explanation: Defines the age-at-onset range and weakness distribution of myotilinopathy.
- name: MFM4
  display_name: Myofibrillar myopathy 4 (zaspopathy, LDB3/ZASP)
  description: >
    Zaspopathy, caused by variants in LDB3 encoding ZASP (Z-band alternatively
    spliced PDZ motif-containing protein). Late-adult onset (44-73 years in the
    original series) with distal-predominant weakness in a subset; also known as
    Markesbery-Griggs late-onset distal myopathy. Cardiac involvement and
    neuropathy occur in a minority. Gene assignment verified against OMIM 609452
    / NCBI GeneID 11155.
  subtype_term:
    preferred_term: myofibrillar myopathy 4
    term:
      id: MONDO:0012277
      label: myofibrillar myopathy 4
  genes:
  - preferred_term: LDB3
    term:
      id: hgnc:15710
      label: LDB3
  evidence:
  - reference: PMID:15668942
    reference_title: "Mutations in ZASP define a novel form of muscular dystrophy in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We therefore searched for mutations in ZASP in 54 MFM patients and detected 3 heterozygous missense mutations in 11. Their age at onset was 44 to 73 years."
    explanation: Original description of ZASP/LDB3 mutations as a cause of MFM with late-adult onset.
- name: MFM5
  display_name: Myofibrillar myopathy 5 (filaminopathy, FLNC)
  description: >
    Filaminopathy, caused by variants in FLNC encoding filamin C. The
    prototypical variant (p.Trp2710Ter) lies in the dimerization domain and
    abolishes proper dimerization, producing massive cytoplasmic filamin
    C-containing aggregates. Clinically limb-girdle (proximal-predominant), with
    common respiratory muscle weakness and reported cardiac conduction and
    structural abnormalities. Gene assignment verified against OMIM 609524 / NCBI
    GeneID 2318.
  subtype_term:
    preferred_term: myofibrillar myopathy 5
    term:
      id: MONDO:0012289
      label: myofibrillar myopathy 5
  genes:
  - preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  evidence:
  - reference: PMID:15929027
    reference_title: "A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a co-segregating, heterozygous nonsense mutation (8130G-->A; W2710X) in the filamin c gene (FLNC) on chromosome 7q32.1"
    explanation: Original FLNC MFM family with the dimerization-domain nonsense variant.
- name: MFM6
  display_name: Myofibrillar myopathy 6 (BAG3-opathy, BAG3)
  description: >
    BAG3-related MFM, caused almost invariably by the recurrent de novo
    heterozygous BAG3 p.Pro209Leu variant. Distinct from other MFM subtypes in
    its childhood onset, rapid progression, severe early cardiomyopathy (which
    may precede weakness and require transplantation), severe axonal sensorimotor
    neuropathy, rigid spine and adolescent respiratory failure. BAG3 is the
    mammalian orthologue of Drosophila Starvin and the organising co-chaperone of
    chaperone-assisted selective autophagy (CASA). Gene assignment verified
    against OMIM 612954 / NCBI GeneID 9531.
  subtype_term:
    preferred_term: myofibrillar myopathy 6
    term:
      id: MONDO:0013061
      label: myofibrillar myopathy 6
  genes:
  - preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  evidence:
  - reference: PMID:19085932
    reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a heterozygous p.Pro209Leu mutation in three patients. All presented in childhood, had progressive limb and axial muscle weakness, and experienced development of cardiomyopathy and severe respiratory insufficiency in their teens"
    explanation: Defines the BAG3 p.Pro209Leu childhood-onset severe MFM subtype.
- name: MFM7
  display_name: Myofibrillar myopathy 7 (KY)
  description: >
    KY-related myopathy, caused by biallelic variants in KY encoding
    kyphoscoliosis peptidase, a Z-disc-associated protein. Presents as a
    congenital myopathy with core targetoid defects, kyphoscoliosis and tongue
    atrophy. Gene assignment verified against OMIM 617114 / NCBI GeneID 339855
    and the MONDO:0014922 definition.
  subtype_term:
    preferred_term: myofibrillar myopathy 7
    term:
      id: MONDO:0014922
      label: myofibrillar myopathy 7
  genes:
  - preferred_term: KY
    term:
      id: hgnc:26576
      label: KY
  evidence:
  - reference: PMID:27484770
    reference_title: "Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."
    explanation: >-
      Original report assigning KY as a myopathy gene. PubMed provides only the
      title for this short Acta Neuropathologica communication (no abstract
      body), so the quoted snippet is the article title itself.
- name: MFM8
  display_name: Myofibrillar myopathy 8 (PYROXD1)
  description: >
    PYROXD1-related myopathy, caused by biallelic variants in PYROXD1, a pyridine
    nucleotide-disulphide oxidoreductase. Early-onset myopathy with internalized
    nuclei and myofibrillar disorganization; slowly progressive, with facial
    weakness, nasal speech and swallowing difficulties. Gene assignment verified
    against OMIM 617258 / NCBI GeneID 79912 and the MONDO:0014993 definition.
  subtype_term:
    preferred_term: myofibrillar myopathy 8
    term:
      id: MONDO:0014993
      label: myofibrillar myopathy 8
  genes:
  - preferred_term: PYROXD1
    term:
      id: hgnc:26162
      label: PYROXD1
  evidence:
  - reference: PMID:27745833
    reference_title: "Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands."
    explanation: >-
      Original gene-discovery report for PYROXD1 myopathy (MFM8); the quoted
      histopathology is the myofibrillar-pattern lesion that places it in this
      group.
  - reference: PMID:27745833
    reference_title: "Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "facial weakness, nasal speech, swallowing difficulties"
    explanation: Documents the facial and bulbar involvement characteristic of MFM8.
- name: MFM9
  display_name: Myofibrillar myopathy 9 / hereditary myopathy with early respiratory failure (TTN)
  description: >
    Hereditary myopathy with early respiratory failure, caused by heterozygous
    variants in the region of TTN encoding the 119th fibronectin-3 domain of
    titin. Third-to-fifth-decade onset with distal leg weakness and,
    distinctively, early nocturnal respiratory symptoms out of proportion to limb
    weakness. MONDO does not currently expose a `myofibrillar myopathy 9` class
    under MONDO:0018943; the OMIM designation MFM9 corresponds to OMIM 603689
    (verified via NCBI `mim2gene_medgen` → GeneID 7273, TTN). HMERF is included
    here because contemporary MFM reviews explicitly place it inside the group.
  genes:
  - preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  evidence:
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of HMERF is established in a proband with typical clinical findings and/or a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin on molecular genetic testing."
    explanation: GeneReviews defines the TTN A-band FN3-119 domain as the HMERF locus.
  - reference: PMID:26342832
    reference_title: "Myofibrillar myopathies: State of the art, present and future challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group"
    explanation: Justifies including HMERF/TTN within the MFM group.
- name: FHL1-Related
  display_name: FHL1 muscular dystrophy with myofibrillar myopathy pathology
  description: >
    X-linked FHL1-related muscular dystrophy. LIM2-domain variants produce
    menadione-NBT-positive reducing bodies composed of 13-nm tubulofilaments that
    emanate from Z-discs; a variant outside the LIM domains produced a mild
    late-onset phenotype with MFM pathology and no reducing bodies. Features
    include muscle hypertrophy, rigid spine and joint contractures.
  genes:
  - preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  evidence:
  - reference: PMID:22094483
    reference_title: "Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FHL1 dystrophies can be associated with MFM pathology. Mutations in the LIM2 domain are associated with reducing bodies composed of distinct tubulofilaments."
    explanation: Establishes FHL1 as a cause of MFM-pattern pathology.
- name: DNAJB6-Related
  display_name: DNAJB6 limb-girdle muscular dystrophy (LGMD1D) with myofibrillar pathology
  description: >
    Dominant DNAJB6 G/F-domain variants (p.Phe89Ile, p.Phe93Leu) cause LGMD1D
    with Z-disc myofibrillar disintegration, rimmed vacuoles and accumulation of
    myotilin, desmin and alphaB-crystallin. DNAJB6 interacts with the CASA
    complex including BAG3, placing it mechanistically inside the MFM
    proteostasis group.
  genes:
  - preferred_term: DNAJB6
    term:
      id: hgnc:14888
      label: DNAJB6
  evidence:
  - reference: PMID:22366786
    reference_title: "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar myopathy-causing protein BAG3"
    explanation: Links DNAJB6 disease to the BAG3/CASA proteostasis axis of MFM.
- name: MFM10
  display_name: Myofibrillar myopathy 10 (supervillin, SVIL)
  description: >
    Biallelic loss-of-function variants in SVIL encoding supervillin cause a
    childhood/adolescence-onset myopathy with myofibrillar disorganization and
    autophagic vacuoles. Supervillin is a sarcolemmal myosin II- and
    F-actin-binding protein that potentially attaches the sarcolemma to
    myofibrillar Z-lines — a costameric rather than strictly Z-disc location.
    Note that the reported patients had no or only minor muscle weakness and only
    mild cardiac manifestations, so this is a mild outlier within the group.
    Gene assignment verified against OMIM 619040 / NCBI GeneID 6840.
  subtype_term:
    preferred_term: myofibrillar myopathy 10
    term:
      id: MONDO:0033620
      label: myofibrillar myopathy 10
  genes:
  - preferred_term: SVIL
    term:
      id: hgnc:11480
      label: SVIL
  evidence:
  - reference: PMID:32779703
    reference_title: "Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL."
    explanation: Original SVIL gene-discovery report establishing recessive loss of function as the mechanism.
  - reference: PMID:32779703
    reference_title: "Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines."
    explanation: >-
      Places supervillin at the costamere-to-Z-line link rather than within the
      Z-disc proper, which is why this subtype extends the group beyond the
      classic Z-disc proteins.
- name: MFM11
  display_name: Myofibrillar myopathy 11 (myosin chaperone UNC-45B)
  description: >
    Bi-allelic variants in UNC45B, encoding the myosin-directed chaperone
    UNC-45B, cause childhood-onset progressive muscle weakness, extending the MFM
    group beyond Z-disc structural proteins into the sarcomeric chaperone
    machinery. Mutant UNC-45B is reduced in muscle and mislocalized away from the
    A-band towards the Z-disc. Gene
    assignment verified against OMIM 619178 / NCBI GeneID 146862. Two further
    numbered members of the OMIM MFM series are not separately modelled here:
    MFM12 (MYL2, OMIM 619424, MONDO:0859168) and MFM13 (HSPB8, OMIM 621078,
    MONDO:0976133); HSPB8 is of particular mechanistic interest because it is the
    small heat-shock protein partner of BAG3 in the CASA complex. Also out of
    scope for this release, but reported in the wider protein-aggregate myopathy
    spectrum and worth a future look: PLEC, ACTA1 (a patient with an ACTA1
    variant appears in the Mayo cohort cited under `genetic[DES]`), VCP, and the
    digenic SQSTM1-TIA1 combination.
  subtype_term:
    preferred_term: myofibrillar myopathy 11
    term:
      id: MONDO:0030927
      label: myofibrillar myopathy 11
  genes:
  - preferred_term: UNC45B
    term:
      id: hgnc:14304
      label: UNC45B
  evidence:
  - reference: PMID:33217308
    reference_title: "Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness."
    explanation: Original UNC45B gene-discovery report establishing the recessive childhood-onset phenotype.
  - reference: PMID:33217308
    reference_title: "Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere."
    explanation: >-
      Documents the mislocalization toward the Z-disc that connects this
      chaperonopathy to the Z-disc-centred MFM group.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: RARE
  notes: >-
    Orphanet (ORPHA:593) and MONDO both classify myofibrillar myopathy as a rare
    disorder, and no reliable numeric point-prevalence estimate is published for
    the group as a whole; published series are tertiary-referral cohorts, which
    cannot establish population epidemiology. Recorded as a qualitative class
    rather than a fabricated rate.
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The term myofibrillar myopathies (MFM) refers to uncommon neuromuscular disorders that pathologically are characterized by myofibrillar degeneration and ectopic expression of several proteins."
    explanation: >-
      Supports the qualitative rarity class only; the source characterizes MFM as
      "uncommon" without providing a population rate.

progression:
- phase: Muscular or cardiac onset in mid-adult life
  age_range: Median 42.3 years (IQR 20.2-57.0)
  notes: >-
    Most patients present with skeletal muscle symptoms, but a substantial
    minority (14 of 80 in the Mayo cohort) present with cardiac symptoms first.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at symptom onset was 42.3 years"
    explanation: Establishes the typical age at onset in the largest published MFM cohort.
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "66 presented with muscular onset and 14 with cardiac onset."
    explanation: Documents the two presenting routes and their relative frequency.
- phase: Emergence of cardiac and respiratory involvement
  age_range: Median 7 (cardiac) and 9 (respiratory) years after myopathy onset
  notes: >-
    Cardiopulmonary involvement typically emerges years after the myopathy
    declares itself, which is the rationale for ongoing rather than one-off
    surveillance.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."
    explanation: Quantifies the latency from myopathy onset to cardiopulmonary involvement.
- phase: Progressive loss of ambulation
  age_range: Gait aids median 10 years, wheelchair median 19 years after onset
  notes: >-
    Progression is strongly subtype-dependent. By age 60, 67% of patients with
    desminopathy required gait aids and 31% were wheelchair-bound, versus 12% and
    0% for myotilinopathy and 25% and 0% for LDB3-related myopathy.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gait aids were required in 46 patients (median 10.0 years after onset), and 17 became wheelchair-bound (median 19.0 years after onset)."
    explanation: Quantifies the ambulation-loss timeline in the largest published MFM natural-history cohort.
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By age 60, 67% and 31% of patients with desminopathy required gait aids and were wheelchair-bound, respectively, compared with 12% and 0% of those with myotilinopathy and 25% and 0% of those with LDB3-related myopathy."
    explanation: Documents the subtype dependence of progression rate.
- phase: Cardiopulmonary mortality
  notes: >-
    Death in MFM is predominantly cardiopulmonary rather than a consequence of
    limb weakness itself.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients (2 with DES, 1 with ACTA1, 4 genetically uncharacterized) died, mainly due to cardiopulmonary complications."
    explanation: Establishes cardiopulmonary failure as the dominant cause of death.

pathophysiology:
- name: Z-Disc and Chaperone Protein Variant
  description: >
    The initiating lesion is a pathogenic variant in a Z-disc structural protein
    (desmin, myotilin, ZASP/LDB3, filamin C) or in a Z-disc-associated molecular
    chaperone or co-chaperone (alphaB-crystallin, BAG3, DNAJB6, UNC45B). Each
    of the six classical MFM gene products (desmin, alphaB-crystallin, myotilin,
    ZASP, filamin C, Bag3) is an integral part of the Z-disc or is closely
    associated with it, which is why the pathology converges on that structure
    regardless of which of them is mutated. The expanded gene set reaches the
    same Z-disc lesion from other compartments rather than by being Z-disc
    structural proteins: TTN through its A-band FN3-119 domain, UNC45B as a
    myosin-directed chaperone that mislocalizes from the A-band toward the
    Z-disc, SVIL from the costamere-to-Z-line link, and PYROXD1 as a
    nuclear-cytoplasmic oxidoreductase. Mutant proteins misfold or lose their
    normal binding capacity — for example the FLNC p.Trp2710Ter truncation
    disrupts the dimerization domain so that filamin C can no longer dimerize.
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Protein Folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  locations:
  - preferred_term: Skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  genes:
  - preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  - preferred_term: CRYAB
    term:
      id: hgnc:2389
      label: CRYAB
  - preferred_term: MYOT
    term:
      id: hgnc:12399
      label: MYOT
  - preferred_term: LDB3
    term:
      id: hgnc:15710
      label: LDB3
  - preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  - preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  - preferred_term: KY
    term:
      id: hgnc:26576
      label: KY
  - preferred_term: PYROXD1
    term:
      id: hgnc:26162
      label: PYROXD1
  - preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  - preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  - preferred_term: DNAJB6
    term:
      id: hgnc:14888
      label: DNAJB6
  - preferred_term: SVIL
    term:
      id: hgnc:11480
      label: SVIL
  - preferred_term: UNC45B
    term:
      id: hgnc:14304
      label: UNC45B
  evidence:
  - reference: PMID:21496631
    reference_title: "Myofibrillar myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, all MFM mutations have appeared in Z-disk-associated proteins: namely, desmin, αB-crystallin, myotilin, ZASP, filamin C, and Bag3."
    explanation: Establishes that the causative lesion is uniformly in a Z-disc-associated protein.
  - reference: PMID:28269794
    reference_title: "Myofibrillar Myopathies: New Perspectives from Animal Models to Potential Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc in the muscular fibers."
    explanation: >-
      States the dual structural / protein-quality-control character of the MFM
      gene set that this trigger node encodes. evidence_source is OTHER because
      this is a narrative review (primarily of animal models) rather than a
      primary human study.
  - reference: PMID:15929027
    reference_title: "A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly."
    explanation: Worked molecular example of how an MFM variant destroys the normal protein function.
  downstream:
  - target: Chaperone-Assisted Selective Autophagy Failure
    causal_link_type: DIRECT
    description: >-
      Variants in BAG3, CRYAB and DNAJB6 directly impair the CASA machinery;
      variants in structural clients such as filamin C increase the substrate
      load on it.
  - target: Desmin Intermediate Filament Network Disruption
    causal_link_type: DIRECT
    description: >-
      Mutant desmin, or loss of its alphaB-crystallin chaperone, destabilises the
      intermediate filament network directly.
  - target: Peripheral Neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Peripheral nerve involvement accompanies several MFM genotypes (notably
      BAG3 and MYOT) but the mechanism by which the Z-disc protein defect injures
      peripheral axons has not been established.
  - target: Sensorimotor Neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe axonal sensorimotor neuropathy in BAG3 disease; the mechanism in
      nerve is unestablished.
  - target: Cataract
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      AlphaB-crystallin is abundant in the lens as well as in muscle, so a CRYAB
      chaperone defect can also produce lens opacification.
    evidence:
    - reference: PMID:38212463
      reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "have also been \nreported in families with only a cataract phenotype"
      explanation: Establishes the CRYAB-variant-to-cataract link that this edge asserts.

- name: Chaperone-Assisted Selective Autophagy Failure
  description: >
    The Z-disc is under continuous mechanical, thermal and oxidative stress
    during contraction, and its damaged components are disposed of by
    chaperone-assisted selective autophagy (CASA). In this pathway BAG3
    (mammalian orthologue of Drosophila Starvin) coordinates the activity of the
    constitutive chaperone Hsc70/HSPA8 and the small heat-shock protein HspB8;
    disposal is initiated by the chaperone-associated ubiquitin ligase CHIP and
    the autophagic ubiquitin adaptor p62. Damaged filamin is a canonical CASA
    client. CASA is mechanistically distinct from chaperone-mediated autophagy —
    it proceeds through macroautophagy of ubiquitinated aggregates (aggrephagy)
    rather than direct lysosomal translocation of the client. This node explains
    why CRYAB and BAG3, which are chaperones rather than structural Z-disc
    proteins, produce the identical Z-disc lesion, and DNAJB6 disease joins the
    same axis through its interaction with the CASA complex. Impaired CASA
    results in Z-disc disintegration and progressive muscle weakness in flies,
    mice and humans.
  role: amplifier
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Aggrephagy
    term:
      id: GO:0035973
      label: aggrephagy
    modifier: DECREASED
  - preferred_term: Protein Quality Control for Misfolded Proteins
    term:
      id: GO:0006515
      label: protein quality control for misfolded or incompletely synthesized proteins
    modifier: DECREASED
  molecular_functions:
  - preferred_term: Hsc70/HSPA8 chaperone activity within the CASA complex
    term:
      id: GO:0140662
      label: ATP-dependent protein folding chaperone
    modifier: DECREASED
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Stv and its mammalian ortholog BAG-3 coordinate the activity of Hsc70 and the small heat shock protein HspB8 during disposal that is initiated by the chaperone-associated ubiquitin ligase CHIP and the autophagic ubiquitin adaptor p62."
    explanation: Defines the molecular composition of the CASA machinery centred on BAG3.
  - reference: PMID:20060297
    reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."
    explanation: Directly connects CASA failure to the defining Z-disc lesion of MFM.
  - reference: PMID:22366786
    reference_title: "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect."
    explanation: Shows loss of anti-aggregation chaperone capacity as the mechanism in a CASA-complex partner.
  downstream:
  - target: Ectopic Protein Aggregate Accumulation
    causal_link_type: DIRECT
    description: Failure to clear damaged Z-disc components leaves them to aggregate.
    evidence:
    - reference: PMID:20060297
      reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Instead of keeping Z disk proteins in a folded conformation, this machinery facilitates the degradation of damaged components, such as filamin, through chaperone-assisted selective autophagy (CASA)."
      explanation: >-
        Establishes that CASA is the disposal route for damaged Z-disc proteins,
        so its failure leaves those proteins to accumulate.
  - target: Myofibrillar Disintegration Beginning at the Z-Disc
    causal_link_type: DIRECT
    description: >-
      Loss of CASA-mediated turnover of damaged Z-disc components causes Z-disc
      disintegration directly, as shown in Drosophila, mouse and human muscle.
    evidence:
    - reference: PMID:20060297
      reference_title: "Chaperone-assisted selective autophagy is essential for muscle maintenance."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Impaired CASA results in Z disk disintegration and progressive muscle weakness in flies, mice, and men."
      explanation: Direct cross-species evidence for the CASA-failure to Z-disc-disintegration edge.

- name: Desmin Intermediate Filament Network Disruption
  description: >
    Desmin is the principal intermediate filament protein of cardiac, skeletal
    and smooth muscle, forming a continuous cytoskeletal network that links
    adjacent Z-discs to each other and to the sarcolemma, nucleus and
    mitochondria. Mutant desmin — or loss of its dedicated chaperone
    alphaB-crystallin — destabilises this network so that it can no longer
    maintain the spatial organisation of the contractile apparatus. Muscle cell
    lines transfected with mutant CRYAB reproduce intracellular aggregates
    containing both desmin and alphaB-crystallin, identical to those seen in
    patient muscle fibres.
  role: amplifier
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Intermediate Filament Cytoskeleton Organization
    term:
      id: GO:0045104
      label: intermediate filament cytoskeleton organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:19587455
    reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "desminopathy, a disease caused by dysfunctional mutations in desmin, a type III intermediate filament protein, or alphaB-crystallin, a chaperone for desmin"
    explanation: Establishes the desmin/alphaB-crystallin chaperone-client relationship underlying this node.
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Muscle cell lines transfected with the mutant CRYAB cDNA showed intracellular aggregates that contain both desmin and alphaB-crystallin as observed in muscle fibers from DRM patients."
    explanation: In vitro reconstitution of desmin network aggregation by a chaperone mutation.
  downstream:
  - target: Myofibrillar Disintegration Beginning at the Z-Disc
    causal_link_type: DIRECT
    description: >-
      Loss of the desmin network that mechanically couples adjacent Z-discs
      permits their disintegration under contractile load.
    evidence:
    - reference: PMID:19587455
      reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "It interacts with other proteins \nto form a continuous cytoskeletal network that maintains a spatial \nrelationship between the contractile apparatus and other structural \nelements of the cell, thus providing maintenance of cellular integrity, \nforce transmission, and mechanochemical signaling"
      explanation: >-
        States the load-bearing function of the desmin network — maintaining the
        spatial relationship of the contractile apparatus and transmitting force
        — whose loss is what permits Z-disc/myofibril disintegration.

- name: Myofibrillar Disintegration Beginning at the Z-Disc
  description: >
    The defining, gene-agnostic lesion of the group. Ultrastructural studies
    implicate the Z-disc as the site of the initial pathological change: Z-disc
    streaming and breakdown is followed by disintegration of the myofibrils
    themselves and accumulation of granular and filamentous (granulofilamentous)
    material that on longitudinal sections appears to derive from the Z-disc.
    This node is the central effector to which every genetic route converges, and
    it is why MFM is a pathologically rather than genetically defined entity.
  role: central_effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  - preferred_term: Myofibril Assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  locations:
  - preferred_term: Skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:21496631
    reference_title: "Myofibrillar myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MFMs are characterized by a distinct pathological pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins"
    explanation: Canonical statement of the defining lesion.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy shows disintegration of myofibrils starting from the Z-disk and accumulation of granular and filamentous material among the myofilaments."
    explanation: Ultrastructural confirmation that disintegration begins at the Z-disc.
  downstream:
  - target: Ectopic Protein Aggregate Accumulation
    causal_link_type: DIRECT
    description: Degraded myofibrillar filaments aggregate into pleomorphic inclusions.
    evidence:
    - reference: PMID:19085932
      reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "disintegration of Z disks and then of myofibrils is followed by ectopic accumulation of multiple proteins"
      explanation: >-
        States the temporal ordering: Z-disc/myofibril disintegration precedes
        and is followed by ectopic protein accumulation.
  - target: Progressive Skeletal Muscle Fiber Degeneration
    causal_link_type: DIRECT
    description: Loss of contractile-apparatus integrity leads to fibre degeneration and weakness.
    evidence:
    - reference: PMID:21496631
      reference_title: "Myofibrillar myopathies."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "These include progressive muscle weakness that often involves or begins in distal muscles, but limb-girdle or scapuloperoneal distributions can also occur."
      explanation: >-
        The same review that defines the morphological lesion reports the
        progressive weakness that accompanies it, but this sentence describes the
        clinical distribution rather than demonstrating the lesion-to-degeneration
        step, hence PARTIAL.
  - target: Cardiomyocyte Z-Disc Aggregate Pathology
    causal_link_type: DIRECT
    description: >-
      The same lesion occurs in cardiomyocytes, which express the MFM proteins at
      comparable levels to skeletal muscle.
    evidence:
    - reference: PMID:21496631
      reference_title: "Myofibrillar myopathies."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Cardiomyopathy and peripheral neuropathy are frequent associated features."
      explanation: >-
        Establishes cardiomyopathy as a frequent accompaniment of the
        myofibrillar lesion rather than an unrelated finding; the source states
        association, not causation, hence PARTIAL.
  - target: Myotonic Discharges on EMG
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Abnormal electrical irritability with myotonic discharges accompanies the
      structural lesion; the membrane mechanism is not established.

- name: Ectopic Protein Aggregate Accumulation
  description: >
    Degraded myofibrillar filaments aggregate into pleomorphic granular or
    hyaline inclusions in which multiple proteins are ectopically expressed:
    desmin, alphaB-crystallin, myotilin, dystrophin, sarcoglycans, NCAM, plectin,
    gelsolin, ubiquitin, filamin C and sometimes congophilic amyloid material.
    Immunohistochemically these focal accumulations affect 2-15% of muscle fibres
    and correspond to the fibre regions with lost ATPase and oxidative enzyme
    activity. Importantly, immunoblotting shows no change in total protein
    content, indicating mislocalisation and aggregation rather than
    overexpression — which is why immunohistochemistry, not immunoblot, is the
    diagnostic tool.
  role: effector
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Response to Unfolded Protein
    term:
      id: GO:0006986
      label: response to unfolded protein
    modifier: INCREASED
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemical studies demonstrate focal accumulation of desmin, alphaB-crystallin and myotilin in abnormal muscle fibers while immunoblot analysis does not highlight differences in the expression of these proteins"
    explanation: Documents aggregation without increased total protein, defining the ectopic-accumulation mechanism.
  - reference: PMID:19085932
    reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression of FLAG-labeled mutant and wild-type Bag3 in COS cells showed abnormal aggregation of the mutant protein"
    explanation: Demonstrates that the mutant MFM protein itself aggregates in a cellular model.
  downstream:
  - target: Progressive Skeletal Muscle Fiber Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Whether aggregates are directly cytotoxic or a marker of a more proximal
      stress pathway is unresolved (see the corresponding knowledge gap).
    evidence:
    - reference: PMID:22106715
      reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "These deposits correspond to the abnormal fiber regions without, or with reduced, ATPase and/or oxidative enzyme activity"
      explanation: >-
        Shows spatial co-localisation of aggregates with metabolically failing
        fibre regions, which is consistent with but does not establish a causal
        aggregate-to-degeneration edge — hence PARTIAL and an indirect link type.

- name: Progressive Skeletal Muscle Fiber Degeneration
  description: >
    Aggregate-laden fibres lose oxidative and ATPase enzyme activity in the
    affected regions, degenerate, and are progressively replaced by endomysial
    connective tissue and fat. Apoptotic nuclear loss is a documented additional
    mechanism in BAG3 disease, where 8% of nuclei were apoptotic on electron
    microscopy — consistent with BAG3's antiapoptotic function. Clinically this
    produces the slowly progressive proximal and distal weakness that defines
    MFM, with distal predominance in the majority, together with axial, bulbar
    and spinal manifestations.
  role: consequence
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: Apoptotic Process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  locations:
  - preferred_term: Skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:19085932
    reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy showed disintegration of Z disks, extensive accumulation of granular debris and larger inclusions, and apoptosis of 8% of the nuclei."
    explanation: Quantifies myonuclear apoptosis as a degeneration mechanism in BAG3 MFM.
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myofibrillar myopathy is characterized by slowly progressive weakness that can involve both proximal and distal muscles."
    explanation: Links fibre degeneration to the clinical weakness phenotype.
  downstream:
  - target: Respiratory Muscle Involvement
    causal_link_type: DIRECT
    description: Involvement of diaphragm and intercostal muscles by the same degenerative process.
    evidence:
    - reference: PMID:19587455
      reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Respiratory \nmuscle weakness is a frequent component of desminopathy."
      explanation: Establishes respiratory muscle involvement as part of the same myopathic process.
  - target: Distal Muscle Weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19587455
      reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized  by bilateral weakness in distal leg muscles \nspreading proximally and leading eventually to tetraparesis and \nwheelchair dependence"
      explanation: Describes the distal-onset weakness that the fibre-degeneration node produces.
  - target: Proximal Muscle Weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301672
      reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "slowly progressive weakness that can involve both proximal and distal muscles"
      explanation: Establishes proximal involvement as an output of the same degenerative process.
  - target: Dysphagia
    causal_link_type: DIRECT
    description: Bulbar muscle involvement.
    evidence:
    - reference: PMID:41183253
      reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dysphagia occurred in 16 patients, with 4 requiring feeding tubes."
      explanation: Documents dysphagia as a manifestation in the MFM natural-history cohort.
  - target: Muscle Stiffness
    causal_link_type: DIRECT
  - target: Muscle Cramps
    causal_link_type: DIRECT
  - target: Joint Contractures
    causal_link_type: DIRECT
    description: Secondary to chronic weakness and axial rigidity, prominent in FHL1 disease.
  - target: Skeletal Muscle Hypertrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      FHL1-related disease produces hypertrophied rather than wasted muscle; the
      mechanism of this divergence is not established.
  - target: Myalgia
    causal_link_type: DIRECT
  - target: Spinal Rigidity
    causal_link_type: DIRECT
    description: Axial and paraspinal muscle involvement, prominent in BAG3 and FHL1 disease.
  - target: Elevated Serum Creatine Kinase
    causal_link_type: DIRECT
    description: Sarcolemmal leak of creatine kinase from degenerating fibres.

- name: Cardiomyocyte Z-Disc Aggregate Pathology
  description: >
    Desmin and the other MFM proteins are as highly expressed in cardiac as in
    skeletal muscle, so the same Z-disc aggregate pathology occurs in
    cardiomyocytes. The resulting cardiomyocyte insult drives two clinically
    distinct arms: a conduction/arrhythmia arm (atrioventricular and bundle
    branch block, atrial and ventricular tachyarrhythmia, syncope, sudden cardiac
    death) and a structural arm (dilated, hypertrophic or restrictive
    cardiomyopathy progressing to congestive heart failure). This is the main
    driver of mortality in MFM and the reason cardiac surveillance is the
    dominant management concern. In BAG3 disease the cardiomyopathy can be the
    presenting feature and precede neuromuscular weakness by years, requiring
    transplantation in childhood. The node is declared conformant to the `Primary
    Cardiomyocyte Insult` trigger of the `cardiomyopathy_maladaptive_remodeling`
    module, whose definition explicitly covers "a variant in a sarcomeric or
    cytoskeletal protein gene that perturbs sarcomere assembly and force
    generation" — the situation here — and it carries both biological processes
    that module trigger expects (sarcomere organization and muscle contraction,
    both ABNORMAL). Scope note: only **trigger-level** conformance is asserted.
    The module's downstream neurohormonal-activation, ventricular-remodeling and
    heart-failure nodes are not duplicated here because MFM-specific evidence for
    them was not identified, and the module is explicitly kept distinct from the
    electrical mechanism modelled by `cardiac_ion_channel_repolarization`; the
    conduction/arrhythmia manifestations below are therefore attached as
    phenotypic outputs of this cardiomyocyte insult, not as a claim that this
    entry instantiates the module's electrical arm.
  role: consequence
  biological_scale: CELLULAR
  conforms_to: cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  - preferred_term: Muscle Contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: ABNORMAL
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:33802723
    reference_title: "The Role of Z-disc Proteins in Myopathy and Cardiomyopathy."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle."
    explanation: >-
      Establishes that the Z-disc machinery disrupted in MFM operates in
      cardiomyocytes as well as skeletal myofibres, which is the basis for
      cardiac involvement and for conformance to the cardiomyopathy module's
      cytoskeletal-variant trigger. Marked PARTIAL because this is a generic
      statement of Z-disc biology rather than a direct observation of MFM
      aggregate pathology in cardiomyocytes; evidence_source is OTHER because
      the paper is a narrative review.
  - reference: PMID:25728519
    reference_title: "BAG3 myofibrillar myopathy presenting with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe the first case in which cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years (age 12)"
    explanation: Shows the cardiac arm can be the presenting and dominant manifestation.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 10 patients who underwent to heart assessment, seven had cardiac involvement. Two of these patients had signs of congestive heart failure and arrhythmia; two had signs of congestive heart failure without arrhythmia; and three had arrhythmia without congestive failure."
    explanation: Documents both the structural (heart failure) and electrical (arrhythmia) arms in a clinical cohort.
  downstream:
  - target: Cardiomyopathy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22106715
      reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Congestive heart failure is not uncommon; in our series it was documented in 4 of 21 patients."
      explanation: Documents the structural heart-failure output of the cardiac node.
  - target: Cardiac Conduction Disease and Arrhythmia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22106715
      reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There is an increased incidence of electrocardiographic abnormalities, including atrial arrhythmias, atrioventricular conduction defects and bundle branch block."
      explanation: Documents the electrical output of the cardiac node.
  - target: Atrioventricular Block
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22106715
      reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atrioventricular conduction defects and bundle branch block"
      explanation: Names atrioventricular conduction block specifically among MFM cardiac findings.
  - target: Sudden Cardiac Death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Via malignant ventricular arrhythmia or high-grade conduction block.
    evidence:
    - reference: PMID:19587455
      reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "this would ensure prevention of sudden death from cardiac arrhythmias and other complications"
      explanation: >-
        Names arrhythmia as the route to sudden death in desminopathy, but the
        sentence is the review's rationale for diagnosis rather than an
        incidence observation, hence PARTIAL.

- name: Respiratory Muscle Involvement
  description: >
    The mechanism-level node: the same aggregate-driven fibre degeneration
    involves the diaphragm and intercostal muscles, so the respiratory pump loses
    capacity. Pump failure declares itself first during sleep, when accessory
    muscle recruitment falls away. In HMERF/TTN disease this arm is
    characteristically early and out of proportion to limb weakness, and in BAG3
    disease it reaches severity in the teens. Together with the cardiac arm it is
    the principal cause of death in MFM. The measured clinical consequence is
    modelled separately as the `Respiratory Insufficiency due to Muscle Weakness`
    phenotype.
  role: outcome
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: Skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The usual presenting findings are gait disturbance relating to distal leg weakness or nocturnal respiratory symptoms due to respiratory muscle weakness."
    explanation: Documents the ventilatory-failure route in the TTN/HMERF form.
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven patients (2 with DES, 1 with ACTA1, 4 genetically uncharacterized) died, mainly due to cardiopulmonary complications."
    explanation: Establishes cardiopulmonary failure as the dominant cause of death.
  downstream:
  - target: Respiratory Insufficiency due to Muscle Weakness
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24575448
      reference_title: "Hereditary Myopathy with Early Respiratory Failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "nocturnal respiratory symptoms due to respiratory muscle weakness"
      explanation: >-
        GeneReviews (HMERF) attributes the respiratory symptoms directly to
        respiratory muscle weakness, which is exactly this edge.

phenotypes:
- category: Neuromuscular
  name: Distal Muscle Weakness
  description: >
    Weakness beginning in and predominantly affecting the distal limb muscles,
    typically the anterior and posterior compartments of the lower leg with foot
    drop, later involving finger and wrist extensors. This is the single most
    characteristic clinical feature of MFM.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%."
    explanation: >-
      GeneReviews quantifies distal weakness at about 80%, mapping to the
      VERY_FREQUENT band (80-99%).
- category: Neuromuscular
  name: Proximal Muscle Weakness
  description: >
    Limb-girdle-pattern weakness of the shoulder and pelvic girdle. Proximal
    involvement is the presenting pattern in a large minority and is the dominant
    pattern in filaminopathy (FLNC).
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients had weakness, commonly distal-predominant (n = 34), followed by proximal-predominant (n = 24) and diffuse (n = 11) weakness"
    explanation: >-
      24 of 69 patients with a described pattern (~35%) were proximal-predominant
      and a further 11 diffuse, supporting the FREQUENT band (30-79%).
- category: Cardiovascular
  name: Cardiomyopathy
  description: >
    Structural heart muscle disease — dilated, hypertrophic or restrictive —
    developing a median of about 7 years after myopathy onset and progressing to
    congestive heart failure. Cardiomyopathy can be the presenting feature,
    particularly in BAG3 disease. This is the principal management driver in MFM.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  diagnostic: true
  notes: >-
    Banded on the only source that quantifies *overt structural cardiomyopathy*
    specifically. The Mayo cohort's 31/80 (39%) figure is for "cardiac
    involvement", a composite that also includes conduction disease and
    arrhythmia — modelled here as a separate phenotype — so it is not used to
    band this structural phenotype.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overt cardiomyopathy is present in 15%-30%."
    explanation: >-
      GeneReviews quantifies overt cardiomyopathy at 15%-30%, which falls in the
      OCCASIONAL band (5-29%) at all but the extreme upper bound.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Congestive heart failure is not uncommon; in our series it was documented in 4 of 21 patients."
    explanation: >-
      Independent cohort: overt heart failure in 4 of 21 (19%), consistent with
      the OCCASIONAL band.
- category: Cardiovascular
  name: Cardiac Conduction Disease and Arrhythmia
  description: >
    Atrioventricular and bundle branch block, atrial arrhythmias (including
    paroxysmal supraventricular tachycardia), sinus block and ventricular
    tachyarrhythmia. Conduction disease may precede structural cardiomyopathy and
    frequently requires pacemaker implantation.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  frequency: FREQUENT
  notes: >-
    Banded from the composite "cardiac involvement" figure, which chiefly
    comprises conduction and rhythm abnormalities: 31 of 80 (39%) in the Mayo
    cohort and 7 of 10 assessed in the Verona cohort.
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Arrhythmias included paroxysmal supraventricular tachycardia in three patients, left bundle branch block in two affected brothers with desmin mutation, and sinus block in one patient. Two patients with arrhythmias underwent pacemaker implantation."
    explanation: Documents the specific arrhythmia spectrum and its device consequence.
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."
    explanation: >-
      31 of 80 patients (39%) had cardiac involvement — a composite dominated by
      conduction and rhythm disease — supporting the FREQUENT band here.
- category: Cardiovascular
  name: Atrioventricular Block
  description: >
    Conduction block at the atrioventricular node is a characteristic
    manifestation of desminopathy and may cause dizziness and syncope requiring a
    permanent pacemaker.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  subtype: MFM1
  evidence:
  - reference: PMID:19587455
    reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients  experience  dizziness  and syncopal and fainting episodes associated with conduction blocks \nand require insertion of a permanent pacemaker"
    explanation: Documents conduction block with syncope in desminopathy.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >
    Fatal arrhythmia is a recognised and preventable outcome in desminopathy; the
    case for reliable diagnosis and molecular testing rests substantially on
    preventing it.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:19587455
    reference_title: "Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "this would ensure prevention of sudden death from cardiac arrhythmias and other complications"
    explanation: >-
      Identifies sudden arrhythmic death as an outcome that diagnosis is intended
      to prevent; the review does not quantify its occurrence, hence PARTIAL.
- category: Respiratory
  name: Respiratory Insufficiency due to Muscle Weakness
  description: >
    Diaphragmatic and intercostal weakness producing nocturnal hypoventilation
    with oxygen desaturation, progressing to daytime hypercapnic respiratory
    failure. Emerges a median of about 9 years after myopathy onset; in HMERF
    (TTN) it may be the presenting feature.
  phenotype_term:
    preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."
    explanation: 33 of 80 patients (41%) had respiratory involvement, supporting the FREQUENT band.
- category: Neurological
  name: Peripheral Neuropathy
  description: >
    A length-dependent peripheral neuropathy, usually axonal and large-fibre but
    sometimes small-fibre, accompanies MFM in a substantial minority. It is
    typically mild, but is severe and sensorimotor in BAG3 disease. Its presence
    alongside a myopathy is a useful diagnostic pointer toward MFM.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral neuropathy is present in about 20% of affected individuals."
    explanation: >-
      GeneReviews quantifies peripheral neuropathy at about 20%, mapping to the
      OCCASIONAL band (5-29%).
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral neuropathy was found in 21 patients (13 with axonal large fiber neuropathy and 8 with small fiber neuropathy), mostly mild in severity."
    explanation: Characterizes the neuropathy subtypes and their mild severity.
- category: Neuromuscular
  name: Sensorimotor Neuropathy
  description: >
    Severe axonal sensorimotor neuropathy is a defining accompaniment of
    BAG3-related MFM and can dominate the clinical and biopsy picture.
  phenotype_term:
    preferred_term: Sensorimotor neuropathy
    term:
      id: HP:0007141
      label: Sensorimotor neuropathy
  subtype: MFM6
  evidence:
  - reference: PMID:25728519
    reference_title: "BAG3 myofibrillar myopathy presenting with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype comprised distal weakness and severe sensorimotor neuropathy."
    explanation: Documents severe sensorimotor neuropathy in BAG3-related MFM.
- category: Gastrointestinal
  name: Dysphagia
  description: >
    Bulbar weakness producing swallowing difficulty, which in a minority
    progresses to requiring enteral feeding.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia occurred in 16 patients, with 4 requiring feeding tubes."
    explanation: >-
      16 of 80 patients (20%) had dysphagia, mapping to the OCCASIONAL band
      (5-29%).
- category: Neuromuscular
  name: Muscle Cramps
  description: >
    Cramping is reported by a minority of individuals, sometimes preceding
    demonstrable weakness.
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  notes: >-
    `frequency` intentionally omitted: GeneReviews says only "a minority of
    individuals", which does not pin an HPO band.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps."
    explanation: >-
      GeneReviews lists cramps among the minority symptoms; the phrase "a
      minority" is not band-determining, so no frequency is asserted.
- category: Neuromuscular
  name: Muscle Stiffness
  description: >
    A minority of individuals report muscle stiffness and aching, sometimes
    preceding demonstrable weakness.
  phenotype_term:
    preferred_term: Muscle stiffness
    term:
      id: HP:0003552
      label: Muscle stiffness
  notes: >-
    `frequency` intentionally omitted: GeneReviews says only "a minority of
    individuals", which does not pin an HPO band.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A minority of individuals experience sensory symptoms, muscle stiffness, aching, or cramps."
    explanation: >-
      GeneReviews documents the association; it says only "a minority", which is
      not band-determining, so no frequency is asserted.
- category: Neuromuscular
  name: Myalgia
  description: >
    Muscle pain, sometimes with elevated creatine kinase, can be the presenting
    complaint in patients who have no demonstrable weakness at diagnosis.
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the remaining four patients complained of myalgias associated with elevated serum CK (three patients) or had similarly affected family members (one patient)"
    explanation: Documents myalgia as a presenting complaint in MFM.
- category: Ophthalmological
  name: Cataract
  description: >
    Lens opacification is a distinguishing feature of alphaB-crystallinopathy,
    reflecting the fact that alphaB-crystallin is abundant in the lens as well as
    in cardiac and skeletal muscle.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  subtype: MFM2
  evidence:
  - reference: PMID:38212463
    reference_title: "CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in \ndesmin-related myopathies with or without cardiomyopathy and have also been \nreported in families with only a cataract phenotype."
    explanation: >-
      Directly documents cataract as part of the clinical spectrum of CRYAB
      (alpha-B crystallinopathy) disease alongside desmin-related myopathy.
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "This region contains the alphaB-crystallin gene (CRYAB), a candidate gene encoding a 20-kD protein that is abundant in lens and is also present in a number of non-ocular tissues, including cardiac and skeletal muscle."
    explanation: >-
      Supports the biological basis for lens involvement in CRYAB disease (the
      protein is abundant in lens); this abstract does not itself enumerate
      cataract as a clinical finding, hence PARTIAL.
- category: Musculoskeletal
  name: Spinal Rigidity
  description: >
    A rigid spine is characteristic of BAG3-related MFM (two of the three
    original patients) and of FHL1-related disease, where joint contractures also
    occur.
  phenotype_term:
    preferred_term: Spinal rigidity
    term:
      id: HP:0003306
      label: Spinal rigidity
  subtype: MFM6
  evidence:
  - reference: PMID:19085932
    reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two had rigid spines, and one a peripheral neuropathy"
    explanation: Documents rigid spine in BAG3-related MFM.
- category: Musculoskeletal
  name: Joint Contractures
  description: >
    Joint contractures accompany the rigid spine in FHL1-related disease.
  phenotype_term:
    preferred_term: Flexion contracture
    term:
      id: HP:0001371
      label: Flexion contracture
  subtype: FHL1-Related
  evidence:
  - reference: PMID:22094483
    reference_title: "Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures"
    explanation: Documents joint contractures in the FHL1 arm of the MFM spectrum.
- category: Musculoskeletal
  name: Skeletal Muscle Hypertrophy
  description: >
    Muscle hypertrophy rather than wasting is a distinguishing feature of
    FHL1-related disease within this otherwise atrophic group.
  phenotype_term:
    preferred_term: Skeletal muscle hypertrophy
    term:
      id: HP:0003712
      label: Skeletal muscle hypertrophy
  subtype: FHL1-Related
  evidence:
  - reference: PMID:22094483
    reference_title: "Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures"
    explanation: Documents muscle hypertrophy in the FHL1 arm of the MFM spectrum.
- category: Laboratory
  name: Elevated Serum Creatine Kinase
  description: >
    Serum creatine kinase is commonly modestly elevated — a mean of about
    four-fold above the upper limit of normal in one cohort, ranging from normal
    to nine-fold — so it is neither sensitive nor specific.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  reports_on:
  - target: Progressive Skeletal Muscle Fiber Degeneration
    relationship: READOUT_OF
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Serum CK was determined in 12 patients and the mean level was found to be 4-fold above the upper normal limit (range, from normal to 9-fold)."
    explanation: Quantifies the degree of CK elevation in MFM.
- category: Neurophysiological
  name: Myotonic Discharges on EMG
  description: >
    Electromyography of affected muscles shows myopathic motor unit potentials
    with abnormal irritability, often including myotonic discharges — a useful
    electrodiagnostic pointer.
  phenotype_term:
    preferred_term: "EMG: myotonic discharges"
    term:
      id: HP:0100284
      label: "EMG: myotonic discharges"
  reports_on:
  - target: Myofibrillar Disintegration Beginning at the Z-Disc
    relationship: READOUT_OF
  evidence:
  - reference: PMID:21496631
    reference_title: "Myofibrillar myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electromyography of the affected muscles reveals myopathic motor unit potentials and abnormal irritability, often with myotonic discharges."
    explanation: Documents the characteristic EMG finding.

histopathology:
- name: Myofibrillar dissolution with Z-disc disintegration
  description: >
    The defining biopsy lesion: foci of myofibrillar dissolution associated with
    disintegration of the Z-disc and accumulation of myofibrillar degradation
    products, visible on Engel-Gomori trichrome as amorphous dark blue material
    (eosinophilic on H&E).
  diagnostic: true
  evidence:
  - reference: PMID:21496631
    reference_title: "Myofibrillar myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The MFMs are characterized by a distinct pathological pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins that include desmin, αB-crystallin, dystrophin, and sometimes congophilic material."
    explanation: Canonical description of the diagnostic biopsy lesion.
- name: Granulofilamentous material on electron microscopy
  description: >
    Ultrastructurally, focal areas of myofibrillar disruption with Z-disc
    streaming and abundant granular and filamentous material that on longitudinal
    section appears to derive from the Z-disc, either interspersed among
    myofibrils or subsarcolemmal.
  diagnostic: true
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural examination showed single or multiple focal areas of different size with myofibrillar disruption, streaming of Z-disk, and abundant granulofilamentous material which was either diffusely interspersed among the myofibrils or located under the sarcolemma"
    explanation: Ultrastructural signature of MFM.
- name: Focal loss of oxidative and ATPase enzyme activity
  description: >
    Histochemistry shows focal intrafibre areas with reduction or loss of ATPase
    and oxidative enzyme (NADH, SDH, COX) activity, corresponding to the regions
    occupied by protein aggregates.
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies from all MFM patients showed areas with a loss or reduction of ATPase and oxidative enzyme activity (COX, SDH and NADH)"
    explanation: Documents the histochemical hallmark present in all cohort biopsies.
- name: Rimmed and non-rimmed vacuoles
  description: >
    Sparse small vacuoles, rimmed or not, appear in roughly half of MFM biopsies;
    they contain cytoplasmic degradation products and reflect the autophagic arm
    of the disease. Their presence contributes to diagnostic confusion with
    inclusion body myositis.
  frequency: FREQUENT
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "rimmed and non-rimmed vacuoles observed in 45% of cases and cytoplasmic bodies in only 10%"
    explanation: >-
      Quantifies rimmed/non-rimmed vacuoles at 45% of biopsies, mapping to the
      FREQUENT band (30-79%).
- name: Ectopic desmin, alphaB-crystallin and myotilin immunoreactivity
  description: >
    Immunohistochemistry shows focal accumulation of desmin, alphaB-crystallin
    and myotilin in 2-15% of muscle fibres regardless of the underlying gene.
    AlphaB-crystallin deposits are typically the most numerous. Immunoblotting is
    uninformative because total protein content is unchanged.
  diagnostic: true
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all muscle biopsies from patients with MFM, abnormal fibers with focal areas of increased reactivity for desmin, αB-crystallin and myotilin were observed"
    explanation: Documents the immunohistochemical diagnostic pattern.

genetic:
- name: DES
  gene_term:
    preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  relationship_type: CAUSATIVE
  subtype: MFM1
  frequency: >-
    The most common genetically characterized MFM: 23 of 56 genetically solved
    patients (41%) in the Mayo natural-history cohort.
  notes: >-
    Encodes desmin, the principal muscle intermediate filament protein.
    Autosomal dominant. Confirmed against OMIM 601419 / NCBI GeneID 1674.
  case_fractions:
  - population: Mayo Clinic MFM referral cohort (1993-2024), genetically solved patients
    case_fraction_percent: 41.1
    cohort_size: 56
    notes: 23 of 56 genetically characterized patients carried DES variants.
    evidence:
    - reference: PMID:41183253
      reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Eighty patients were identified; 56 were genetically characterized (23 with DES, 10 with MYOT, 9 with LDB3, 2 with FLNC, 2 with BAG3, 2 with CRYAB, 1 with FHL1, and 7 others)."
      explanation: Quantifies the DES share of genetically solved MFM in a large referral cohort.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty patients were identified; 56 were genetically characterized (23 with DES, 10 with MYOT, 9 with LDB3, 2 with FLNC, 2 with BAG3, 2 with CRYAB, 1 with FHL1, and 7 others)."
    explanation: Quantifies DES as the most frequent MFM gene in a large referral cohort.
- name: CRYAB
  gene_term:
    preferred_term: CRYAB
    term:
      id: hgnc:2389
      label: CRYAB
  relationship_type: CAUSATIVE
  subtype: MFM2
  notes: >-
    Encodes alphaB-crystallin, a small heat-shock protein and the molecular
    chaperone for desmin. Dominant missense (p.Arg120Gly) causes adult-onset
    MFM2A; biallelic frameshift alleles cause fatal infantile hypertonic MFM2B.
    Confirmed against OMIM 608810 (adult-onset) and OMIM 613869 (infantile, NCBI
    GeneID 1410).
  evidence:
  - reference: PMID:9731540
    reference_title: "A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results are the first to identify a defect in a molecular chaperone as a cause for an inherited human muscle disorder."
    explanation: Establishes CRYAB as the first chaperone gene implicated in inherited human muscle disease.
- name: MYOT
  gene_term:
    preferred_term: MYOT
    term:
      id: hgnc:12399
      label: MYOT
  relationship_type: CAUSATIVE
  subtype: MFM3
  notes: >-
    Encodes myotilin, a key Z-disc component. Autosomal dominant. Mutations
    cluster in the serine-rich exon 2, which is also the LGMD1A hotspot.
    Confirmed against OMIM 609200 / NCBI GeneID 9499.
  evidence:
  - reference: PMID:15111675
    reference_title: "Mutations in myotilin cause myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1) Mutations in myotilin cause MFM; 2) exon 2 of MYOT is a hotspot for mutations; 3) peripheral neuropathy, cardiomyopathy, and distal weakness greater than proximal weakness are part of the spectrum of myotilinopathy"
    explanation: Establishes MYOT causality and the exon 2 hotspot.
- name: LDB3
  gene_term:
    preferred_term: LDB3
    term:
      id: hgnc:15710
      label: LDB3
  relationship_type: CAUSATIVE
  subtype: MFM4
  notes: >-
    Encodes ZASP (Z-band alternatively spliced PDZ motif-containing protein).
    Autosomal dominant. Most variants lie in exon 6 at a motif important for
    linking ZASP to the Z-disc. Confirmed against OMIM 609452 / NCBI GeneID 11155.
  evidence:
  - reference: PMID:15668942
    reference_title: "Mutations in ZASP define a novel form of muscular dystrophy in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk; one carried a missense mutation in exon 9 (R268C)."
    explanation: Localizes the ZASP variants to the Z-disc-linking motif.
- name: FLNC
  gene_term:
    preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  relationship_type: CAUSATIVE
  subtype: MFM5
  notes: >-
    Encodes filamin C, an actin-crosslinking Z-disc protein and a canonical CASA
    client. Autosomal dominant. Confirmed against OMIM 609524 / NCBI GeneID 2318.
  evidence:
  - reference: PMID:15929027
    reference_title: "A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins."
    explanation: Links the FLNC dimerization defect to the aggregate phenotype.
- name: BAG3
  gene_term:
    preferred_term: BAG3
    term:
      id: hgnc:939
      label: BAG3
  relationship_type: CAUSATIVE
  subtype: MFM6
  variant_origin: DE_NOVO
  notes: >-
    Encodes BAG cochaperone 3, the organising co-chaperone of chaperone-assisted
    selective autophagy. Autosomal dominant. Nearly all reported MFM6 cases carry
    the recurrent p.Pro209Leu variant, which typically arises de novo in the
    parental germline. Confirmed against OMIM 612954 / NCBI GeneID 9531.
  evidence:
  - reference: PMID:19085932
    reference_title: "Mutation in BAG3 causes severe dominant childhood muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation is not present in 400 alleles of 200 unrelated controls, in unaffected parents of Patients 1 and 2, and in the unaffected sibling of Patient 2."
    explanation: Establishes the de novo dominant nature of the recurrent BAG3 p.Pro209Leu variant.
- name: KY
  gene_term:
    preferred_term: KY
    term:
      id: hgnc:26576
      label: KY
  relationship_type: CAUSATIVE
  subtype: MFM7
  notes: >-
    Encodes kyphoscoliosis peptidase, a Z-disc-associated protein. Autosomal
    recessive. Gene-disease assignment for MFM7 verified against OMIM 617114 /
    NCBI GeneID 339855 rather than taken from secondary sources.
  evidence:
  - reference: PMID:27484770
    reference_title: "Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects."
    explanation: >-
      Original KY myopathy report; the cached PubMed record for this short
      communication carries no abstract body, so the snippet is the article title.
- name: PYROXD1
  gene_term:
    preferred_term: PYROXD1
    term:
      id: hgnc:26162
      label: PYROXD1
  relationship_type: CAUSATIVE
  subtype: MFM8
  notes: >-
    Encodes a pyridine nucleotide-disulphide oxidoreductase. Autosomal recessive.
    Gene-disease assignment for MFM8 verified against OMIM 617258 / NCBI GeneID
    79912.
  evidence:
  - reference: PMID:27745833
    reference_title: "Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization."
    explanation: >-
      Original PYROXD1 gene-discovery report; the cached PubMed record carries no
      abstract body, so the snippet is the article title.
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  relationship_type: CAUSATIVE
  subtype: MFM9
  notes: >-
    Heterozygous variants in the A-band region encoding the 119th fibronectin-3
    domain of titin cause HMERF (OMIM 603689, NCBI GeneID 7273), designated MFM9
    in the OMIM series. Autosomal dominant with variable expressivity.
  evidence:
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a heterozygous pathogenic variant in the region of TTN that encodes the 119th fibronectin-3 domain of titin"
    explanation: Defines the specific TTN domain implicated in HMERF.
- name: FHL1
  gene_term:
    preferred_term: FHL1
    term:
      id: hgnc:3702
      label: FHL1
  relationship_type: CAUSATIVE
  subtype: FHL1-Related
  notes: Encodes four and a half LIM domains protein 1; X-linked.
  evidence:
  - reference: PMID:22094483
    reference_title: "Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM."
    explanation: Documents the discovery route of FHL1 within an MFM cohort.
- name: DNAJB6
  gene_term:
    preferred_term: DNAJB6
    term:
      id: hgnc:14888
      label: DNAJB6
  relationship_type: CAUSATIVE
  subtype: DNAJB6-Related
  notes: >-
    Encodes a J-domain (Hsp40-family) co-chaperone. Autosomal dominant.
    G/F-domain variants (p.Phe89Ile, p.Phe93Leu) act by a
    cytoplasmic-isoform-specific dominant toxic mechanism.
  evidence:
  - reference: PMID:22366786
    reference_title: "Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we studied nine LGMD-affected families from Finland, the United States and Italy and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6"
    explanation: Establishes the DNAJB6 variants and their dominant inheritance.
- name: SVIL
  gene_term:
    preferred_term: SVIL
    term:
      id: hgnc:11480
      label: SVIL
  relationship_type: CAUSATIVE
  subtype: MFM10
  notes: >-
    Encodes supervillin. Autosomal recessive loss of function. Gene-disease
    assignment for MFM10 verified against OMIM 619040 / NCBI GeneID 6840.
  evidence:
  - reference: PMID:32779703
    reference_title: "Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles."
    explanation: >-
      Original SVIL myopathy report; the cached PubMed record carries no abstract
      body, so the snippet is the article title.
- name: UNC45B
  gene_term:
    preferred_term: UNC45B
    term:
      id: hgnc:14304
      label: UNC45B
  relationship_type: CAUSATIVE
  subtype: MFM11
  notes: >-
    Encodes the myosin-specific chaperone UNC-45B. Gene-disease assignment for
    MFM11 verified against OMIM 619178 / NCBI GeneID 146862.
  evidence:
  - reference: PMID:33217308
    reference_title: "Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores."
    explanation: >-
      Original UNC45B myopathy report; the cached PubMed record carries no
      abstract body, so the snippet is the article title.

diagnosis:
- name: Muscle Biopsy with Histochemistry, Immunohistochemistry and Electron Microscopy
  description: >
    Muscle biopsy remains the diagnostic cornerstone. Light microscopy
    (Engel-Gomori trichrome, ATPase, NADH/SDH/COX), immunohistochemistry for
    desmin, alphaB-crystallin and myotilin, and electron microscopy together
    establish the myofibrillar pattern. Immunoblotting is not informative.
    Because the lesions can be focal, biopsy can be falsely reassuring, which has
    increased the role of muscle MRI in selecting a target muscle.
  evidence:
  - reference: PMID:26342832
    reference_title: "Myofibrillar myopathies: State of the art, present and future challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging"
    explanation: Documents the limits of biopsy and the complementary role of imaging.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, unlike immunoblot, immunohistochemistry together with light and electron microscopy is a useful diagnostic tool in MFM."
    explanation: Establishes which biopsy modalities are diagnostically useful.
- name: Molecular Genetic Testing of MFM Genes
  description: >
    A multi-gene panel or exome covering DES, CRYAB, MYOT, LDB3, FLNC, BAG3,
    FHL1, DNAJB6, TTN, KY and PYROXD1. Historically the genetic basis was
    established in only about half of cases; in a contemporary tertiary cohort 56
    of 80 patients were genetically characterized. Because prognosis and cardiac
    surveillance intensity differ sharply between subtypes, genetic diagnosis is
    not merely confirmatory.
  evidence:
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the phenotypic variability, genetic diagnosis is crucial for patient management and prognosis."
    explanation: Establishes the management rationale for molecular diagnosis.
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases."
    explanation: Quantifies the historical diagnostic yield of genetic testing in MFM.

imaging_findings:
- name: Selective Pattern of Muscle Involvement on MRI
  modality: MRI
  description: >
    Muscle MRI shows disorder-specific patterns of selective muscle involvement
    that can direct both biopsy site and gene selection, and has become
    increasingly important because biopsy lesions are focal.
  diagnostic: true
  evidence:
  - reference: PMID:26342832
    reference_title: "Myofibrillar myopathies: State of the art, present and future challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders"
    explanation: Documents the diagnostic role of muscle MRI in MFM.

treatments:
- name: Cardiac Pacemaker or Implantable Cardioverter Defibrillator
  description: >
    Device therapy for arrhythmia and cardiac conduction defects. Because
    conduction block and ventricular arrhythmia in MFM (especially desminopathy)
    can cause syncope and sudden death, pacemaker or ICD implantation is a
    central and potentially life-saving intervention.
  therapeutic_modality: DEVICE
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: pacemaker or implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_phenotypes:
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  target_mechanisms:
  - target: Cardiomyocyte Z-Disc Aggregate Pathology
    treatment_effect: MODULATES
    description: >-
      Does not modify the underlying aggregate pathology; it substitutes for or
      terminates the arrhythmic consequence of it.
  notes: >-
    The GeneReviews recommendation covers both pacemakers and implantable
    cardioverter defibrillators; NCIT:C80435 (Implantable
    Cardioverter-Defibrillator Placement) is the sibling term for the ICD arm.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consider pacemaker and implantable cardioverter defibrillator (ICD) in individuals with arrhythmia and/or cardiac conduction defects"
    explanation: GeneReviews management recommendation for the arrhythmia arm.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients with arrhythmias underwent pacemaker implantation."
    explanation: Documents real-world pacemaker use in an MFM cohort.
- name: Cardiac Transplantation
  description: >
    Considered for progressive or life-threatening cardiomyopathy. In BAG3
    disease transplantation has been required as early as age eight, before
    neuromuscular weakness became apparent.
  therapeutic_modality: SURGERY
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  target_mechanisms:
  - target: Cardiomyocyte Z-Disc Aggregate Pathology
    treatment_effect: BYPASSES
    description: Replaces the diseased myocardium rather than correcting the aggregate pathology.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consider cardiac transplantation in individuals with progressive or life-threatening cardiomyopathy"
    explanation: GeneReviews management recommendation for advanced cardiomyopathy.
  - reference: PMID:25728519
    reference_title: "BAG3 myofibrillar myopathy presenting with cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cardiomyopathy and cardiac transplantation (age eight) preceded neuromuscular weakness by several years"
    explanation: Worked example of paediatric cardiac transplantation in BAG3-related MFM.
- name: Noninvasive Ventilatory Support
  description: >
    Continuous or bilevel positive airway pressure, initially nocturnal for
    hypoventilation and later extended into the daytime, with progression to
    mechanical ventilation as needed.
  therapeutic_modality: DEVICE
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: continuous or bilevel positive airway pressure ventilation
    term:
      id: NCIT:C124040
      label: Continuous Positive Airway Pressure
  target_phenotypes:
  - preferred_term: Respiratory insufficiency due to muscle weakness
    term:
      id: HP:0002747
      label: Respiratory insufficiency due to muscle weakness
  target_mechanisms:
  - target: Respiratory Muscle Involvement
    treatment_effect: MODULATES
    description: Mechanically supplements the failing respiratory pump.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory support (continuous or bilevel positive airway pressure), initially at night and later in the daytime, in individuals with hypercapnea and other signs of incipient respiratory failure"
    explanation: GeneReviews management recommendation for ventilatory failure.
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Noninvasive ventilation with bilevel positive airway pressure (BiPAP) or continuous positive airway pressure (CPAP) may be indicated for nocturnal hypoventilation initially, followed by mechanical ventilatory support as needed."
    explanation: GeneReviews HMERF management recommendation confirming the ventilatory escalation pathway.
- name: Physical Therapy and Assistive Devices
  description: >
    Range-of-motion physical therapy and assistive devices for advanced muscle
    weakness. Ankle-foot orthoses optimise independent ambulation early in the
    course of distal leg weakness; canes, walkers and wheelchairs follow. Note
    the explicit GeneReviews caveat that the role of strengthening exercise has
    not been defined — this is the closest thing MFM has to an
    "agents/circumstances to avoid" statement, and strengthening programmes
    should not be assumed beneficial.
  therapeutic_modality: BEHAVIORAL
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  target_mechanisms:
  - target: Progressive Skeletal Muscle Fiber Degeneration
    treatment_effect: MODULATES
    description: Mitigates contracture and functional loss; does not modify fibre degeneration.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "range-of-motion physical therapy and assistive devices for those with advanced muscle weakness. Other: The role of strengthening exercises has not been defined."
    explanation: >-
      GeneReviews management recommendation, including the explicit caveat that
      strengthening exercise is of undefined benefit.
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For distal leg weakness, use of ankle-foot orthoses can optimize independent ambulation early in the disease course; later in the disease course other mobility aids (canes, walkers, or wheelchairs) may be required."
    explanation: Specifies the orthotic and mobility-aid escalation for distal leg weakness.
- name: Genetic Counseling
  description: >
    Counseling must accommodate the mixed inheritance of the group: usually
    autosomal dominant, but X-linked for FHL1 and autosomal recessive for CRYAB
    frameshift alleles, PYROXD1, KY and SVIL. When the familial variant is known,
    carrier testing and prenatal testing are possible.
  therapeutic_modality: BEHAVIORAL
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When the pathogenic variant(s) in the family are known, carrier testing and prenatal testing for pregnancies at increased risk is possible."
    explanation: GeneReviews genetic counseling recommendation.
- name: Cardiac and Respiratory Surveillance
  description: >
    Systematic surveillance is the key management lever in MFM because there is
    no disease-modifying therapy and because cardiac and respiratory involvement
    typically emerge years after myopathy onset and are the main causes of death.
    Annual reassessment of muscle strength and clinical status by a neurologist
    and pulmonary function testing every six to twelve months are recommended,
    alongside cardiac assessment.
  therapeutic_modality: BEHAVIORAL
  action_category: MONITORING
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:24575448
    reference_title: "Hereditary Myopathy with Early Respiratory Failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reassessment of muscle strength and clinical status annually by a neurologist; pulmonary function testing every six to 12 months, or guided by individual findings."
    explanation: GeneReviews surveillance schedule.
  - reference: PMID:28269794
    reference_title: "Myofibrillar Myopathies: New Perspectives from Animal Models to Potential Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MFMs share common histological characteristics including progressive disorganization of the interfibrillar network and protein aggregation. Currently no treatment is available."
    explanation: >-
      Establishes the absence of disease-modifying therapy, which is why
      surveillance and organ-specific intervention constitute the management
      strategy.
  - reference: PMID:41183253
    reference_title: "Natural History and Phenotypic Spectrum of Myofibrillar Myopathies and Myopathies Associated With MFM-Related Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement (n = 31) and respiratory involvement (n = 33) were frequent, manifesting at a median of 7 and 9 years, respectively, after myopathy onset."
    explanation: >-
      Establishes the multi-year latency that makes ongoing surveillance, rather
      than a single baseline assessment, necessary.

differential_diagnoses:
- name: Limb-girdle muscular dystrophy
  description: >
    MFM with proximal-predominant weakness — particularly filaminopathy (FLNC)
    and myotilinopathy — is clinically indistinguishable from limb-girdle
    muscular dystrophy at the bedside. The boundary is genuinely blurred: MYOT is
    the LGMD1A gene and myotilinopathy forms a phenotypic continuum spanning
    LGMD1A and MFM; the original FLNC MFM pedigree was described as having
    clinical features of a limb-girdle myopathy; and DNAJB6-related LGMD1D shows
    myofibrillar pathology.
  disease_term:
    preferred_term: limb-girdle muscular dystrophy
    term:
      id: MONDO:0016971
      label: limb-girdle muscular dystrophy
  distinguishing_features:
  - Muscle biopsy showing myofibrillar dissolution with Z-disc disintegration and ectopic desmin/alphaB-crystallin/myotilin aggregates favors MFM
  - Concomitant cardiomyopathy, cardiac conduction disease and peripheral neuropathy point toward MFM
  - Several genes (MYOT/LGMD1A, DNAJB6/LGMD1D, FLNC) span both diagnostic labels, so genetic testing may not fully resolve the boundary
  evidence:
  - reference: PMID:15929027
    reference_title: "A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM"
    explanation: Documents the clinical overlap of MFM with limb-girdle myopathy and its resolution by morphology.
  - reference: PMID:15947064
    reference_title: "Myotilinopathy: refining the clinical and myopathological phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Spanish cohort, the largest group of patients studied so far, shares phenotypic features with both LGMD1A and MFM/MYOT variants thus establishing a continuum of phenotypic manifestations characteristic of myotilinopathy"
    explanation: >-
      Establishes that MFM and LGMD1A are a continuum for MYOT, not cleanly
      separable diagnoses.
- name: Inclusion body myositis
  description: >
    Sporadic inclusion body myositis shares rimmed vacuoles, protein aggregation
    including congophilic material, late-adult onset and slowly progressive
    weakness with MFM, and an endomysial inflammatory infiltrate can be present
    in MFM biopsies.
  disease_term:
    preferred_term: inclusion body myositis
    term:
      id: MONDO:0007827
      label: inclusion body myositis
  distinguishing_features:
  - IBM shows characteristic asymmetric quadriceps and finger-flexor weakness, whereas MFM weakness is more often symmetric with distal leg predominance
  - MFM biopsies show Z-disc-origin granulofilamentous material on electron microscopy and focal desmin/alphaB-crystallin/myotilin immunoreactivity
  - Cardiomyopathy and cardiac conduction disease are features of MFM but not of IBM
  - A pathogenic variant in an MFM gene establishes MFM
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Sparse small vacuoles, rimmed or not, appeared in half of the specimens"
    explanation: >-
      Documents the rimmed-vacuolar pathology in MFM that creates the diagnostic
      overlap with inclusion body myositis; the source does not itself discuss
      IBM, hence PARTIAL.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "In one biopsy specimen there was an endomysial inflammatory infiltrate."
    explanation: >-
      Documents that an inflammatory infiltrate — the histological hallmark used
      to suspect myositis — can occur in genuine MFM.
- name: Distal myopathy
  description: >
    Because distal weakness is present in about 80% of MFM patients, MFM enters
    the differential of every hereditary distal myopathy. Indeed several
    eponymous distal myopathies have turned out to be MFM subtypes:
    Markesbery-Griggs late-onset distal myopathy is LDB3/ZASP-related MFM4.
  disease_term:
    preferred_term: distal myopathy
    term:
      id: MONDO:0018949
      label: distal myopathy
  distinguishing_features:
  - Myofibrillar pathology on biopsy distinguishes MFM from non-aggregating distal myopathies such as Welander or Laing distal myopathy
  - Associated cardiomyopathy and peripheral neuropathy favor MFM
  - Some historical distal myopathy eponyms (Markesbery-Griggs) are now classified as MFM subtypes
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal muscle weakness is present in about 80% of individuals and is more pronounced than proximal weakness in about 25%."
    explanation: Establishes why MFM must be considered in any distal myopathy presentation.
- name: VCP-related multisystem proteinopathy
  description: >
    VCP (valosin-containing protein) disease is the closest molecular
    near-neighbour outside the modelled gene set: VCP is a proteostasis ATPase,
    its muscle pathology is rimmed-vacuolar with p62/TDP-43 and desmin/myotilin
    inclusions that overlap the MFM immunohistochemical panel, and in the
    Japanese 297-case protein-aggregate-myopathy screen VCP was the second most
    frequent gene among solved cases. It is included as a differential rather
    than a subtype because its defining multisystem phenotype (Paget disease of
    bone and frontotemporal dementia) is outside the MFM concept.
  disease_term:
    preferred_term: inclusion body myopathy with Paget disease of bone and frontotemporal dementia
    term:
      id: MONDO:0000507
      label: inclusion body myopathy with Paget disease of bone and frontotemporal dementia
  distinguishing_features:
  - Paget disease of bone and frontotemporal dementia in the proband or family point to VCP rather than MFM
  - VCP inclusions are p62- and TDP-43-positive; TDP-43 is not part of the MFM aggregate signature
  - A purely myopathic VCP presentation without CNS or bone involvement is well described and is the hardest case to separate clinically
  evidence:
  - reference: PMID:37091525
    reference_title: "VCP-related myopathy: a case series and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43"
    explanation: >-
      Shows that VCP myopathy is worked up with the same desmin/myotilin panel
      used for MFM, plus p62 and TDP-43 — the overlap that makes it a
      differential and the markers that separate it.
  - reference: PMID:37091525
    reference_title: "VCP-related myopathy: a case series and a review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement"
    explanation: >-
      Documents the purely myopathic VCP presentation, which is the presentation
      that is genuinely hard to distinguish from MFM.
- name: Pompe disease (glycogen storage disease II)
  description: >
    Late-onset Pompe disease presents with slowly progressive proximal and axial
    weakness plus early diaphragmatic weakness and respiratory failure — the same
    combination that characterizes MFM, and particularly HMERF. It is the single
    most important treatable mimic, since enzyme replacement therapy is
    available.
  disease_term:
    preferred_term: glycogen storage disease II
    term:
      id: MONDO:0009290
      label: glycogen storage disease II
  distinguishing_features:
  - Pompe disease is diagnosed by deficient acid alpha-glucosidase activity on dried blood spot and biallelic GAA variants
  - Pompe muscle biopsy shows PAS-positive glycogen-filled lysosomal vacuoles with acid phosphatase reactivity, not Z-disc granulofilamentous material
  - Muscle glycogen content is normal in MFM
  - Pompe disease has a licensed disease-modifying enzyme replacement therapy; MFM management is supportive
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The muscle fiber lipid and glycogen content was normal."
    explanation: >-
      Documents normal muscle glycogen in MFM, one of the morphological features
      that separates it from the glycogen-storage mimic. Marked PARTIAL because
      it supports a single distinguishing feature from the MFM side only; no
      Pompe-side source is cited here.

discussions:
- discussion_id: gap_mfm_unsolved_genetic_basis
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What causes myofibrillar myopathy in the roughly half of patients in whom no
    pathogenic variant is found in any known MFM gene?
  rationale: >-
    Despite the addition of KY, PYROXD1, TTN, FHL1, DNAJB6, SVIL, UNC45B, MYL2
    and HSPB8 to the original six genes, a large fraction of pathologically
    confirmed MFM remains genetically unsolved. In the 21-patient Verona cohort
    the genetic basis was established in only 28% of cases; GeneReviews puts the
    historical figure at about 50%, and even the contemporary Mayo cohort left 24
    of 80 patients uncharacterized. Whether the remainder reflects additional
    Z-disc/proteostasis genes, non-coding or structural variation in known genes,
    or a non-Mendelian route is unresolved, and it directly limits both prognosis
    and family counseling.
  attaches_to:
  - pathophysiology#Z-Disc and Chaperone Protein Variant
  proposed_experiments:
  - experiment_id: exp_mfm_genome_sequencing_panel_negative
    name: Genome sequencing of biopsy-confirmed, panel-negative MFM
    description: >-
      Apply short- and long-read genome sequencing with structural- and
      non-coding-variant analysis to biopsy-confirmed MFM cohorts that are
      negative on a comprehensive MFM gene panel, to test whether the missing
      heritability lies in undetected variation within known genes.
  - experiment_id: exp_mfm_muscle_rnaseq
    name: Muscle RNA sequencing for aberrant splicing and allelic imbalance
    description: >-
      Sequence RNA from patient muscle to detect aberrant splicing events and
      allele-specific expression at known MFM loci that escape DNA-level panels.
  - experiment_id: exp_mfm_aggregate_proteomics
    name: Proteomic profiling of laser-captured aggregates
    description: >-
      Laser-capture microdissect the protein aggregates from genetically
      unsolved MFM biopsies and characterise their constituents by mass
      spectrometry to nominate novel candidate genes.
  evidence:
  - reference: PMID:20301672
    reference_title: "Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, the genetic basis of myofibrillar myopathy has been elucidated in only about 50% of cases."
    explanation: Quantifies the diagnostic gap that motivates this knowledge gap.
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, the genetic basis of MFM was established in only 28% of our cases and these data are consistent with those reported in other studies."
    explanation: Independent cohort quantification of the unsolved fraction.
- discussion_id: gap_mfm_aggregate_causality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is protein aggregation in myofibrillar myopathy the cause of muscle fibre
    degeneration, or a downstream marker of a more proximal stress-induced
    pathway?
  rationale: >-
    The mechanisms leading to protein aggregation are not fully understood, and
    it has been proposed that the fibre abnormalities in MFM represent a common
    step of a stress-induced pathway that can be triggered by different stimuli —
    which would make the aggregates a consequence rather than the primary toxic
    species. This distinction determines whether therapeutic strategies should
    target aggregate clearance (for example by augmenting chaperone-assisted
    selective autophagy) or the upstream stress response, and it is the reason
    the aggregate-to-degeneration edge in this entry is typed
    INDIRECT_UNKNOWN_INTERMEDIATES.
  attaches_to:
  - pathophysiology#Ectopic Protein Aggregate Accumulation
  proposed_experiments:
  - experiment_id: exp_mfm_temporal_aggregate_vs_dysfunction
    name: Time-resolved aggregate formation versus fibre dysfunction
    description: >-
      Use inducible MFM models to establish whether measurable contractile
      dysfunction precedes, coincides with, or follows detectable aggregate
      formation.
  - experiment_id: exp_mfm_casa_augmentation_rescue
    name: CASA augmentation rescue experiment
    description: >-
      Test whether pharmacological or genetic augmentation of chaperone-assisted
      selective autophagy rescues muscle function, and whether any rescue tracks
      with reduction in aggregate burden.
  evidence:
  - reference: PMID:22106715
    reference_title: "Clinical, morphological and genetic studies in a cohort of 21 patients with myofibrillar myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, the mechanisms leading to protein aggregation are not fully understood and recent studies proposed that the fiber abnormalities in MFM probably are a common step of a stress-induced pathway, triggered by different stimuli"
    explanation: States the unresolved causal direction between aggregation and fibre injury.

📚

References & Deep Research

References

2

PMID:20301672

Myofibrillar Myopathy – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

No top-level findings curated for this source.

PMID:24575448

Hereditary Myopathy with Early Respiratory Failure.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Myofibrillar Myopathy: Disease Characteristics Research Report

Edison Scientific Literature 24 citations 2026-08-01T05:11:50.303951

Myofibrillar Myopathy: Disease Characteristics Research Report

Executive summary

Myofibrillar myopathy (MFM) is not one molecular disease but a genetically heterogeneous group of inherited protein-aggregate myopathies. Its defining lesion is focal myofibrillar dissolution, usually beginning at the Z-disc, followed by accumulation of desmin, myotilin, αB-crystallin and other sarcomeric or protein-quality-control proteins. Skeletal muscle is invariably central, but cardiac muscle, respiratory muscles and peripheral nerves can also be affected. Clinical onset ranges from infancy to late adulthood, although classic DES-, FLNC- and MYOT-associated disease is commonly adult-onset and slowly progressive. No approved disease-modifying treatment exists; present implementation consists of molecular diagnosis, cardiac and respiratory surveillance, rehabilitation, assistive devices and treatment of organ-specific complications. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 1-6)

The following reusable ontology-oriented summary complements the narrative report. IDs marked “suggested” should be checked against the current source ontology before database ingestion.

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 (olive2021246thenmcinternational pages 1-6, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 1-6)
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 (olive2021246thenmcinternational pages 6-10, olive2021246thenmcinternational pages 1-6)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 6-10)
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 (olive2021246thenmcinternational pages 1-6, luo2019characterizationofchinese pages 6-7, olive2005myotilinopathyrefiningthe pages 1-2)
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 (olive2021246thenmcinternational pages 1-6, luo2019characterizationofchinese pages 6-7)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, luo2019characterizationofchinese pages 6-7)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, luo2019characterizationofchinese pages 6-7)
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 (olive2021246thenmcinternational pages 6-10, luo2019characterizationofchinese pages 6-7)
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 (olive2021246thenmcinternational pages 1-6, luo2019characterizationofchinese pages 6-7, olive2005myotilinopathyrefiningthe pages 1-2)
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 (olive2021246thenmcinternational pages 1-6, olive2005myotilinopathyrefiningthe pages 1-2, wadmore2021theroleof pages 1-2)
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 (wadmore2021theroleof pages 1-2, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
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 (olive2021246thenmcinternational pages 6-10, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
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 (olive2021246thenmcinternational pages 1-6, wadmore2021theroleof pages 1-2)
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 (findlay2024dominantlyinheritedmuscle pages 8-9)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 1-6)
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 (luo2019characterizationofchinese pages 6-7, wadmore2021theroleof pages 1-2)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, wadmore2021theroleof pages 1-2, findlay2024dominantlyinheritedmuscle pages 8-9)
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 (olive2021246thenmcinternational pages 1-6, luo2019characterizationofchinese pages 6-7, olive2005myotilinopathyrefiningthe pages 1-2)
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 (olive2021246thenmcinternational pages 6-10, luo2019characterizationofchinese pages 6-7)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, luo2019characterizationofchinese pages 6-7)
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 (olive2021246thenmcinternational pages 6-10, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
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 (olive2021246thenmcinternational pages 6-10, olive2021246thenmcinternational pages 1-6)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, luo2019characterizationofchinese pages 6-7)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 6-10)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 6-10)
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 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, findlay2024dominantlyinheritedmuscle pages 8-9)
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 (olive2021246thenmcinternational pages 6-10, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 1-6)

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.

1. Disease information

Definition and classification

MFM is a histopathologic and mechanistic disease category characterized by myofibrillar degradation beginning around the Z-disc, pleomorphic sarcoplasmic inclusions, protein aggregation and, variably, rimmed vacuoles. The category overlaps distal myopathies, limb-girdle muscular dystrophies, hereditary myopathy with early respiratory failure and other protein-aggregate myopathies. Consequently, “MFM” may describe a biopsy pattern before a molecular subtype is known rather than a single etiologic diagnosis. (olive2021246thenmcinternational pages 6-10, olive2021246thenmcinternational pages 1-6)

A foundational review states directly: “Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc.” It further identifies “progressive disorganization of the interfibrillar network and protein aggregation” as shared pathology. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)

Identifiers and synonyms

MONDO: Myofibrillar myopathy is represented in MONDO, but the exact current parent-class ID should be validated through the live MONDO release before ingestion; individual molecular subtypes have separate records.
OMIM: MFM is distributed across subtype records rather than represented adequately by one number. A commonly cited record is MFM1, OMIM 601419 for desmin-related MFM; other numbered MFM records correspond to CRYAB, MYOT, LDB3, FLNC, BAG3 and additional gene-specific diseases.
Orphanet: Orphanet organizes MFM and several gene-defined subtypes as rare genetic myopathies; current ORPHA identifiers should likewise be resolved through the live API.
ICD-10: no highly specific universal MFM code; cases are commonly captured under hereditary/progressive muscular dystrophy or other specified myopathy categories, depending on jurisdiction.
ICD-11: classified within genetic/developmental disorders of muscle; exact extension coding should be jurisdictionally validated.
MeSH: generally indexed through Myopathies, Structural, Congenital, Muscular Diseases, gene-specific terms, and pathology concepts rather than one perfectly specific heading.
Synonyms: myofibrillar myopathies; MFM; desmin-related myopathy/desminopathy when DES-associated; αB-crystallinopathy; myotilinopathy; filamin-C myopathy/filaminopathy; ZASP-related myopathy; BAG3 myopathy; protein-aggregate myopathy.

The evidence summarized here is aggregated disease-level literature, not individual EHR data. Some statistics derive from retrospective patient cohorts or individual pedigrees.

2. Etiology, risk and protective factors

MFM is principally Mendelian. Pathogenic germline variants affect structural Z-disc/intermediate-filament proteins or proteins responsible for sarcomeric proteostasis. Classic genes are DES, CRYAB, MYOT, LDB3/ZASP, FLNC and BAG3. The broader MFM-like/protein-aggregate spectrum includes FHL1, TTN, DNAJB6, PLEC, ACTA1, HSPB8, PYROXD1, KY, and digenic SQSTM1–TIA1, among others. The expansion reflects genuine biological overlap and the fact that one gene can cause several pathologic phenotypes. (olive2021246thenmcinternational pages 6-10, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)

Most classic forms are autosomal dominant with variable, often age-dependent penetrance and marked intrafamilial expressivity. Recessive, X-linked and digenic disorders occur in the broader spectrum. De novo dominant variants are particularly important in severe childhood BAG3 disease. Variants include missense substitutions, small insertions/deletions, truncating and splice variants; the functional effect is gene- and domain-specific and may be dominant-negative, toxic gain-of-function, aggregation-prone or loss-of-function.

No reproducible environmental cause, infectious trigger, toxin, diet, smoking exposure or protective allele has been established for inherited MFM. Mechanical loading is biologically relevant because contraction repeatedly unfolds or damages Z-disc proteins, but ordinary exercise is not established as a primary cause. Excessive unaccustomed exercise may aggravate symptoms in an already vulnerable muscle; conversely, appropriately dosed rehabilitation may preserve function. Evidence for formal gene–environment interactions, validated protective variants, epigenetic risk states or specific diets is presently insufficient.

3. Phenotypes

The phenotype is genotype-dependent and cannot be summarized by one frequency. In two major cohorts summarized by the ENMC workshop, mean onset was 52 years in 82 Mayo Clinic patients and 42 years in 48 French patients. Childhood disease occurs, especially with BAG3, while TTN-related phenotypes can range from infancy through adulthood. (olive2021246thenmcinternational pages 6-10, luo2019characterizationofchinese pages 6-7, olive2021246thenmcinternational pages 1-6)

Progressive muscle weakness: distal, proximal, limb-girdle, scapuloperoneal or mixed; axial and facial weakness can occur. Suggested HPO: HP:0001324, HP:0003701, HP:0002460, HP:0003323 and HP:0000204. Weakness impairs walking, stairs, rising, hand use and eventually independent activities.
Cardiac disease: dilated, hypertrophic or restrictive cardiomyopathy; conduction block and ventricular arrhythmia; risk is particularly important in DES and BAG3 disease. Suggested HPO: HP:0001638, HP:0001644, HP:0001639, HP:0001723, HP:0001678. An older synthesis estimated cardiac complications in approximately 60–70% across selected MFM series and reported pacemaker/defibrillator implantation or transplantation in approximately 10%; these are referral-cohort estimates, not population rates. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
Respiratory muscle weakness: restrictive ventilatory defect, nocturnal hypoventilation and respiratory failure; it may be disproportionate to limb weakness. Respiratory insufficiency and/or dysphagia were reported in approximately one-third in a historical synthesis. Suggested HPO: HP:0002093 and HP:0002091. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
Peripheral neuropathy: motor or sensorimotor, frequently axonal, especially in BAG3 and some DES phenotypes. Suggested HPO: HP:0009830, HP:0003447 and HP:0007141. In one 18-person Chinese series, motor/sensorimotor axonopathy was the predominant neuropathy pattern. (luo2019characterizationofchinese pages 6-7)
Bulbar/axial/orthopedic features: dysphagia (HP:0002015), dysphonia (HP:0001618), rigid spine, scoliosis (HP:0002650), contractures (HP:0001371), myalgia (HP:0003326), stiffness and occasional ophthalmoparesis (HP:0000602). (olive2005myotilinopathyrefiningthe pages 1-2, olive2021246thenmcinternational pages 1-6)
Laboratory abnormalities: serum creatine kinase is often normal or mildly/moderately elevated and is neither sensitive nor specific. EMG is generally myopathic with irritability; nerve-conduction testing may disclose concomitant neuropathy. (olive2021246thenmcinternational pages 6-10)

Validated MFM-specific quality-of-life instruments and robust EQ-5D/SF-36 population estimates are lacking. The major burdens are progressive mobility loss, fatigue, ventilatory dependency, dysphagia and anxiety associated with arrhythmia or sudden-death risk.

4. Genetic and molecular information

The six canonical proteins occupy complementary roles: DES forms the extrasarcomeric intermediate-filament network; FLNC crosslinks actin and links Z-discs to membrane complexes; MYOT and LDB3/ZASP scaffold the Z-disc; CRYAB is a small heat-shock chaperone; and BAG3 coordinates chaperone-assisted selective autophagy. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, wadmore2021theroleof pages 1-2)

Examples of informative genotype–phenotype relationships include adult-onset DES/FLNC/MYOT disease, childhood-onset severe BAG3 disease and TTN variants causing hereditary myopathy with early respiratory failure or MFM-like pathology. In myotilinopathy, onset in a 13-patient study ranged from 42 to 77 years, initially affecting distal or proximal legs and later upper limbs. (olive2005myotilinopathyrefiningthe pages 1-2)

A Japanese screen summarized by ENMC evaluated 297 cases from 288 families and found a causal variant in 89 cases (34%). TTN was most frequent among solved cases (18 cases), followed by VCP, DES and FHL1. This both demonstrates substantial locus heterogeneity and shows that many patients remain genetically unresolved. (olive2021246thenmcinternational pages 6-10)

Variant interpretation must be transcript- and domain-specific. Rare frequency in gnomAD is necessary but not sufficient; segregation, phenotype, biopsy localization, functional evidence and ACMG/AMP criteria should be integrated. Population allele frequency cannot be supplied generically because it is variant-specific. The causal variants are overwhelmingly germline, not somatic. No recurrent chromosomal aneuploidy, translocation or epigenetic signature defines MFM. Modifier-gene and variant-load hypotheses are plausible, but no modifier is sufficiently validated for routine clinical prediction.

5. Environmental information

No infectious agent, radiation exposure, occupational toxin or lifestyle exposure is recognized as causal. Mechanical strain likely interacts with genetically impaired Z-disc maintenance and protein quality control, providing a biologically plausible but incompletely quantified gene–environment relationship. Smoking and obesity may worsen cardiopulmonary reserve but are nonspecific comorbidity modifiers. Vaccination, nutrition and moderate activity should follow general neuromuscular-care principles rather than MFM-specific evidence.

6. Mechanism and pathophysiology

The principal causal chain is:

pathogenic variant → unstable/misfolded or dysfunctional Z-disc/intermediate-filament protein → impaired sarcomeric force transmission and proteostasis → Z-disc streaming and myofibrillar dissolution → recruitment of chaperones, ubiquitin and structural proteins into aggregates → autophagic/UPS overload, mitochondrial and energetic dysfunction → myofiber degeneration, fibrosis and progressive weakness. Cardiac involvement follows an analogous chain in cardiomyocytes, with conduction-system disease or arrhythmogenic remodeling in susceptible genotypes. (olive2021246thenmcinternational pages 1-6, wadmore2021theroleof pages 1-2)

Upstream events are variant-dependent protein dysfunction and mechanical instability. Intermediate processes include protein misfolding, aggregate formation and failure of CASA/aggrephagy, involving BAG3, HSPB8/HSPA, DNAJB6, SQSTM1/p62 and autophagy machinery. Downstream lesions include vacuolization, mitochondrial injury, fiber loss and fibrosis. Suggested GO terms include Z-disc organization/sarcomere organization (GO:0045214), protein folding (GO:0006457), response to unfolded protein (GO:0006986), autophagy (GO:0006914), selective autophagy (GO:0061919), ubiquitin-dependent protein catabolism (GO:0006511), mitochondrial organization (GO:0007005) and oxidative phosphorylation (GO:0006119).

Proteomic work has shown that aggregates contain many proteins beyond the mutant protein, supporting a shared secondary aggregate proteome. However, disease-specific single-cell atlases, spatial transcriptomics, lipidomics and clinically validated metabolomic signatures remain sparse. Immune inflammation is not considered the initiating mechanism, although secondary inflammatory responses may accompany degeneration.

7. Anatomical structures affected

The primary site is skeletal muscle tissue (UBERON:0001134), involving skeletal myofibers (CL:0000188), often bilaterally but sometimes asymmetrically. Distribution varies by genotype and may emphasize distal lower limbs, proximal girdles, paraspinal muscles, neck, diaphragm (UBERON:0001103) or facial/bulbar musculature. Secondary/parallel targets are heart (UBERON:0000948), cardiomyocytes (CL:0000746), respiratory musculature and, in mixed phenotypes, peripheral nerves and Schwann cells.

Relevant subcellular compartments are Z-disc (GO:0030018), myofibril (GO:0030016), sarcomere (GO:0030017), intermediate filament (GO:0005882), protein-containing aggregate (GO:0061702), autophagosome (GO:0005776), lysosome (GO:0005764) and mitochondrion (GO:0005739).

8. Temporal development

The usual course is chronic, insidious and progressive. Adult-onset disease may advance over decades; severe childhood BAG3 disease can progress rapidly. Early stages feature focal distal or proximal weakness, cramps or exercise limitation. Intermediate disease brings generalized, axial or bulbar weakness and orthopedic deformity. Advanced disease may include loss of ambulation, ventilatory dependence, cardiomyopathy, conduction block or transplantation. Sustained spontaneous remission is not characteristic. Critical intervention windows are before irreversible respiratory decompensation or malignant arrhythmia, supporting surveillance from diagnosis rather than symptom-triggered testing alone. (olive2021246thenmcinternational pages 6-10, luo2019characterizationofchinese pages 6-7)

9. Inheritance and population

MFM is rare, but robust population prevalence and incidence per 100,000 are unavailable. Referral cohorts cannot establish population epidemiology. Both sexes are affected in autosomal disease; sex effects arise in X-linked FHL1-related disease. Most classic disease is autosomal dominant with variable, age-dependent penetrance; recessive and X-linked subtypes occur. Expressivity is markedly variable, even within families. Anticipation is not established. Germline mosaicism is theoretically possible in apparently de novo disease but is not a defining feature. Founder variants exist in individual populations, yet no universal carrier frequency can be stated.

10. Diagnostics

A practical workflow is:

Phenotyping: three-generation pedigree; distribution of weakness; CK; ECG, echocardiography and ambulatory rhythm monitoring; spirometry sitting and supine, maximal inspiratory pressure and sleep assessment; EMG/NCS.
Muscle MRI: identifies selective fatty replacement, guides biopsy and can support a genotype hypothesis.
Genomics: a comprehensive neuromuscular panel including canonical and overlap genes is generally first-line. Exome or genome sequencing is appropriate when panel testing is negative, with CNV analysis and periodic reanalysis. RNA sequencing from muscle may resolve splice variants. Standard karyotype, FISH and chromosomal microarray have low yield unless syndromic features suggest a structural disorder. Repeat-expansion and mitochondrial testing are differential-directed, not routine MFM tests.
Muscle biopsy: modified Gomori trichrome may show amorphous/hyaline inclusions and rimmed vacuoles; immunohistochemistry commonly demonstrates desmin, myotilin, αB-crystallin, ubiquitin/p62 and genotype-related proteins; electron microscopy shows Z-line streaming and granulofilamentous material. Biopsy can establish the pattern but cannot reliably identify the gene. (luo2019characterizationofchinese pages 6-7, olive2005myotilinopathyrefiningthe pages 1-2, olive2021246thenmcinternational pages 1-6)

Important differentials include sporadic inclusion-body myositis, immune-mediated necrotizing myopathy, Pompe disease, myotonic dystrophy, GNE myopathy, VCP multisystem proteinopathy, muscular dystrophies, nemaline/core myopathies, hereditary motor neuropathy and TTN-related hereditary myopathy with early respiratory failure.

Cascade genetic testing is appropriate after identification of a pathogenic familial variant. MFM is not included in routine newborn screening; prenatal or preimplantation testing is technically possible for a known familial pathogenic variant after counseling.

11. Outcome and prognosis

No reliable five- or ten-year survival estimate exists for MFM as a group. Prognosis depends on genotype, age at onset, respiratory involvement and cardiac phenotype. Cardiac conduction disease, ventricular arrhythmia, restrictive/dilated cardiomyopathy and respiratory failure are the major potentially fatal complications. DES and BAG3 disease may require pacing, defibrillation, ventilation or transplantation. In the 18-person Chinese cohort, 3 of 8 DES-associated patients required pacemakers, illustrating the clinical importance of rhythm surveillance. (luo2019characterizationofchinese pages 6-7)

Recovery of lost muscle is generally limited because the disease is degenerative. Rehabilitation may maintain function but does not reverse the molecular lesion. No validated circulating prognostic biomarker is established; genotype, serial pulmonary function, rhythm monitoring, ventricular function, ambulation and swallowing status remain the most actionable predictors.

12. Treatment and current implementation

There is no approved MFM-specific pharmacotherapy, gene therapy, ASO, siRNA or cell therapy. The 2017 review’s abstract stated plainly: “Currently no treatment is available.” Current care remains multidisciplinary and genotype-informed. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)

Physiotherapy and low-to-moderate individualized aerobic/strength activity, avoiding overwork injury; occupational therapy, orthoses, mobility aids and fall prevention. Suggested NCIt: Physical Therapy, Occupational Therapy, Orthotic Device and Assistive Device.
Noninvasive ventilation, cough augmentation and vaccination/rapid treatment of respiratory infections when respiratory weakness develops. Suggested NCIt: Ventilatory Support.
Guideline-directed cardiomyopathy therapy; pacemaker for conduction disease, ICD for arrhythmic risk and heart transplantation in selected end-stage cases. Suggested NCIt: Cardiac Pacing, Implantable Cardioverter Defibrillator Placement and Heart Transplantation. (olive2021246thenmcinternational pages 6-10, batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
Swallowing assessment, texture modification, nutritional support and gastrostomy when necessary.
Pain, contracture, scoliosis and psychosocial management.

No treatment-response percentage is defensible because controlled MFM therapeutic trials are lacking. Experimental directions include allele-selective silencing for dominant toxic variants, enhancement of CASA/autophagy, chemical chaperones, aggregate clearance and correction of mitochondrial dysfunction. Dominant-negative/toxic gain-of-function mechanisms make simple gene addition less suitable than for recessive loss-of-function disease. A 2024 authoritative review emphasizes RNA-interference and viral tools as increasingly plausible platforms for dominant muscle disorders, but MFM translation remains preclinical. (findlay2024dominantlyinheritedmuscle pages 8-9)

13. Prevention

Primary prevention is not possible after conception except through reproductive options. Genetic counseling should address autosomal-dominant 50% transmission risk where applicable, variable penetrance, de novo disease and subtype-specific inheritance. Preimplantation genetic testing or prenatal diagnosis can be offered for a confirmed familial pathogenic variant.

Secondary prevention comprises cascade testing and presymptomatic cardiac/respiratory surveillance. Tertiary prevention includes early ventilation, rhythm treatment, fall prevention, contracture management, aspiration precautions and rehabilitation. There is no disease-specific vaccine, prophylactic drug or population screening program.

14. Other species and natural disease

Orthologs of DES, FLNC, CRYAB, BAG3 and other MFM genes are deeply conserved across vertebrates and many invertebrates. Nevertheless, well-validated naturally occurring veterinary homologs are much less established than induced laboratory models, and MFM is not zoonotic or transmissible.

Commercial claims of equine “MFM” require particular caution. A 2023 Quarter Horse study found no MFM histopathology and no association of marketed MYOT/FLNC/MYOZ3 variants with PSSM2; therefore, these tests should not be extrapolated to human MFM or treated as validated natural-disease models.

15. Model organisms and advanced technologies

Mouse knock-in/transgenic models, zebrafish, Drosophila and cultured muscle systems reproduce varying combinations of aggregate formation, Z-disc disruption, weakness, cardiomyopathy and defective autophagy. They are useful for temporal mechanistic analysis and therapy screening, but overexpression models may exaggerate aggregate toxicity and rarely reproduce the full human age-dependent multisystem course. (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2, olive2021246thenmcinternational pages 30-34)

Drosophila expression of disease-associated CRYAB variants produces myofibrillar disruption and cardiac abnormalities, supporting evolutionary conservation of sarcomeric proteostasis. Zebrafish provide rapid imaging of muscle architecture and have been used to study FLNC/BAG3-associated autophagy defects. Mouse DES/CRYAB models better approximate mammalian cardiac and skeletal physiology but differ in lifespan and loading.

Patient-derived and gene-edited induced-pluripotent-stem-cell cardiomyocytes are an important recent implementation. Human models permit isogenic comparison, contractility testing and mitochondrial phenotyping but remain developmentally immature. These systems are particularly valuable for variant-specific dominant disease and personalized therapeutic screening.

Recent developments and evidence limitations

The 2024 literature increasingly frames MFM as a convergence of mechanical Z-disc injury, dominant protein toxicity and failed proteostasis, rather than a passive storage disorder. Dominantly inherited FLNC disease was reviewed as typically adult-onset and slowly progressive, with grip weakness followed by ankle plantar-flexion weakness in a recognized phenotype. (findlay2024dominantlyinheritedmuscle pages 8-9)

The principal limitations are the absence of population registries, small genotype-specific cohorts, inconsistent historical use of “MFM,” incomplete molecular diagnosis and lack of randomized trials. Exact PMID metadata was not available for every retrieved source; DOI URLs and publication dates are therefore supplied below rather than inventing identifiers.

Key sources

Olivé M, et al. 246th ENMC International Workshop: Protein aggregate myopathies. Neuromuscular Disorders. Published February 2021. https://doi.org/10.1016/j.nmd.2020.11.003 (olive2021246thenmcinternational pages 6-10, olive2021246thenmcinternational pages 1-6)
Batonnet-Pichon S, et al. Myofibrillar Myopathies: New Perspectives from Animal Models to Potential Therapeutic Approaches. Journal of Neuromuscular Diseases. Published February 2017. https://doi.org/10.3233/JND-160203 (batonnetpichon2017myofibrillarmyopathiesnew pages 1-2)
Wadmore K, et al. The Role of Z-disc Proteins in Myopathy and Cardiomyopathy. International Journal of Molecular Sciences. Published March 2021. https://doi.org/10.3390/ijms22063058 (wadmore2021theroleof pages 1-2)
Olivé M, et al. Myotilinopathy: refining the clinical and myopathological phenotype. Brain. Published October 2005. https://doi.org/10.1093/brain/awh576 (olive2005myotilinopathyrefiningthe pages 1-2)
Findlay AR. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms. Published October 2024. https://doi.org/10.1242/dmm.050720 (findlay2024dominantlyinheritedmuscle pages 8-9)

Knowledge-base interpretation: MFM should be represented as a parent protein-aggregate myopathy linked to gene-defined child diseases, not as one uniform Mendelian entity. Frequencies, inheritance, prognosis and surveillance should be attached to the molecular subtype whenever possible.

References

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(findlay2024dominantlyinheritedmuscle pages 8-9): Andrew R. Findlay. Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches. Disease Models & Mechanisms, Oct 2024. URL: https://doi.org/10.1242/dmm.050720, doi:10.1242/dmm.050720. This article has 9 citations and is from a domain leading peer-reviewed journal.
(olive2021246thenmcinternational pages 30-34): Montse Olivé, Lilli Winter, Dieter O. Fürst, Rolf Schröder, Anthony Behin, Alexandra Breukel, Matthias Brumhard, Robert Bryson-Richardson, Kristl Claeys, Ana Ferreiro, Dieter Fürst, Hans H. Goebel, Vandana Gupta, Rudolf Kley, Ami Mankodi, Satoru Noguchi, Anders Oldfors, Montse Olivé, Rolf Schröder, Duygu Selcen, Vincent Timmerman, Bjarne Udd, Maggie Walter, Conrad Weihl, Gerhard Wiche, and Lilly Winter. 246th enmc international workshop: protein aggregate myopathies 24–26 may 2019, hoofddorp, the netherlands. Neuromuscular Disorders, 31(2):158-166, Feb 2021. URL: https://doi.org/10.1016/j.nmd.2020.11.003, doi:10.1016/j.nmd.2020.11.003. This article has 14 citations and is from a peer-reviewed journal.

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Myofibrillar Myopathy

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Myofibrillar Myopathy: Disease Characteristics Research Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risk and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment and current implementation

13. Prevention

14. Other species and natural disease

15. Model organisms and advanced technologies

Recent developments and evidence limitations

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