MYH2-Related Myopathy

Mendelian MONDO:0011577 Pathograph 37 Show in embeddings browser

MYH2-related myopathy (myopathy, proximal, and ophthalmoplegia; MYPOP) is a congenital myosin myopathy caused by pathogenic variants in MYH2, which encodes myosin heavy chain IIa (MyHC IIa), the motor isoform that defines fast type 2A skeletal muscle fibres. It is inherited in both an autosomal dominant and an autosomal recessive manner, and the two forms reach a shared clinical core, external ophthalmoplegia with predominantly proximal limb weakness, by different molecular routes. The dominant form was the first human myopathy traced to a skeletal myosin heavy chain gene. The founding Swedish family carries the E706K missense change in the SH1 helix of the motor domain; affected members are born with joint contractures that resolve in early childhood, have ophthalmoplegia and a mild childhood myopathy, and deteriorate from the fourth or fifth decade, when biopsies show dystrophic change and rimmed vacuoles with 15- to 21-nm tubulofilamentous inclusions. That late pathology is why the disorder was first named hereditary inclusion body myopathy 3. The mutant motor is profoundly impaired and structurally labile, and the degenerative changes track the level of mutant protein expressed. Other dominant alleles lie in the distal tail and impair thick filament assembly rather than the motor. The recessive form is a loss-of-function disease: biallelic truncating, splice, or missense variants leave little or no MyHC IIa protein, and biopsies show small or absent type 2A fibres with type 1 predominance, usually without vacuoles. It is typically early-onset, mild, and slowly progressive or static, although recessive genotypes with dominant-like vacuolar pathology are reported. Across the literature, ophthalmoparesis and proximal weakness are each present in close to nine in ten patients, facial and neck flexor weakness in more than half, and ptosis in about one in five.

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2
Inheritance
10
Pathophys.
24
Phenotypes
37
Pathograph
1
Genes
2
Variants
1
Medical Actions
2
Subtypes
4
Differentials
2
Models
1
Deep Research
👪

Inheritance

2
Autosomal dominant HP:0000006
Heterozygous motor-domain or distal-tail variants, inherited or de novo.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:9708547 SUPPORT Human Clinical
"We describe a new myopathy in a large family with 19 affected cases. Inheritance was autosomal dominant."
Dominant transmission in the original family.
PMID:23489661 SUPPORT Human Clinical
"We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
De novo dominant occurrence.
Autosomal recessive HP:0000007
Biallelic MYH2 variants, homozygous or compound heterozygous.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:24193343 SUPPORT Human Clinical
"Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers."
Recessive inheritance of truncating alleles.
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Subtypes

2
Autosomal dominant MYH2 myopathy (hereditary inclusion body myopathy 3) MONDO:0019195
MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
Heterozygous MYH2 variants. The prototype is the E706K motor-domain missense variant in the original Swedish family, with congenital joint contractures that normalise in early childhood, external ophthalmoplegia, proximal weakness that is static in childhood and progressive from adulthood, and rimmed vacuoles with tubulofilamentous inclusions in older patients. Other dominant alleles, several de novo, lie in the distal tail around the assembly competence domain (L1870P, L1877P, and a splice variant skipping exon 39) and give neonatal, oculopharyngodistal-like, or ophthalmoplegia-free presentations. MONDO:0019195 is the Orphanet concept defined on the E706K phenotype; the tail-variant presentations are included here by inheritance rather than because they match that phenotype.
Show evidence (4 references)
PMID:11114175 SUPPORT Human Clinical
"We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region."
Identifies the E706K variant in the family originally described with autosomal dominant myopathy with joint contractures, ophthalmoplegia, and rimmed vacuoles.
PMID:36380287 SUPPORT Human Clinical
"Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases."
Records how few dominant families and sporadic cases were known when the splice-variant family was reported.
CGGV:assertion_76685544-e687-4b2e-8656-2960d0324eee-2026-06-22T160000.000Z SUPPORT Other
"MYH2 | HGNC:7572 | myopathy, proximal, and ophthalmoplegia | MONDO:0011577 | AD | Moderate"
ClinGen classifies the autosomal dominant MYH2 relationship as Moderate, curated separately from the recessive one.
+ 1 more reference
Autosomal recessive MYH2 myopathy (MyHC IIa deficiency) MONDO:0018206
MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Biallelic MYH2 variants, homozygous or compound heterozygous, including nonsense, frameshift, splice, and missense alleles. Muscle shows small or absent type 2A fibres with reduced or absent MyHC IIa transcript and protein. Onset is usually in childhood with mild generalised or proximal weakness, ophthalmoplegia, and often facial weakness, and the course is relatively favourable.
Show evidence (2 references)
PMID:24193343 SUPPORT Human Clinical
"We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations."
Defines the clinical and biopsy hallmark of the recessive form across seven patients from five families, including missense genotypes.
CGGV:assertion_ba72d803-f94a-4036-88e5-3abae412c0da-2024-06-10T160000.000Z SUPPORT Other
"MYH2 | HGNC:7572 | myopathy, proximal, and ophthalmoplegia | MONDO:0011577 | AR | Definitive"
ClinGen classifies the autosomal recessive MYH2 relationship as Definitive, with a loss-of-function mechanism.
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Pathophysiology

10
MYH2 E706K Motor-Domain Missense Variant
The founding dominant allele. Glu706 lies in the SH1 helix, the region of the motor domain that transmits conformational change at the nucleotide-binding site to the neck and so drives the lever-arm swing. A charge reversal there is predicted to cripple the motor.
MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired MyHC IIa Motor Function The substitution directly degrades the chemomechanical cycle of the mutant heavy chain.
Multiple congenital joint contractures Congenital contractures that resolve in early childhood are part of the E706K phenotype. The cited sources establish the association, not the mechanism; reduced fetal muscle function is the presumed but unmeasured intermediate.
Show evidence (1 reference)
PMID:11114175 SUPPORT Human Clinical
"By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family."
Places the variant in the SH1 helix and states the predicted functional consequence.
Impaired MyHC IIa Motor Function
Mutant MyHC IIa hydrolyses ATP and moves actin far more slowly than wild type. The defect was measured in the in vitro motility assay on myosin from patient muscle and in purified homozygous Drosophila myosin, and persists in heterozygous flies as a reduced rate of strong actin binding. The C. elegans model shows the lesion is primarily functional, since thick filaments still form.
type IIa muscle fibre CL:0002214 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type IIa muscle fibre, annotated with type IIa muscle cell (CL:0002214). CL:0002214 is a cell type from the Cell Ontology.
myosin IIa motor activity GO:0000146 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased myosin IIa motor activity, annotated with microfilament motor activity (GO:0000146). GO:0000146 is a molecular function from the Gene Ontology. ↓ DECREASED
Animal models
Drosophila E701K myosin heavy chain transgenic (IBM3 model) Drosophila melanogaster recapitulates Purified mutant myosin shows depressed ATPase and actin sliding.
C. elegans unc-54 E710K model Caenorhabditis elegans recapitulates Mutant worms are severely paralysed despite forming thick filaments.
Downstream
Mutant Myosin Instability and Aggregation The same substitution that impairs the motor renders the head domain labile, so it collapses and aggregates.
Focal Myofilament Disorganization Reduced power output from the mutant motor is proposed to produce focal myofibrillar disorganisation, the principal childhood lesion.
Proximal muscle weakness Fibres that incorporate a crippled motor generate less power, the functional basis of the early, non-progressive weakness.
Show evidence (4 references)
PMID:17005402 SUPPORT In Vitro
"A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level."
Single-fibre and in vitro motility measurements on biopsies from E706K patients, studied ex vivo.
PMID:22496423 SUPPORT Model Organism
"ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin."
Purified homozygous E701K (human E706K) Drosophila myosin quantifies the motor defect.
PMID:28258125 SUPPORT Model Organism
"Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state."
Heterozygous flies, the genotype that matches the dominant human disease, retain a kinetic motor defect.
+ 1 more reference
Mutant Myosin Instability and Aggregation
E706K myosin heads have a strong propensity to collapse and aggregate, and in patient muscle the mutant transcript outstrips the corresponding protein, consistent with increased turnover of the mutant heavy chain. This is the route from a motor lesion to the protein-aggregate pathology of the adult disease.
Downstream
Sarcomeric Protein Breakdown with Rimmed Vacuole Formation Aggregated and misfolded myosin is not cleared efficiently, and the breakdown products accumulate in vacuolated fibres.
Show evidence (2 references)
PMID:22496423 SUPPORT Model Organism
"Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate."
Direct biophysical evidence of the instability of the mutant head.
PMID:11889243 SUPPORT Human Clinical
"The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein."
Patient biopsies show the protein deficit relative to transcript that the instability predicts.
Sarcomeric Protein Breakdown with Rimmed Vacuole Formation
In older patients with the dominant form, fibres expressing MyHC IIa develop rimmed vacuoles and cytoplasmic and intranuclear inclusions of 15- to 21-nm tubulofilaments like those of sporadic inclusion body myositis. Rimmed vacuoles are consistently found in fibres expressing the mutant isoform, and the aggregates carry features of defective degradation of misfolded protein.
type IIa muscle fibre CL:0002214 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type IIa muscle fibre, annotated with type IIa muscle cell (CL:0002214). CL:0002214 is a cell type from the Cell Ontology.
Animal models
Drosophila E701K myosin heavy chain transgenic (IBM3 model) Drosophila melanogaster partially recapitulates Mutant fibres develop cytoplasmic inclusions and disorganised filaments.
Downstream
Rimmed vacuoles The histological readout of this node.
Muscle fiber cytoplasmatic inclusion bodies Tubulofilamentous aggregates in the cytoplasm of affected fibres.
Muscle fiber intranuclear inclusion bodies The same filaments are also found within myonuclei.
Progressive Muscle Fibre Degeneration Protein breakdown and aggregation accompany the dystrophic change of the adult disease.
Show evidence (3 references)
PMID:11889243 SUPPORT Human Clinical
"The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type."
Ties rimmed vacuole formation to fibres expressing the mutant isoform.
PMID:22918376 SUPPORT REVIEW SYNTHESIS Human Clinical
"Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins."
Review synthesis placing the inclusions at the late stage of the dominant disease and attributing them to defective degradation.
PMID:22496423 SUPPORT Model Organism
"Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments."
The Drosophila E701K model recapitulates the inclusion pathology.
Focal Myofilament Disorganization
The main childhood biopsy lesion in the dominant form is focal disorganisation of myofilaments. In the heterozygous Drosophila model the sarcomere deteriorates with age, with Z-line streaming.
sarcomere organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Proximal muscle weakness Disorganised myofibrils contribute to reduced force production.
Progressive Muscle Fibre Degeneration Childhood disorganisation precedes the adult dystrophic change; the progression is age-dependent in patients and in the fly model.
Show evidence (2 references)
PMID:9708547 SUPPORT Human Clinical
"The major histopathological change of skeletal muscle in childhood was focal disorganization of myofilaments."
Human biopsy finding that defines this node.
PMID:28258125 SUPPORT Model Organism
"With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype."
The heterozygous model shows age-dependent sarcomeric disorganisation.
Progressive Muscle Fibre Degeneration
In adults with the dominant form, deterioration of muscle function from 30 to 50 years of age coincides with dystrophic change, and the extent of pathology tracks the level of mutant MyHC IIa expressed. Young patients express the isoform at undetectable levels and have minor pathology.
Downstream
Progressive proximal muscle weakness in adulthood Fibre degeneration underlies the adult-onset deterioration of the dominant form.
Quadriceps muscle atrophy Atrophy is most prominent in the pectoralis and quadriceps.
Show evidence (3 references)
PMID:11889243 SUPPORT Human Clinical
"Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes."
Correlates mutant isoform expression with dystrophic change and progression.
PMID:11889243 SUPPORT Human Clinical
"The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration."
The authors' conclusion that the myosin defect drives degeneration.
PMID:9708547 SUPPORT Human Clinical
"In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
Adult biopsy pathology in the original family.
MYH2 Distal-Tail Variant Impairing Thick Filament Assembly
Dominant variants in the light meromyosin region of the tail, including the de novo L1870P and L1877P missense changes and a splice variant that deletes residues 1860-1891, fall in or near the assembly competence domain. In vitro, MYH2 tail mutants have disrupted coiled-coil structure and filament packing, and L1870P reduces helical content.
MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee.
myosin II filament assembly GO:0031038 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myosin II filament assembly, annotated with myosin II filament organization (GO:0031038). GO:0031038 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Loss or Atrophy of Type 2A Muscle Fibres The splice-variant family has markedly fewer and smaller type 2 fibres, the same end state as the recessive form, reached through a dominant assembly defect.
Dysphagia Severe neonatal dysphagia was the presenting feature of the de novo L1870P tail variant; the intermediate steps are not characterised.
Neonatal respiratory distress Respiratory distress at birth with the de novo L1870P tail variant; the intermediate steps are not characterised.
Show evidence (3 references)
PMID:36380287 SUPPORT Human Clinical
"Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860-1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877-1905)."
Patient cDNA confirms an in-frame tail deletion overlapping the assembly region.
PMID:37788100 SUPPORT In Vitro
"Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted."
Purified tail mutants, including MYH2 variants, show the assembly defect.
PMID:37788100 SUPPORT In Vitro
"The helical content for the MYH2 mutation L1870P was significantly reduced"
Measured structural effect of the de novo MYH2 tail variant.
Biallelic MYH2 Loss of Function
Recessive truncating, splice, and missense alleles on both copies leave muscle with little or no MyHC IIa. With null alleles no type IIa fibres are found at all and the transcript is markedly reduced; with missense alleles type 2A fibres are small or absent and transcript and protein are reduced or absent.
MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee.
myosin IIa motor activity GO:0000146 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves myosin IIa motor activity, annotated with microfilament motor activity (GO:0000146), qualified as loss of function. GO:0000146 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Loss or Atrophy of Type 2A Muscle Fibres Without MyHC IIa, fast type 2A fibres cannot form or are hypotrophic.
Altered Myosin Kinetics and Reduced Force in Residual Fibres Fibres that remain carry altered myosin with abnormal energetics and kinetics.
Show evidence (3 references)
PMID:20418530 SUPPORT Human Clinical
"We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2."
Establishes the null mechanism of the recessive form.
PMID:20418530 SUPPORT Human Clinical
"No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced."
Biopsy protein and transcript findings.
PMID:24193343 SUPPORT Human Clinical
"Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein."
Extends the loss-of-function mechanism to recessive missense genotypes.
Loss or Atrophy of Type 2A Muscle Fibres
The unifying biopsy feature of MYH2 myopathy: ATPase histochemistry shows absent or reduced and small type 2A fibres, with type 1 fibres predominating. In the dominant E706K family the type 2A fibres were the ones that looked abnormal. Muscles normally rich in type 2 fibres, such as the laryngeal muscles, are proposed to be most exposed.
type IIa muscle fibre CL:0002214 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type IIa muscle fibre, annotated with type IIa muscle cell (CL:0002214). CL:0002214 is a cell type from the Cell Ontology.
skeletal muscle fiber development GO:0048741 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased skeletal muscle fiber development (GO:0048741). GO:0048741 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
External ophthalmoplegia Ophthalmoplegia is the most consistent clinical sign of both forms. Why the extraocular muscles are so vulnerable to MyHC IIa loss is not explained by the cited sources.
Proximal muscle weakness Loss of fast type 2A fibres reduces limb muscle force.
Weakness of facial musculature Facial weakness accompanies the ocular involvement in most series.
Neck flexor weakness Axial involvement is frequent across the literature.
Recurrent aspiration pneumonia Weakness of laryngeal muscles, which are normally rich in type 2 fibres, is the proposed cause of infantile aspiration in MYH2 deficiency.
Type 1 muscle fiber predominance With type 2A fibres absent, type 1 fibres dominate the biopsy.
Type 2 muscle fiber atrophy Residual type 2A fibres are small.
Ptosis Ptosis is a less frequent ocular manifestation.
Distal upper limb muscle weakness Distal, mostly upper-limb, involvement in a minority of patients; its distribution is not explained by the cited sources.
Hypotonia Reduced muscle force presents as hypotonia in infantile-onset cases.
Increased variability in muscle fiber diameter Small or hypotrophic type 2A fibres alongside normal-sized fibres widen the fibre size distribution.
Internally nucleated skeletal muscle fibers Part of the myopathic remodelling reported with MyHC IIa loss.
Fatty replacement of skeletal muscle Increased interstitial adipose tissue and fatty infiltration accompany MyHC IIa loss in recessive null and dominant splice-variant patients.
Show evidence (3 references)
PMID:41252304 SUPPORT Human Clinical
"The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres."
In a 13-patient series, type 2A fibre loss or reduction is the most informative biopsy finding.
PMID:20418530 SUPPORT Human Clinical
"Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function."
Links absence of the isoform to the myopathy.
PMID:11114175 SUPPORT Human Clinical
"Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal."
Type 2A fibre selectivity in the dominant family.
Altered Myosin Kinetics and Reduced Force in Residual Fibres
In fibres from patients with truncating MYH2 variants, myosin heads in the disordered-relaxed state consume more ATP, actomyosin kinetics are faster, and fibre force is reduced, alongside an acetylated MyHC IIa species.
Downstream
Proximal muscle weakness Reduced fibre force contributes to weakness.
Show evidence (1 reference)
PMID:36745529 SUPPORT In Vitro
"This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force."
Ex vivo mechanics on fibres dissected from four patients.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MYH2-Related Myopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

24
Digestive 1
Dysphagia VERY_RARE HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Dysphagia (n = 4/86, 4.6%) and respiratory involvement (n = 2/86, 2.3%) at the time of neurological examination were rare."
Dysphagia in about 5% of published patients at examination.
PMID:23489661 SUPPORT Human Clinical
"We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
Severe neonatal dysphagia with the de novo L1870P variant.
Eye 2
External ophthalmoplegia VERY_FREQUENT HP:0000544 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is External ophthalmoplegia (HP:0000544). HP:0000544 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41252304 SUPPORT Human Clinical
"Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
Ophthalmoparesis in 87% of 86 published patients.
PMID:22918376 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding."
Review synthesis of ophthalmoplegia as the consistent sign.
PMID:37154181 SUPPORT Human Clinical
"Patient -2 presented with early adult onset CPEO without limb weakness."
An isolated CPEO-like presentation.
Ptosis OCCASIONAL HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Ptosis was noticed in less than one third of patients (n = 17/86, 19.7%)."
Ptosis in 20% of published patients.
PMID:42491855 SUPPORT Human Clinical
"We report a six-year-old boy born to consanguineous parents who presented with congenital bilateral ptosis, external ophthalmoplegia, and progressive non-fluctuating proximal muscle weakness."
Congenital bilateral ptosis with a homozygous recessive variant.
Head and Neck 1
Weakness of facial musculature FREQUENT HP:0030319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial weakness, annotated with Weakness of facial musculature (HP:0030319). HP:0030319 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
Facial weakness in 64% of published patients.
PMID:27177998 SUPPORT Human Clinical
"We present a family with myopathy with early onset proximal muscle weakness, facial muscle involvement and ophthalmoplegia."
Facial involvement in a recessive splice-variant family.
Immune 1
Recurrent aspiration pneumonia HP:0002100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent aspiration pneumonia (HP:0002100). HP:0002100 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28729039 SUPPORT Human Clinical
"The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers."
Aspiration pneumonia in two brothers with the proposed mechanism.
PMID:28729039 SUPPORT Human Clinical
"His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage."
Severity of the aspiration phenotype.
Limbs 2
Distal upper limb muscle weakness FREQUENT HP:0008959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal upper limb muscle weakness (HP:0008959). HP:0008959 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Distal muscle involvement is unneglectable (n = 36/86, 41.8%) and is usually isolated in the upper limbs (n = 31/36, 86.1%)."
Frequency and distribution of distal weakness.
PMID:25529940 SUPPORT Human Clinical
"Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia."
Distal-predominant presentation with the de novo L1877P variant.
Quadriceps muscle atrophy HP:0009050 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Quadriceps muscle atrophy (HP:0009050). HP:0009050 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9708547 SUPPORT Human Clinical
"Muscle atrophy was most prominent in the pectoralis and quadriceps muscles."
Distribution of atrophy in the original family.
Metabolism 1
Mildly elevated creatine kinase HP:0008180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Normal to mildly elevated creatine kinase, annotated with Mildly elevated creatine kinase (HP:0008180). HP:0008180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41252304 SUPPORT Human Clinical
"CK levels mostly ranged from normal value to 5x upper limit value."
CK range across published patients.
Musculoskeletal 12
Proximal muscle weakness VERY_FREQUENT HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701). HP:0003701 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
Proximal weakness in 86% of 86 published patients.
PMID:20418530 SUPPORT Human Clinical
"The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis."
Mild, early-onset weakness in the recessive null families.
Progressive proximal muscle weakness in adulthood HP:0009073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive proximal muscle weakness (HP:0009073). HP:0009073 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:9708547 SUPPORT Human Clinical
"The clinical course was nonprogressive in childhood, but most adult cases experienced deterioration of muscle function, starting from 30 to 50 years of age."
Natural history in the original 19-case family.
PMID:17434305 SUPPORT REVIEW SYNTHESIS Human Clinical
"The disease is mild in childhood but may be progressive in adulthood, with proximal muscle weakness affecting ambulation."
Review summary of the dominant natural history.
PMID:29934118 SUPPORT Human Clinical
"We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles."
The same progressive course with a homozygous recessive genotype.
Neck flexor weakness FREQUENT HP:0003722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neck flexor weakness (HP:0003722). HP:0003722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41252304 SUPPORT Human Clinical
"Axial involvement, especially in neck flexor muscles, was also frequent (n = 49/86, 56.9%)."
Axial and neck flexor weakness in 57% of published patients.
Multiple congenital joint contractures Arthrogryposis multiplex congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple congenital joint contractures, annotated with Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:9708547 SUPPORT Human Clinical
"Characteristic clinical features were congenital joint contractures, which normalized during early childhood, external ophthalmoplegia, and proximal muscle weakness."
Congenital contractures in the original dominant family.
PMID:41252304 SUPPORT Human Clinical
"None of the patients of this study presented with joint contractures, which were observed in the first reported cohort of MYH2-related myopathy but have been less commonly reported in subsequent studies."
Contractures are concentrated in the first cohort.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41252304 SUPPORT Human Clinical
"Two cases of infantile onset (Patient 8 and 10) presented with motor developmental delay and muscle hypotonia without respiratory involvement."
Infantile hypotonia in two of 13 series patients.
PMID:34459418 SUPPORT Human Clinical
"This case describes a full term baby boy with hypotonia, dysmorphic features, dysphagia, and aspiration."
Neonatal hypotonia with a heterozygous variant.
Rimmed vacuoles HP:0003805 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rimmed vacuoles (HP:0003805). HP:0003805 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:9708547 SUPPORT Human Clinical
"In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
Rimmed vacuoles in adult biopsies of the original family.
PMID:41252304 SUPPORT Human Clinical
"Although rimmed vacuoles were a characteristic feature in initial reports of MYH2-related myopathy, they were absent in our case series."
Rimmed vacuoles are not a constant feature.
PMID:29934118 SUPPORT Human Clinical
"Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant."
Vacuolar pathology with a homozygous recessive genotype.
Type 1 muscle fiber predominance HP:0003803 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type 1 muscle fiber predominance (HP:0003803). HP:0003803 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28729039 SUPPORT Human Clinical
"A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers."
Type 1 predominance with a homozygous truncating variant.
PMID:36380287 SUPPORT Human Clinical
"Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers."
Type 1 predominance with a dominant tail splice variant.
Type 2 muscle fiber atrophy HP:0003554 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small type 2A muscle fibres, annotated with Type 2 muscle fiber atrophy (HP:0003554). HP:0003554 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24193343 SUPPORT Human Clinical
"Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein."
Small type 2A fibres in recessive missense genotypes.
PMID:36380287 SUPPORT Human Clinical
"The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers."
Reduced type 2 fibre size in the dominant splice family.
Increased variability in muscle fiber diameter HP:0003557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased variability in muscle fiber diameter (HP:0003557). HP:0003557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20418530 SUPPORT Human Clinical
"Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
Myopathic biopsy changes in recessive null patients.
Internally nucleated skeletal muscle fibers HP:0031237 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Internally nucleated skeletal muscle fibers (HP:0031237). HP:0031237 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20418530 SUPPORT Human Clinical
"Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
Internalised nuclei in recessive null patients.
Fatty replacement of skeletal muscle HP:0012548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatty replacement of skeletal muscle (HP:0012548). HP:0012548 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36380287 SUPPORT Human Clinical
"There was fatty infiltration, which was also demonstrated by MRI."
Fatty infiltration on biopsy and MRI in the dominant splice family.
PMID:20418530 SUPPORT Human Clinical
"Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
Increased interstitial adipose tissue in recessive null patients.
EMG: myopathic abnormalities HP:0003458 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic EMG, annotated with EMG: myopathic abnormalities (HP:0003458). HP:0003458 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41252304 SUPPORT Human Clinical
"EMG performed in 22 patients was consistent with a myopathic pattern with short and brief motor unit potentials."
Myopathic EMG in the 22 published patients tested.
Nervous System 1
Postural tremor HP:0002174 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postural tremor (HP:0002174). HP:0002174 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41252304 SUPPORT Human Clinical
"Notably, two patients presented with postural tremor of the upper limbs as their first symptom."
Tremor as an unusual presenting symptom.
Respiratory 1
Neonatal respiratory distress VERY_RARE HP:0002643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal respiratory distress (HP:0002643). HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23489661 SUPPORT Human Clinical
"We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
Respiratory distress at birth in a de novo dominant case.
Cellular 2
Muscle fiber cytoplasmatic inclusion bodies HP:0100303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cytoplasmic tubulofilamentous inclusions, annotated with Muscle fiber cytoplasmatic inclusion bodies (HP:0100303). HP:0100303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9708547 SUPPORT Human Clinical
"In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
Cytoplasmic filamentous inclusions in adult biopsies.
Muscle fiber intranuclear inclusion bodies HP:0100304 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intranuclear tubulofilamentous inclusions, annotated with Muscle fiber intranuclear inclusion bodies (HP:0100304). HP:0100304 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9708547 SUPPORT Human Clinical
"In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
Intranuclear filamentous inclusions in adult biopsies.
🧬

Genetic Associations

1
MYH2
Gene: MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant Autosomal recessive
Show evidence (3 references)
PMID:11114175 SUPPORT Human Clinical
"We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy."
First report of MYH2 as the causal gene.
PMID:20418530 SUPPORT Human Clinical
"All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations."
Establishes recessive MYH2 disease.
PMID:15741996 SUPPORT Human Clinical
"The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2."
Constraint on MYH2 variation in controls.
Variants (2)
c.2116G>A p.(Glu706Lys)
Gene: MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee.
Founding dominant motor-domain variant (E706K) in the SH1 helix, from the original Swedish family.
Show evidence (1 reference)
PMID:11114175 SUPPORT Human Clinical
"We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region."
Variant identification.
c.5673+1G>C (exon 39 skipping)
Gene: MYH2 hgnc:7572 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MYH2 (hgnc:7572). hgnc:7572 is a gene from the HUGO Gene Nomenclature Committee.
Dominant splice-donor variant causing in-frame skipping of exon 39 and loss of residues 1860-1891 of the distal tail.
Show evidence (2 references)
PMID:36380287 SUPPORT Human Clinical
"Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C."
Segregating dominant splice variant.
PMID:36774715 SUPPORT Human Clinical
"A novel variant, MYH2 c.5673+1G>C, was detected in the proband and subsequently found to segregate with disease in five additional family members."
The same splice variant segregating in a four-generation dominant family without contractures or ophthalmoplegia, reported independently.
💊

Medical Actions

1
Endurance exercise training
Action: Endurance exercise trainingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Endurance exercise training, annotated with Exercise Intervention (NCIT:C62739). NCIT:C62739 is a clinical intervention from the NCI Thesaurus. Ontology label: Exercise Intervention NCIT:C62739
Platform: Behavioral / lifestyle
No disease-modifying treatment exists. An eight-week endurance programme in six E706K patients shifted MyHC expression from fast to slow isoforms and increased maximal workload, without reducing MyHC IIa or changing isometric strength. The authors propose training as a way to alter expression of the defective isoform.
Mechanism Target:
Impaired MyHC IIa Motor Function — Aims to shift fibres toward the slow isoform and away from the mutant fast isoform.
Show evidence (2 references)
PMID:14991352 SUPPORT Human Clinical
"There was a clear and consistent shift from fast to slow MyHC isoform expression, but the training program did not result in the desired reduction of MyHC IIa, which may be due to the limited time period of training."
Isoform shift without reduction of MyHC IIa in six patients.
PMID:14991352 SUPPORT Human Clinical
"All patients showed an increase in maximal workload but no significant change in isometric muscle strength."
Functional outcome of the training programme.
🔬

Diagnosis

2
Muscle biopsy with ATPase histochemistry for type 2A fibres
ATPase staining or MyHC isoform immunohistochemistry to detect absent, reduced, or small type 2A fibres, the most consistent biopsy finding.
Show evidence (1 reference)
PMID:41252304 SUPPORT Human Clinical
"The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres."
Identifies the most informative stain.
MYH2 genetic testing
Exome, genome, or panel sequencing including MYH2 in patients with congenital or early-onset ophthalmoplegia and proximal weakness, or with a CPEO-like presentation and limb-girdle weakness.
Show evidence (2 references)
PMID:42491855 SUPPORT Human Clinical
"This case expands the mutational spectrum of MYH2-associated disease and highlights the importance of genetic evaluation in children presenting with congenital ophthalmoplegia and proximal muscle weakness."
Recommends genetic evaluation for this presentation.
PMID:41252304 SUPPORT Human Clinical
"External ophthalmoparesis, though not a defining feature, should raise suspicion of MYH2-related myopathy in patients with a CPEO-like presentation and limb-girdle weakness."
Clinical trigger for testing.
📊

Prevalence

2
Western Sweden, 1985-2022
Birth Prevalence 3.9 per 100,000 (0.8–17.6) live births 1–9 per 100,000 (births)
Birth prevalence 3.9 per 100,000 live births (95% CI 0.8 to 17.6), the highest of any gene in a population-based study of congenital myopathies. The figure is dominated by one family with 20 affected members and the authors know of no Swedish MYH2 founder variant, so it should not be generalised beyond this region.
Show evidence (2 references)
PMID:41159764 SUPPORT Human Clinical
"The most common genetic causes were MYH2 and RYR1 (Fig 3B), with birth prevalences of 3.9 per 100.000 (95% CI = 0.8 to 17.6) and 2.0 per 100,000 (95% CI = 1.0 to 4.0), respectively."
Regional birth prevalence of MYH2 congenital myopathy.
PMID:41159764 SUPPORT Human Clinical
"This was at least partly explained by a variant identified in 20 affected individuals from one family."
The estimate reflects one large family.
Western Sweden, 1985-2022
Point Prevalence 1.1 per 100,000 (0.2–4.9) 1–9 per 100,000
Point prevalence 1.1 per 100,000 inhabitants (95% CI 0.2 to 4.9).
Show evidence (1 reference)
PMID:41159764 SUPPORT Human Clinical
"The most common causative genes were MYH2 at 1.1 per 100,000 inhabitants (95% CI = 0.2 to 4.9) and RYR1 at 0.6 per 100,000 inhabitants (95% CI = 0.3 to 1.2)."
Regional point prevalence.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from MYH2-Related Myopathy:

Sporadic inclusion body myositis
Overlapping Features Shares rimmed vacuoles and tubulofilamentous inclusions with the adult dominant form, which is why this disease was first named hereditary inclusion body myopathy 3. Sporadic inclusion body myositis is an acquired, late-onset inflammatory myopathy.
Show evidence (1 reference)
PMID:11889243 SUPPORT Human Clinical
"Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients."
The shared histology that motivates the differential.
Chronic progressive external ophthalmoplegia of other causes
Overlapping Features Adult-onset MYH2 myopathy can present as isolated CPEO; mitochondrial disorders, centronuclear myopathies, congenital myasthenic syndromes, and oculopharyngeal muscular dystrophy are the main alternatives.
Show evidence (2 references)
PMID:37154181 SUPPORT Human Clinical
"MYH2 myopathy has to be considered in adult patients with CPEO."
Places MYH2 myopathy in the CPEO differential.
PMID:37154181 SUPPORT Human Clinical
"CPEO is seen in various neuromuscular conditions such as mitochondrial disorders, centronuclear myopathies, congenital myasthenic syndromes and oculopharyngeal muscular dystrophy."
Lists the alternative causes of CPEO.
Oculopharyngodistal myopathy
Overlapping Features A de novo dominant MYH2 tail variant produced a distal, bulbar, and ocular phenotype first classified as oculopharyngodistal myopathy.
Show evidence (1 reference)
PMID:25529940 SUPPORT Human Clinical
"This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum."
Phenotypic overlap with oculopharyngodistal myopathy.
Congenital myasthenic syndromes
Overlapping Features Recessive MYH2 myopathy with congenital ptosis and ophthalmoplegia overlaps clinically with neuromuscular junction disorders.
Show evidence (1 reference)
PMID:42491855 SUPPORT Human Clinical
"Autosomal recessive MYH2-related myopathy is uncommon and may be difficult to recognize because of overlapping clinical features with neuromuscular junction disorders."
Overlap with neuromuscular junction disorders.
🐁

Animal Models

2
Drosophila E701K myosin heavy chain transgenic (IBM3 model)
Transgenic flies expressing the fly equivalent of E706K in indirect flight and jump muscles, studied as homozygotes and as heterozygotes matching the dominant human genotype.
Species
Drosophila melanogaster
Genotype
Mhc transgene carrying E701K (human MYH2 E706K), homozygous and heterozygous
Publication
PMID:22496423
Pathograph links
Impaired MyHC IIa Motor Function recapitulates fidelity: moderate observes: molecular Purified mutant myosin shows depressed ATPase and actin sliding.
Limitations: Drosophila flight muscle expresses a single myosin heavy chain gene, so the fibre-type selectivity of the human disease cannot be modelled.
Show evidence (1 reference)
PMID:22496423 SUPPORT Model Organism
"ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin."
Motor defect in the model.
Sarcomeric Protein Breakdown with Rimmed Vacuole Formation partially recapitulates fidelity: moderate observes: cellular Mutant fibres develop cytoplasmic inclusions and disorganised filaments.
Limitations: Inclusions were shown in homozygous flies; rimmed vacuoles as such are a human histological feature not described in the fly.
Show evidence (1 reference)
PMID:22496423 SUPPORT Model Organism
"Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments."
Inclusion pathology in the model.
Show evidence (1 reference)
PMID:22496423 SUPPORT Model Organism
"Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers."
Establishes the model.
C. elegans unc-54 E710K model
Species
Caenorhabditis elegans
Genotype
unc-54 null carrying an E710K (human E706K) unc-54 extrachromosomal array
Publication
PMID:16130113
Pathograph links
Impaired MyHC IIa Motor Function recapitulates fidelity: low observes: cellular Mutant worms are severely paralysed despite forming thick filaments.
Limitations: Nematode body wall myosin B expressed from extrachromosomal arrays in a null background, so allele dosage and the heterozygous context of the human disease are not modelled.
Show evidence (1 reference)
PMID:16130113 SUPPORT Model Organism
"We conclude that the MyHC E706K (E710K in C. elegans) mutation is pathogenic and that the effect is primarily functional rather than structural because thick filaments are formed."
Functional rather than structural defect.
Show evidence (1 reference)
PMID:16130113 SUPPORT Model Organism
"Analysis of unc-54 null mutants with extrachromosomal arrays of the unc-54 gene with the E710K mutation were severely paralyzed but showed formation of thick filaments in the body wall muscle."
Establishes the nematode model phenotype.
{ }

Source YAML

click to show 
name: MYH2-Related Myopathy
creation_date: "2026-09-28T12:50:06Z"
description: >-
  MYH2-related myopathy (myopathy, proximal, and ophthalmoplegia; MYPOP) is a
  congenital myosin myopathy caused by pathogenic variants in MYH2, which encodes
  myosin heavy chain IIa (MyHC IIa), the motor isoform that defines fast type 2A
  skeletal muscle fibres. It is inherited in both an autosomal dominant and an
  autosomal recessive manner, and the two forms reach a shared clinical core,
  external ophthalmoplegia with predominantly proximal limb weakness, by
  different molecular routes.

  The dominant form was the first human myopathy traced to a skeletal myosin
  heavy chain gene. The founding Swedish family carries the E706K missense
  change in the SH1 helix of the motor domain; affected members are born with
  joint contractures that resolve in early childhood, have ophthalmoplegia and a
  mild childhood myopathy, and deteriorate from the fourth or fifth decade, when
  biopsies show dystrophic change and rimmed vacuoles with 15- to 21-nm
  tubulofilamentous inclusions. That late pathology is why the disorder was first
  named hereditary inclusion body myopathy 3. The mutant motor is profoundly
  impaired and structurally labile, and the degenerative changes track the level
  of mutant protein expressed. Other dominant alleles lie in the distal tail and
  impair thick filament assembly rather than the motor.

  The recessive form is a loss-of-function disease: biallelic truncating, splice,
  or missense variants leave little or no MyHC IIa protein, and biopsies show
  small or absent type 2A fibres with type 1 predominance, usually without
  vacuoles. It is typically early-onset, mild, and slowly progressive or static,
  although recessive genotypes with dominant-like vacuolar pathology are
  reported. Across the literature, ophthalmoparesis and proximal weakness are
  each present in close to nine in ten patients, facial and neck flexor weakness
  in more than half, and ptosis in about one in five.
category: Mendelian
disease_term:
  preferred_term: myopathy, proximal, and ophthalmoplegia
  term:
    id: MONDO:0011577
    label: myopathy, proximal, and ophthalmoplegia
synonyms:
- MYPOP
- MYH2 myopathy
- Myosin IIa myopathy
- Hereditary myosin myopathy with external ophthalmoplegia
- Inclusion body myopathy 3, autosomal dominant
- Myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles
notes: >-
  Scope. This entry covers every MYH2 myopathy, dominant and recessive, as MONDO
  does: MONDO:0011577 (OMIM:605637) is defined as any congenital myopathy caused
  by a mutation in MYH2, with both inheritance patterns, and its two MONDO
  children (MONDO:0019195, the Orphanet dominant hereditary inclusion body
  myopathy-joint contractures-ophthalmoplegia syndrome, and MONDO:0018206,
  childhood-onset autosomal recessive myopathy with external ophthalmoplegia)
  are carried as has_subtypes rows rather than separate entries. MONDO also
  files MONDO:0011577 under inclusion body myositis (MONDO:0007827). That
  placement reflects the historical name inclusion body myopathy 3 and the
  rimmed vacuoles of the dominant form; the disease shares no mechanism with
  sporadic inclusion body myositis, which is an acquired inflammatory and
  degenerative myopathy curated separately as Inclusion_Body_Myositis.

  The dominant and recessive forms are not cleanly separable by phenotype.
  Rimmed vacuoles and progressive proximal weakness, the features that defined
  the dominant form, are reported with a homozygous missense genotype
  (p.Arg246His), and a dominant distal-tail splice variant produces a
  progressive myopathy without ophthalmoplegia. Subtype attribution on
  phenotypes below therefore marks where a feature was characterised, not a
  feature restricted to that form.

  Frequencies are cohort proportions from a systematic literature review of 86
  published patients, not population estimates. That review's own 13-patient
  series had later onset, no congenital contractures, and no rimmed vacuoles,
  so the literature proportions are weighted toward the early Swedish dominant
  family.

  No GeneReviews chapter exists for this disease.
has_subtypes:
- name: Autosomal dominant
  display_name: Autosomal dominant MYH2 myopathy (hereditary inclusion body myopathy 3)
  subtype_term:
    preferred_term: hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome
    term:
      id: MONDO:0019195
      label: hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome
  genes:
  - preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  description: >-
    Heterozygous MYH2 variants. The prototype is the E706K motor-domain missense
    variant in the original Swedish family, with congenital joint contractures
    that normalise in early childhood, external ophthalmoplegia, proximal
    weakness that is static in childhood and progressive from adulthood, and
    rimmed vacuoles with tubulofilamentous inclusions in older patients. Other
    dominant alleles, several de novo, lie in the distal tail around the
    assembly competence domain (L1870P, L1877P, and a splice variant skipping
    exon 39) and give neonatal, oculopharyngodistal-like, or ophthalmoplegia-free
    presentations. MONDO:0019195 is the Orphanet concept defined on the E706K
    phenotype; the tail-variant presentations are included here by inheritance
    rather than because they match that phenotype.
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:9708547
      reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a new myopathy in a large family with 19 affected cases. Inheritance was autosomal dominant."
      explanation: >-
        The original description of the dominant form in a 19-case family.
  evidence:
  - reference: PMID:11114175
    reference_title: "Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region."
    explanation: >-
      Identifies the E706K variant in the family originally described with
      autosomal dominant myopathy with joint contractures, ophthalmoplegia, and
      rimmed vacuoles.
  - reference: PMID:36380287
    reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whereas recessive MyHC IIa myopathy has been described in many cases, myopathy caused by dominant MYH2 variants is rare and has been described with clinical manifestations and muscle pathology in only one family and two sporadic cases."
    explanation: >-
      Records how few dominant families and sporadic cases were known when the
      splice-variant family was reported.
  - reference: CGGV:assertion_76685544-e687-4b2e-8656-2960d0324eee-2026-06-22T160000.000Z
    reference_title: "MYH2 / myopathy, proximal, and ophthalmoplegia (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH2 | HGNC:7572 | myopathy, proximal, and ophthalmoplegia | MONDO:0011577 | AD | Moderate"
    explanation: >-
      ClinGen classifies the autosomal dominant MYH2 relationship as Moderate,
      curated separately from the recessive one.
  - reference: CGGV:assertion_76685544-e687-4b2e-8656-2960d0324eee-2026-06-22T160000.000Z
    reference_title: "MYH2 / myopathy, proximal, and ophthalmoplegia (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A dominant negative mechanism has been suggested however has not been established."
    explanation: >-
      The expert panel's statement that the dominant mechanism is unproven,
      which is why no node in this entry asserts a dominant-negative effect.
- name: Autosomal recessive
  display_name: Autosomal recessive MYH2 myopathy (MyHC IIa deficiency)
  subtype_term:
    preferred_term: childhood-onset autosomal recessive myopathy with external ophthalmoplegia
    term:
      id: MONDO:0018206
      label: childhood-onset autosomal recessive myopathy with external ophthalmoplegia
  genes:
  - preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  description: >-
    Biallelic MYH2 variants, homozygous or compound heterozygous, including
    nonsense, frameshift, splice, and missense alleles. Muscle shows small or
    absent type 2A fibres with reduced or absent MyHC IIa transcript and protein.
    Onset is usually in childhood with mild generalised or proximal weakness,
    ophthalmoplegia, and often facial weakness, and the course is relatively
    favourable.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:20418530
      reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations."
      explanation: >-
        The first recessive families, with unaffected carrier parents.
  evidence:
  - reference: PMID:24193343
    reference_title: "Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations."
    explanation: >-
      Defines the clinical and biopsy hallmark of the recessive form across
      seven patients from five families, including missense genotypes.
  - reference: CGGV:assertion_ba72d803-f94a-4036-88e5-3abae412c0da-2024-06-10T160000.000Z
    reference_title: "MYH2 / myopathy, proximal, and ophthalmoplegia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH2 | HGNC:7572 | myopathy, proximal, and ophthalmoplegia | MONDO:0011577 | AR | Definitive"
    explanation: >-
      ClinGen classifies the autosomal recessive MYH2 relationship as
      Definitive, with a loss-of-function mechanism.
pathophysiology:
- name: MYH2 E706K Motor-Domain Missense Variant
  biological_scale: MOLECULAR
  description: >-
    The founding dominant allele. Glu706 lies in the SH1 helix, the region of
    the motor domain that transmits conformational change at the
    nucleotide-binding site to the neck and so drives the lever-arm swing. A
    charge reversal there is predicted to cripple the motor.
  genes:
  - preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:11114175
    reference_title: "Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family."
    explanation: >-
      Places the variant in the SH1 helix and states the predicted functional
      consequence.
  downstream:
  - target: Impaired MyHC IIa Motor Function
    causal_link_type: DIRECT
    description: >-
      The substitution directly degrades the chemomechanical cycle of the mutant
      heavy chain.
  - target: Multiple congenital joint contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Congenital contractures that resolve in early childhood are part of the
      E706K phenotype. The cited sources establish the association, not the
      mechanism; reduced fetal muscle function is the presumed but unmeasured
      intermediate.
- name: Impaired MyHC IIa Motor Function
  biological_scale: MOLECULAR
  description: >-
    Mutant MyHC IIa hydrolyses ATP and moves actin far more slowly than wild
    type. The defect was measured in the in vitro motility assay on myosin from
    patient muscle and in purified homozygous Drosophila myosin, and persists in
    heterozygous flies as a reduced rate of strong actin binding. The C. elegans
    model shows the lesion is primarily functional, since thick filaments still
    form.
  cell_types:
  - preferred_term: type IIa muscle fibre
    term:
      id: CL:0002214
      label: type IIa muscle cell
  molecular_functions:
  - preferred_term: myosin IIa motor activity
    modifier: DECREASED
    term:
      id: GO:0000146
      label: microfilament motor activity
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:17005402
    reference_title: "Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level."
    explanation: >-
      Single-fibre and in vitro motility measurements on biopsies from E706K
      patients, studied ex vivo.
  - reference: PMID:22496423
    reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin."
    explanation: >-
      Purified homozygous E701K (human E706K) Drosophila myosin quantifies the
      motor defect.
  - reference: PMID:28258125
    reference_title: "A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state."
    explanation: >-
      Heterozygous flies, the genotype that matches the dominant human disease,
      retain a kinetic motor defect.
  - reference: PMID:16130113
    reference_title: "A Caenorhabditis elegans model of the myosin heavy chain IIa E706K [corrected] mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We conclude that the MyHC E706K (E710K in C. elegans) mutation is pathogenic and that the effect is primarily functional rather than structural because thick filaments are formed."
    explanation: >-
      The nematode model separates the functional motor defect from a
      filament-assembly defect.
  downstream:
  - target: Mutant Myosin Instability and Aggregation
    causal_link_type: DIRECT
    description: >-
      The same substitution that impairs the motor renders the head domain
      labile, so it collapses and aggregates.
  - target: Focal Myofilament Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced power output from the mutant motor is proposed to produce focal
      myofibrillar disorganisation, the principal childhood lesion.
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: >-
      Fibres that incorporate a crippled motor generate less power, the
      functional basis of the early, non-progressive weakness.
- name: Mutant Myosin Instability and Aggregation
  biological_scale: MOLECULAR
  description: >-
    E706K myosin heads have a strong propensity to collapse and aggregate, and
    in patient muscle the mutant transcript outstrips the corresponding protein,
    consistent with increased turnover of the mutant heavy chain. This is the
    route from a motor lesion to the protein-aggregate pathology of the adult
    disease.
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:22496423
    reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate."
    explanation: >-
      Direct biophysical evidence of the instability of the mutant head.
  - reference: PMID:11889243
    reference_title: "Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein."
    explanation: >-
      Patient biopsies show the protein deficit relative to transcript that the
      instability predicts.
  downstream:
  - target: Sarcomeric Protein Breakdown with Rimmed Vacuole Formation
    causal_link_type: DIRECT
    description: >-
      Aggregated and misfolded myosin is not cleared efficiently, and the
      breakdown products accumulate in vacuolated fibres.
- name: Sarcomeric Protein Breakdown with Rimmed Vacuole Formation
  biological_scale: CELLULAR
  description: >-
    In older patients with the dominant form, fibres expressing MyHC IIa develop
    rimmed vacuoles and cytoplasmic and intranuclear inclusions of 15- to 21-nm
    tubulofilaments like those of sporadic inclusion body myositis. Rimmed
    vacuoles are consistently found in fibres expressing the mutant isoform, and
    the aggregates carry features of defective degradation of misfolded protein.
  cell_types:
  - preferred_term: type IIa muscle fibre
    term:
      id: CL:0002214
      label: type IIa muscle cell
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:11889243
    reference_title: "Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type."
    explanation: >-
      Ties rimmed vacuole formation to fibres expressing the mutant isoform.
  - reference: PMID:22918376
    reference_title: "Myosinopathies: pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins."
    explanation: >-
      Review synthesis placing the inclusions at the late stage of the dominant
      disease and attributing them to defective degradation.
  - reference: PMID:22496423
    reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments."
    explanation: >-
      The Drosophila E701K model recapitulates the inclusion pathology.
  downstream:
  - target: Rimmed vacuoles
    causal_link_type: DIRECT
    description: The histological readout of this node.
  - target: Muscle fiber cytoplasmatic inclusion bodies
    causal_link_type: DIRECT
    description: Tubulofilamentous aggregates in the cytoplasm of affected fibres.
  - target: Muscle fiber intranuclear inclusion bodies
    causal_link_type: DIRECT
    description: The same filaments are also found within myonuclei.
  - target: Progressive Muscle Fibre Degeneration
    causal_link_type: DIRECT
    description: >-
      Protein breakdown and aggregation accompany the dystrophic change of the
      adult disease.
- name: Focal Myofilament Disorganization
  biological_scale: CELLULAR
  description: >-
    The main childhood biopsy lesion in the dominant form is focal
    disorganisation of myofilaments. In the heterozygous Drosophila model the
    sarcomere deteriorates with age, with Z-line streaming.
  biological_processes:
  - preferred_term: sarcomere organization
    modifier: DECREASED
    term:
      id: GO:0045214
      label: sarcomere organization
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The major histopathological change of skeletal muscle in childhood was focal disorganization of myofilaments."
    explanation: Human biopsy finding that defines this node.
  - reference: PMID:28258125
    reference_title: "A Drosophila model of dominant inclusion body myopathy type 3 shows diminished myosin kinetics that reduce muscle power and yield myofibrillar defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype."
    explanation: >-
      The heterozygous model shows age-dependent sarcomeric disorganisation.
  downstream:
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: Disorganised myofibrils contribute to reduced force production.
  - target: Progressive Muscle Fibre Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Childhood disorganisation precedes the adult dystrophic change; the
      progression is age-dependent in patients and in the fly model.
- name: Progressive Muscle Fibre Degeneration
  biological_scale: TISSUE
  description: >-
    In adults with the dominant form, deterioration of muscle function from 30 to
    50 years of age coincides with dystrophic change, and the extent of pathology
    tracks the level of mutant MyHC IIa expressed. Young patients express the
    isoform at undetectable levels and have minor pathology.
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:11889243
    reference_title: "Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes."
    explanation: >-
      Correlates mutant isoform expression with dystrophic change and
      progression.
  - reference: PMID:11889243
    reference_title: "Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration."
    explanation: The authors' conclusion that the myosin defect drives degeneration.
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
    explanation: Adult biopsy pathology in the original family.
  downstream:
  - target: Progressive proximal muscle weakness in adulthood
    causal_link_type: DIRECT
    description: >-
      Fibre degeneration underlies the adult-onset deterioration of the dominant
      form.
  - target: Quadriceps muscle atrophy
    causal_link_type: DIRECT
    description: Atrophy is most prominent in the pectoralis and quadriceps.
- name: MYH2 Distal-Tail Variant Impairing Thick Filament Assembly
  biological_scale: MOLECULAR
  description: >-
    Dominant variants in the light meromyosin region of the tail, including the
    de novo L1870P and L1877P missense changes and a splice variant that deletes
    residues 1860-1891, fall in or near the assembly competence domain. In vitro,
    MYH2 tail mutants have disrupted coiled-coil structure and filament packing,
    and L1870P reduces helical content.
  genes:
  - preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  biological_processes:
  - preferred_term: myosin II filament assembly
    modifier: DECREASED
    term:
      id: GO:0031038
      label: myosin II filament organization
  subtypes:
  - Autosomal dominant
  evidence:
  - reference: PMID:36380287
    reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of cDNA confirmed the predicted splicing defect with skipping of exon 39 and loss of residues 1860-1891 in the distal tail of the MyHC IIa, largely overlapping with the filament assembly region (aa1877-1905)."
    explanation: >-
      Patient cDNA confirms an in-frame tail deletion overlapping the assembly
      region.
  - reference: PMID:37788100
    reference_title: "Human skeletal myopathy myosin mutations disrupt myosin head sequestration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted."
    explanation: >-
      Purified tail mutants, including MYH2 variants, show the assembly defect.
  - reference: PMID:37788100
    reference_title: "Human skeletal myopathy myosin mutations disrupt myosin head sequestration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The helical content for the MYH2 mutation L1870P was significantly reduced"
    explanation: Measured structural effect of the de novo MYH2 tail variant.
  downstream:
  - target: Loss or Atrophy of Type 2A Muscle Fibres
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The splice-variant family has markedly fewer and smaller type 2 fibres,
      the same end state as the recessive form, reached through a dominant
      assembly defect.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Severe neonatal dysphagia was the presenting feature of the de novo L1870P
      tail variant; the intermediate steps are not characterised.
  - target: Neonatal respiratory distress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Respiratory distress at birth with the de novo L1870P tail variant; the
      intermediate steps are not characterised.
- name: Biallelic MYH2 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Recessive truncating, splice, and missense alleles on both copies leave
    muscle with little or no MyHC IIa. With null alleles no type IIa fibres are
    found at all and the transcript is markedly reduced; with missense alleles
    type 2A fibres are small or absent and transcript and protein are reduced or
    absent.
  genes:
  - preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  molecular_functions:
  - preferred_term: myosin IIa motor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0000146
      label: microfilament motor activity
  subtypes:
  - Autosomal recessive
  evidence:
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2."
    explanation: Establishes the null mechanism of the recessive form.
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced."
    explanation: Biopsy protein and transcript findings.
  - reference: PMID:24193343
    reference_title: "Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein."
    explanation: Extends the loss-of-function mechanism to recessive missense genotypes.
  downstream:
  - target: Loss or Atrophy of Type 2A Muscle Fibres
    causal_link_type: DIRECT
    description: Without MyHC IIa, fast type 2A fibres cannot form or are hypotrophic.
  - target: Altered Myosin Kinetics and Reduced Force in Residual Fibres
    causal_link_type: DIRECT
    description: >-
      Fibres that remain carry altered myosin with abnormal energetics and
      kinetics.
- name: Loss or Atrophy of Type 2A Muscle Fibres
  biological_scale: CELLULAR
  description: >-
    The unifying biopsy feature of MYH2 myopathy: ATPase histochemistry shows
    absent or reduced and small type 2A fibres, with type 1 fibres predominating.
    In the dominant E706K family the type 2A fibres were the ones that looked
    abnormal. Muscles normally rich in type 2 fibres, such as the laryngeal
    muscles, are proposed to be most exposed.
  cell_types:
  - preferred_term: type IIa muscle fibre
    term:
      id: CL:0002214
      label: type IIa muscle cell
  biological_processes:
  - preferred_term: skeletal muscle fiber development
    modifier: DECREASED
    term:
      id: GO:0048741
      label: skeletal muscle fiber development
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres."
    explanation: >-
      In a 13-patient series, type 2A fibre loss or reduction is the most
      informative biopsy finding.
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function."
    explanation: Links absence of the isoform to the myopathy.
  - reference: PMID:11114175
    reference_title: "Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis of muscle biopsies from patients from the family indicated to us that the type 2A fibers frequently were abnormal, whereas other fiber types appeared normal."
    explanation: Type 2A fibre selectivity in the dominant family.
  downstream:
  - target: External ophthalmoplegia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ophthalmoplegia is the most consistent clinical sign of both forms. Why the
      extraocular muscles are so vulnerable to MyHC IIa loss is not explained by
      the cited sources.
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: Loss of fast type 2A fibres reduces limb muscle force.
  - target: Weakness of facial musculature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Facial weakness accompanies the ocular involvement in most series.
  - target: Neck flexor weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Axial involvement is frequent across the literature.
  - target: Recurrent aspiration pneumonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Weakness of laryngeal muscles, which are normally rich in type 2 fibres, is
      the proposed cause of infantile aspiration in MYH2 deficiency.
  - target: Type 1 muscle fiber predominance
    causal_link_type: DIRECT
    description: With type 2A fibres absent, type 1 fibres dominate the biopsy.
  - target: Type 2 muscle fiber atrophy
    causal_link_type: DIRECT
    description: Residual type 2A fibres are small.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Ptosis is a less frequent ocular manifestation.
  - target: Distal upper limb muscle weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Distal, mostly upper-limb, involvement in a minority of patients; its
      distribution is not explained by the cited sources.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced muscle force presents as hypotonia in infantile-onset cases.
  - target: Increased variability in muscle fiber diameter
    causal_link_type: DIRECT
    description: >-
      Small or hypotrophic type 2A fibres alongside normal-sized fibres widen the
      fibre size distribution.
  - target: Internally nucleated skeletal muscle fibers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Part of the myopathic remodelling reported with MyHC IIa loss.
  - target: Fatty replacement of skeletal muscle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Increased interstitial adipose tissue and fatty infiltration accompany
      MyHC IIa loss in recessive null and dominant splice-variant patients.
- name: Altered Myosin Kinetics and Reduced Force in Residual Fibres
  biological_scale: CELLULAR
  description: >-
    In fibres from patients with truncating MYH2 variants, myosin heads in the
    disordered-relaxed state consume more ATP, actomyosin kinetics are faster,
    and fibre force is reduced, alongside an acetylated MyHC IIa species.
  subtypes:
  - Autosomal recessive
  evidence:
  - reference: PMID:36745529
    reference_title: "Myosin post-translational modifications and function in the presence of myopathy-linked truncating MYH2 mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This was accompanied by 1) a higher ATP demand of myosin heads in the disordered-relaxed conformation; 2) faster actomyosin kinetics; and 3) reduced muscle fiber force."
    explanation: Ex vivo mechanics on fibres dissected from four patients.
  downstream:
  - target: Proximal muscle weakness
    causal_link_type: DIRECT
    description: Reduced fibre force contributes to weakness.
phenotypes:
- name: External ophthalmoplegia
  category: Neuromuscular
  description: >-
    Ophthalmoparesis or complete external ophthalmoplegia, the most consistent
    clinical sign in both forms. It is not obligate: a dominant distal-tail
    splice family lacks it, and isolated adult-onset CPEO-like presentations
    without limb weakness occur.
  phenotype_term:
    preferred_term: External ophthalmoplegia
    term:
      id: HP:0000544
      label: External ophthalmoplegia
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
    explanation: Ophthalmoparesis in 87% of 86 published patients.
  - reference: PMID:22918376
    reference_title: "Myosinopathies: pathology and mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding."
    explanation: Review synthesis of ophthalmoplegia as the consistent sign.
  - reference: PMID:37154181
    reference_title: "MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient -2 presented with early adult onset CPEO without limb weakness."
    explanation: An isolated CPEO-like presentation.
- name: Proximal muscle weakness
  category: Neuromuscular
  description: >-
    Predominantly proximal limb weakness, usually mild to moderate, present from
    childhood in most patients and generalised in some recessive cases.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
    explanation: Proximal weakness in 86% of 86 published patients.
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis."
    explanation: Mild, early-onset weakness in the recessive null families.
- name: Progressive proximal muscle weakness in adulthood
  category: Neuromuscular
  description: >-
    In the dominant form the myopathy is static in childhood, then most adults
    deteriorate from 30 to 50 years of age, with proximal weakness that can
    affect ambulation. Progression is also reported with a recessive missense
    genotype that mimics the dominant form.
  phenotype_term:
    preferred_term: Progressive proximal muscle weakness
    term:
      id: HP:0009073
      label: Progressive proximal muscle weakness
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical course was nonprogressive in childhood, but most adult cases experienced deterioration of muscle function, starting from 30 to 50 years of age."
    explanation: Natural history in the original 19-case family.
  - reference: PMID:17434305
    reference_title: "Hereditary myosin myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The disease is mild in childhood but may be progressive in adulthood, with proximal muscle weakness affecting ambulation."
    explanation: Review summary of the dominant natural history.
  - reference: PMID:29934118
    reference_title: "Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles."
    explanation: The same progressive course with a homozygous recessive genotype.
- name: Weakness of facial musculature
  category: Neuromuscular
  phenotype_term:
    preferred_term: Facial weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  frequency: FREQUENT
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological examination was mainly characterized by the presence of proximal muscle weakness (n = 74/86, 86%) and ophthalmoparesis (n = 75/86, 87.2%), together with facial weakness (n = 55/86, 63.9%)."
    explanation: Facial weakness in 64% of published patients.
  - reference: PMID:27177998
    reference_title: "A novel MYH2 mutation in family members presenting with congenital myopathy, ophthalmoplegia and facial weakness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a family with myopathy with early onset proximal muscle weakness, facial muscle involvement and ophthalmoplegia."
    explanation: Facial involvement in a recessive splice-variant family.
- name: Neck flexor weakness
  category: Neuromuscular
  phenotype_term:
    preferred_term: Neck flexor weakness
    term:
      id: HP:0003722
      label: Neck flexor weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Axial involvement, especially in neck flexor muscles, was also frequent (n = 49/86, 56.9%)."
    explanation: Axial and neck flexor weakness in 57% of published patients.
- name: Distal upper limb muscle weakness
  category: Neuromuscular
  description: >-
    Distal involvement, mostly confined to the upper limbs, in about four in ten
    published patients. A de novo dominant tail variant gave a prominent distal
    and bulbar phenotype first classified as oculopharyngodistal myopathy.
  phenotype_term:
    preferred_term: Distal upper limb muscle weakness
    term:
      id: HP:0008959
      label: Distal upper limb muscle weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distal muscle involvement is unneglectable (n = 36/86, 41.8%) and is usually isolated in the upper limbs (n = 31/36, 86.1%)."
    explanation: Frequency and distribution of distal weakness.
  - reference: PMID:25529940
    reference_title: "Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present a patient with symptoms beginning at age 16 years, of prominent distal but also proximal weakness, bulbar involvement and ophthalmoplegia."
    explanation: Distal-predominant presentation with the de novo L1877P variant.
- name: Ptosis
  category: Neuromuscular
  description: >-
    Present in about one in five patients, and congenital and bilateral in some
    recessive cases.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ptosis was noticed in less than one third of patients (n = 17/86, 19.7%)."
    explanation: Ptosis in 20% of published patients.
  - reference: PMID:42491855
    reference_title: "A Novel Homozygous MYH2 Variant Causing Early-Onset External Ophthalmoplegia and Proximal Myopathy in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a six-year-old boy born to consanguineous parents who presented with congenital bilateral ptosis, external ophthalmoplegia, and progressive non-fluctuating proximal muscle weakness."
    explanation: Congenital bilateral ptosis with a homozygous recessive variant.
- name: Multiple congenital joint contractures
  category: Musculoskeletal
  description: >-
    Congenital contractures of multiple joints that normalise during early
    childhood, characteristic of the original dominant E706K family. They are
    uncommon in later-reported, mostly recessive, patients.
  phenotype_term:
    preferred_term: Multiple congenital joint contractures
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic clinical features were congenital joint contractures, which normalized during early childhood, external ophthalmoplegia, and proximal muscle weakness."
    explanation: Congenital contractures in the original dominant family.
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients of this study presented with joint contractures, which were observed in the first reported cohort of MYH2-related myopathy but have been less commonly reported in subsequent studies."
    explanation: Contractures are concentrated in the first cohort.
- name: Quadriceps muscle atrophy
  category: Neuromuscular
  description: Atrophy most prominent in the pectoralis and quadriceps muscles.
  phenotype_term:
    preferred_term: Quadriceps muscle atrophy
    term:
      id: HP:0009050
      label: Quadriceps muscle atrophy
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle atrophy was most prominent in the pectoralis and quadriceps muscles."
    explanation: Distribution of atrophy in the original family.
- name: Dysphagia
  category: Neuromuscular
  description: >-
    Uncommon at examination across the literature, but severe dysphagia and
    feeding difficulty are presenting features of neonatal and infantile onset,
    including a de novo dominant case with respiratory distress at birth.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  frequency: VERY_RARE
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysphagia (n = 4/86, 4.6%) and respiratory involvement (n = 2/86, 2.3%) at the time of neurological examination were rare."
    explanation: Dysphagia in about 5% of published patients at examination.
  - reference: PMID:23489661
    reference_title: "A new de novo missense mutation in MYH2 expands clinical and genetic findings in hereditary myosin myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
    explanation: Severe neonatal dysphagia with the de novo L1870P variant.
- name: Neonatal respiratory distress
  category: Respiratory
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  frequency: VERY_RARE
  evidence:
  - reference: PMID:23489661
    reference_title: "A new de novo missense mutation in MYH2 expands clinical and genetic findings in hereditary myosin myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
    explanation: Respiratory distress at birth in a de novo dominant case.
- name: Recurrent aspiration pneumonia
  category: Respiratory
  description: >-
    Recurrent aspiration from infancy, severe enough in one boy to require
    pneumonectomy, reported with a homozygous truncating variant.
  phenotype_term:
    preferred_term: Recurrent aspiration pneumonia
    term:
      id: HP:0002100
      label: Recurrent aspiration pneumonia
  subtype: Autosomal recessive
  evidence:
  - reference: PMID:28729039
    reference_title: "Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The aspirations causing pneumonia likely result from weakness of the laryngeal muscles, normally rich in type-2 fibers."
    explanation: Aspiration pneumonia in two brothers with the proposed mechanism.
  - reference: PMID:28729039
    reference_title: "Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His 12-year-old brother underwent pneumonectomy at the age of 10 years due to recurrent aspirations leading to severe lung damage."
    explanation: Severity of the aspiration phenotype.
- name: Hypotonia
  category: Neuromuscular
  description: Infantile hypotonia and motor delay in infantile-onset cases.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two cases of infantile onset (Patient 8 and 10) presented with motor developmental delay and muscle hypotonia without respiratory involvement."
    explanation: Infantile hypotonia in two of 13 series patients.
  - reference: PMID:34459418
    reference_title: "Novel mutation in the MYH2 gene in a symptomatic neonate with a hereditary myosin myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case describes a full term baby boy with hypotonia, dysmorphic features, dysphagia, and aspiration."
    explanation: Neonatal hypotonia with a heterozygous variant.
- name: Rimmed vacuoles
  category: Neuromuscular
  description: >-
    Rimmed vacuoles in adult dominant E706K patients and in some recessive
    missense cases; absent in young patients and in a recent 13-patient series.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
    explanation: Rimmed vacuoles in adult biopsies of the original family.
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although rimmed vacuoles were a characteristic feature in initial reports of MYH2-related myopathy, they were absent in our case series."
    explanation: Rimmed vacuoles are not a constant feature.
  - reference: PMID:29934118
    reference_title: "Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant."
    explanation: Vacuolar pathology with a homozygous recessive genotype.
- name: Muscle fiber cytoplasmatic inclusion bodies
  category: Neuromuscular
  description: Cytoplasmic 15- to 21-nm tubulofilamentous inclusions in adult dominant biopsies.
  phenotype_term:
    preferred_term: Cytoplasmic tubulofilamentous inclusions
    term:
      id: HP:0100303
      label: Muscle fiber cytoplasmatic inclusion bodies
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
    explanation: Cytoplasmic filamentous inclusions in adult biopsies.
- name: Muscle fiber intranuclear inclusion bodies
  category: Neuromuscular
  description: Intranuclear 15- to 21-nm filamentous inclusions in adult dominant biopsies.
  phenotype_term:
    preferred_term: Intranuclear tubulofilamentous inclusions
    term:
      id: HP:0100304
      label: Muscle fiber intranuclear inclusion bodies
  subtype: Autosomal dominant
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments."
    explanation: Intranuclear filamentous inclusions in adult biopsies.
- name: Type 1 muscle fiber predominance
  category: Neuromuscular
  phenotype_term:
    preferred_term: Type 1 muscle fiber predominance
    term:
      id: HP:0003803
      label: Type 1 muscle fiber predominance
  evidence:
  - reference: PMID:28729039
    reference_title: "Congenital myopathy due to myosin heavy chain 2 mutation presenting as chronic aspiration pneumonia in infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A muscle biopsy from the older brother showed absence of type-2 muscle fibers and predominance of type-1 fibers."
    explanation: Type 1 predominance with a homozygous truncating variant.
  - reference: PMID:36380287
    reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy in two of the affected individuals showed prominent type 1 muscle fiber predominance with only a few very small, scattered type 2A fibers and no type 2B fibers."
    explanation: Type 1 predominance with a dominant tail splice variant.
- name: Type 2 muscle fiber atrophy
  category: Neuromuscular
  phenotype_term:
    preferred_term: Small type 2A muscle fibres
    term:
      id: HP:0003554
      label: Type 2 muscle fiber atrophy
  evidence:
  - reference: PMID:24193343
    reference_title: "Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein."
    explanation: Small type 2A fibres in recessive missense genotypes.
  - reference: PMID:36380287
    reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The myopathy is manifesting with slowly progressive muscle weakness without overt ophthalmoplegia and markedly reduced number and size of type 2 fibers."
    explanation: Reduced type 2 fibre size in the dominant splice family.
- name: Increased variability in muscle fiber diameter
  category: Neuromuscular
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
    explanation: Myopathic biopsy changes in recessive null patients.
- name: Internally nucleated skeletal muscle fibers
  category: Neuromuscular
  phenotype_term:
    preferred_term: Internally nucleated skeletal muscle fibers
    term:
      id: HP:0031237
      label: Internally nucleated skeletal muscle fibers
  evidence:
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
    explanation: Internalised nuclei in recessive null patients.
- name: Fatty replacement of skeletal muscle
  category: Neuromuscular
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:36380287
    reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was fatty infiltration, which was also demonstrated by MRI."
    explanation: Fatty infiltration on biopsy and MRI in the dominant splice family.
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue."
    explanation: Increased interstitial adipose tissue in recessive null patients.
- name: Mildly elevated creatine kinase
  category: Laboratory
  description: Creatine kinase ranges from normal to about five times the upper limit.
  phenotype_term:
    preferred_term: Normal to mildly elevated creatine kinase
    term:
      id: HP:0008180
      label: Mildly elevated creatine kinase
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CK levels mostly ranged from normal value to 5x upper limit value."
    explanation: CK range across published patients.
- name: 'EMG: myopathic abnormalities'
  category: Neuromuscular
  phenotype_term:
    preferred_term: Myopathic EMG
    term:
      id: HP:0003458
      label: 'EMG: myopathic abnormalities'
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EMG performed in 22 patients was consistent with a myopathic pattern with short and brief motor unit potentials."
    explanation: Myopathic EMG in the 22 published patients tested.
- name: Postural tremor
  category: Neurological
  description: >-
    Upper-limb postural tremor as the first symptom in two of 13 patients in one
    series. No mechanism linking it to MYH2 is proposed.
  phenotype_term:
    preferred_term: Postural tremor
    term:
      id: HP:0002174
      label: Postural tremor
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, two patients presented with postural tremor of the upper limbs as their first symptom."
    explanation: Tremor as an unusual presenting symptom.
genetic:
- name: MYH2
  gene_term:
    preferred_term: MYH2
    term:
      id: hgnc:7572
      label: MYH2
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    Encodes myosin heavy chain IIa, the major isoform of fast type 2A fibres, in
    the skeletal myosin heavy chain cluster on chromosome 17p13. Dominant alleles
    are motor-domain (E706K) or distal-tail missense and splice variants;
    recessive alleles are truncating, splice, or missense variants. Sequencing of
    50 control individuals found little coding variation in MYH2, consistent
    with strong selective constraint. ClinGen curates the two inheritance modes
    separately against MONDO:0011577: autosomal recessive as Definitive and
    autosomal dominant as Moderate, noting that a dominant-negative mechanism
    for the dominant form has been suggested but not established.
  variants:
  - name: c.2116G>A p.(Glu706Lys)
    description: >-
      Founding dominant motor-domain variant (E706K) in the SH1 helix, from the
      original Swedish family.
    gene:
      preferred_term: MYH2
      term:
        id: hgnc:7572
        label: MYH2
    evidence:
    - reference: PMID:11114175
      reference_title: "Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a missense mutation, Glu-706 --> Lys, which is located in a highly conserved region of the motor domain, the so-called SH1 helix region."
      explanation: Variant identification.
  - name: c.5673+1G>C (exon 39 skipping)
    description: >-
      Dominant splice-donor variant causing in-frame skipping of exon 39 and
      loss of residues 1860-1891 of the distal tail.
    gene:
      preferred_term: MYH2
      term:
        id: hgnc:7572
        label: MYH2
    evidence:
    - reference: PMID:36380287
      reference_title: "Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-genome sequencing identified a heterozygous MYH2 variant, segregating with the disease in the three affected individuals: c.5673 + 1G > C."
      explanation: Segregating dominant splice variant.
    - reference: PMID:36774715
      reference_title: MYH2-associated myopathy caused by a novel splice-site variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A novel variant, MYH2 c.5673+1G>C, was detected in the proband and subsequently found to segregate with disease in five additional family members."
      explanation: >-
        The same splice variant segregating in a four-generation dominant
        family without contractures or ophthalmoplegia, reported independently.
  evidence:
  - reference: PMID:11114175
    reference_title: "Autosomal dominant myopathy: missense mutation (Glu-706 --> Lys) in the myosin heavy chain IIa gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report on a human myopathy associated with a mutation in a fast myosin heavy chain (MyHC) gene, and also the genetic defect in a hereditary inclusion body myopathy."
    explanation: First report of MYH2 as the causal gene.
  - reference: PMID:20418530
    reference_title: "Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations."
    explanation: Establishes recessive MYH2 disease.
  - reference: PMID:15741996
    reference_title: "Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2."
    explanation: Constraint on MYH2 variation in controls.
inheritance:
- name: Autosomal dominant
  description: >-
    Heterozygous motor-domain or distal-tail variants, inherited or de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:9708547
    reference_title: "Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new myopathy in a large family with 19 affected cases. Inheritance was autosomal dominant."
    explanation: Dominant transmission in the original family.
  - reference: PMID:23489661
    reference_title: "A new de novo missense mutation in MYH2 expands clinical and genetic findings in hereditary myosin myopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a new de novo MYH2 missense mutation in a baby affected by a congenital myopathy characterized by severe dysphagia, respiratory distress at birth and external ophthalmoplegia."
    explanation: De novo dominant occurrence.
- name: Autosomal recessive
  description: Biallelic MYH2 variants, homozygous or compound heterozygous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24193343
    reference_title: "Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers."
    explanation: Recessive inheritance of truncating alleles.
diagnosis:
- name: Muscle biopsy with ATPase histochemistry for type 2A fibres
  description: >-
    ATPase staining or MyHC isoform immunohistochemistry to detect absent,
    reduced, or small type 2A fibres, the most consistent biopsy finding.
  evidence:
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres."
    explanation: Identifies the most informative stain.
- name: MYH2 genetic testing
  description: >-
    Exome, genome, or panel sequencing including MYH2 in patients with
    congenital or early-onset ophthalmoplegia and proximal weakness, or with a
    CPEO-like presentation and limb-girdle weakness.
  evidence:
  - reference: PMID:42491855
    reference_title: "A Novel Homozygous MYH2 Variant Causing Early-Onset External Ophthalmoplegia and Proximal Myopathy in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case expands the mutational spectrum of MYH2-associated disease and highlights the importance of genetic evaluation in children presenting with congenital ophthalmoplegia and proximal muscle weakness."
    explanation: Recommends genetic evaluation for this presentation.
  - reference: PMID:41252304
    reference_title: "Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "External ophthalmoparesis, though not a defining feature, should raise suspicion of MYH2-related myopathy in patients with a CPEO-like presentation and limb-girdle weakness."
    explanation: Clinical trigger for testing.
treatments:
- name: Endurance exercise training
  description: >-
    No disease-modifying treatment exists. An eight-week endurance programme in
    six E706K patients shifted MyHC expression from fast to slow isoforms and
    increased maximal workload, without reducing MyHC IIa or changing isometric
    strength. The authors propose training as a way to alter expression of the
    defective isoform.
  treatment_term:
    preferred_term: Endurance exercise training
    term:
      id: NCIT:C62739
      label: Exercise Intervention
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Impaired MyHC IIa Motor Function
    description: >-
      Aims to shift fibres toward the slow isoform and away from the mutant
      fast isoform.
  evidence:
  - reference: PMID:14991352
    reference_title: "Induced shift in myosin heavy chain expression in myosin myopathy by endurance training."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was a clear and consistent shift from fast to slow MyHC isoform expression, but the training program did not result in the desired reduction of MyHC IIa, which may be due to the limited time period of training."
    explanation: Isoform shift without reduction of MyHC IIa in six patients.
  - reference: PMID:14991352
    reference_title: "Induced shift in myosin heavy chain expression in myosin myopathy by endurance training."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients showed an increase in maximal workload but no significant change in isometric muscle strength."
    explanation: Functional outcome of the training programme.
animal_models:
- name: Drosophila E701K myosin heavy chain transgenic (IBM3 model)
  species: Drosophila melanogaster
  genotype: Mhc transgene carrying E701K (human MYH2 E706K), homozygous and heterozygous
  publication: PMID:22496423
  description: >-
    Transgenic flies expressing the fly equivalent of E706K in indirect flight
    and jump muscles, studied as homozygotes and as heterozygotes matching the
    dominant human genotype.
  modeled_mechanisms:
  - target: Impaired MyHC IIa Motor Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Purified mutant myosin shows depressed ATPase and actin sliding.
    limitations: >-
      Drosophila flight muscle expresses a single myosin heavy chain gene, so
      the fibre-type selectivity of the human disease cannot be modelled.
    evidence:
    - reference: PMID:22496423
      reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin."
      explanation: Motor defect in the model.
  - target: Sarcomeric Protein Breakdown with Rimmed Vacuole Formation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Mutant fibres develop cytoplasmic inclusions and disorganised filaments.
    limitations: >-
      Inclusions were shown in homozygous flies; rimmed vacuoles as such are a
      human histological feature not described in the fly.
    evidence:
    - reference: PMID:22496423
      reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments."
      explanation: Inclusion pathology in the model.
  evidence:
  - reference: PMID:22496423
    reference_title: "Expression of the inclusion body myopathy 3 mutation in Drosophila depresses myosin function and stability and recapitulates muscle inclusions and weakness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers."
    explanation: Establishes the model.
- name: C. elegans unc-54 E710K model
  species: Caenorhabditis elegans
  genotype: unc-54 null carrying an E710K (human E706K) unc-54 extrachromosomal array
  publication: PMID:16130113
  modeled_mechanisms:
  - target: Impaired MyHC IIa Motor Function
    relationship: RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Mutant worms are severely paralysed despite forming thick filaments.
    limitations: >-
      Nematode body wall myosin B expressed from extrachromosomal arrays in a
      null background, so allele dosage and the heterozygous context of the
      human disease are not modelled.
    evidence:
    - reference: PMID:16130113
      reference_title: "A Caenorhabditis elegans model of the myosin heavy chain IIa E706K [corrected] mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We conclude that the MyHC E706K (E710K in C. elegans) mutation is pathogenic and that the effect is primarily functional rather than structural because thick filaments are formed."
      explanation: Functional rather than structural defect.
  evidence:
  - reference: PMID:16130113
    reference_title: "A Caenorhabditis elegans model of the myosin heavy chain IIa E706K [corrected] mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of unc-54 null mutants with extrachromosomal arrays of the unc-54 gene with the E710K mutation were severely paralyzed but showed formation of thick filaments in the body wall muscle."
    explanation: Establishes the nematode model phenotype.
differential_diagnoses:
- name: Sporadic inclusion body myositis
  description: >-
    Shares rimmed vacuoles and tubulofilamentous inclusions with the adult
    dominant form, which is why this disease was first named hereditary
    inclusion body myopathy 3. Sporadic inclusion body myositis is an acquired,
    late-onset inflammatory myopathy.
  evidence:
  - reference: PMID:11889243
    reference_title: "Myosin heavy chain IIa gene mutation E706K is pathogenic and its expression increases with age."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients."
    explanation: The shared histology that motivates the differential.
- name: Chronic progressive external ophthalmoplegia of other causes
  description: >-
    Adult-onset MYH2 myopathy can present as isolated CPEO; mitochondrial
    disorders, centronuclear myopathies, congenital myasthenic syndromes, and
    oculopharyngeal muscular dystrophy are the main alternatives.
  evidence:
  - reference: PMID:37154181
    reference_title: "MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYH2 myopathy has to be considered in adult patients with CPEO."
    explanation: Places MYH2 myopathy in the CPEO differential.
  - reference: PMID:37154181
    reference_title: "MYH2-related Myopathy: Expanding the Clinical Spectrum of Chronic Progressive External Ophthalmoplegia (CPEO)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CPEO is seen in various neuromuscular conditions such as mitochondrial disorders, centronuclear myopathies, congenital myasthenic syndromes and oculopharyngeal muscular dystrophy."
    explanation: Lists the alternative causes of CPEO.
- name: Oculopharyngodistal myopathy
  description: >-
    A de novo dominant MYH2 tail variant produced a distal, bulbar, and ocular
    phenotype first classified as oculopharyngodistal myopathy.
  evidence:
  - reference: PMID:25529940
    reference_title: "Adult onset distal and proximal myopathy with complete ophthalmoplegia associated with a novel de novo p.(Leu1877Pro) mutation in MYH2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This expands the phenotype of dominant MYH2 myopathies with the clinical phenotype overlapping the oculopharyngodistal myopathy spectrum."
    explanation: Phenotypic overlap with oculopharyngodistal myopathy.
- name: Congenital myasthenic syndromes
  description: >-
    Recessive MYH2 myopathy with congenital ptosis and ophthalmoplegia overlaps
    clinically with neuromuscular junction disorders.
  evidence:
  - reference: PMID:42491855
    reference_title: "A Novel Homozygous MYH2 Variant Causing Early-Onset External Ophthalmoplegia and Proximal Myopathy in a Consanguineous Family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive MYH2-related myopathy is uncommon and may be difficult to recognize because of overlapping clinical features with neuromuscular junction disorders."
    explanation: Overlap with neuromuscular junction disorders.
prevalence:
- population: Western Sweden, 1985-2022
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.9
  rate_low: 0.8
  rate_high: 17.6
  rate_denominator: LIVE_BIRTHS
  notes: >-
    Birth prevalence 3.9 per 100,000 live births (95% CI 0.8 to 17.6), the
    highest of any gene in a population-based study of congenital myopathies.
    The figure is dominated by one family with 20 affected members and the
    authors know of no Swedish MYH2 founder variant, so it should not be
    generalised beyond this region.
  evidence:
  - reference: PMID:41159764
    reference_title: "Incidence and Prevalence of Congenital Myopathies - A Population-Based Study From Western Sweden."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common genetic causes were MYH2 and RYR1 (Fig 3B), with birth prevalences of 3.9 per 100.000 (95% CI = 0.8 to 17.6) and 2.0 per 100,000 (95% CI = 1.0 to 4.0), respectively."
    explanation: Regional birth prevalence of MYH2 congenital myopathy.
  - reference: PMID:41159764
    reference_title: "Incidence and Prevalence of Congenital Myopathies - A Population-Based Study From Western Sweden."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This was at least partly explained by a variant identified in 20 affected individuals from one family."
    explanation: The estimate reflects one large family.
- population: Western Sweden, 1985-2022
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.1
  rate_low: 0.2
  rate_high: 4.9
  notes: Point prevalence 1.1 per 100,000 inhabitants (95% CI 0.2 to 4.9).
  evidence:
  - reference: PMID:41159764
    reference_title: "Incidence and Prevalence of Congenital Myopathies - A Population-Based Study From Western Sweden."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common causative genes were MYH2 at 1.1 per 100,000 inhabitants (95% CI = 0.2 to 4.9) and RYR1 at 0.6 per 100,000 inhabitants (95% CI = 0.3 to 1.2)."
    explanation: Regional point prevalence.
📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: MYH2-Related Myopathy · 2026-09-28T13:03:24Z · View source

New entry for MONDO:0011577 (myopathy, proximal, and ophthalmoplegia; MYPOP), replacing stub Myopathy_Proximal_And_Ophthalmoplegia. Lump/split: one Disease entry for all MYH2 myopathy, following the MONDO definition, with the two MONDO children carried as has_subtypes rows: MONDO:0019195 (autosomal dominant, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome) and MONDO:0018206 (childhood-onset autosomal recessive myopathy with external ophthalmoplegia). Kept separate from Inclusion_Body_Myositis (sporadic, acquired) despite MONDO filing MONDO:0011577 under MONDO:0007827. Pathograph: dominant motor-domain route (E706K -> impaired motor function -> myosin instability and aggregation -> sarcomeric protein breakdown with rimmed vacuoles -> adult fibre degeneration), dominant distal-tail assembly route, and recessive loss-of-function route converging on loss or atrophy of type 2A fibres. Phenotype frequencies taken from the 86-patient systematic literature review in PMID:41252304. The entry was first curated directly from PubMed abstracts and PMC full texts fetched with just fetch-reference, because the first Perplexity deep-research run failed (Perplexity API: server disconnected without sending a response). A rerun with a streaming request then produced research/MYH2-Related_Myopathy-deep-research-perplexity.md, which was screened as leads only. Its 11 references all resolved, but its term validation flagged 18 mislabelled CURIEs and 2 nonexistent HP terms, so none of its CURIEs were used. preflight-dr could not run because no local MONDO build was present; disease identity was checked by hand (the report names MYH2, OMIM 605637 and MONDO:0011577). The report's lead that ClinGen has curated MYH2 was verified and added: the two ClinGen Gene-Disease Validity assertions against MONDO:0011577 (autosomal recessive Definitive, autosomal dominant Moderate) were cached with the clingen structured source and cited on the subtype rows. The report's claim that expression studies give direct evidence of a dominant-negative effect was not adopted, because the ClinGen dominant curation states that a dominant-negative mechanism has been suggested but not established. A second, independent family carrying the dominant c.5673+1G>C splice variant (PMID:36774715) was added as replication evidence on that variant. Validated with just validate, count-verified-snippets (all snippets verified), validate-terms, check-causal-targets, check-entity-refs, check-duplicate-keys, check-coarse-phenotypes, check-genereviews (no chapter), list-gene-term-mismatches, and validate-disorders.

Perplexity ▸
1. Disease Information
sonar-deep-research 19 citations 2026-09-28T13:16:19.996345

1. Disease Information

1.1 Definition and Overview

MYH2-related myopathy is a hereditary skeletal muscle disorder caused by germline variants in the MYH2 gene that encodes the fast type IIa myosin heavy chain (MyHC IIa), an essential motor protein of fast-twitch skeletal muscle fibers.[2][4][7][15] OMIM lists the clinical phenotype under entry #605637, “congenital myopathy 6 with ophthalmoplegia” (CMYO6), and notes that it is “a relatively mild muscle disorder characterized by childhood onset of symptoms,” with both autosomal dominant and autosomal recessive forms linked to MYH2 mutations at 17p13.1.[5] The disease is part of the broader group of “hereditary myosin myopathies,” which comprises disorders caused by mutations in skeletal myosin heavy chain genes (MYH2, MYH3, MYH7, MYH8), distinguished by fiber-type specificity and clinical presentation.[4][7] In MYH2-related disease, the most consistent clinical feature across inheritance patterns is external ophthalmoplegia—restriction of extraocular movements often accompanied by ptosis—reflecting involvement of extraocular muscles that normally express MyHC IIa.[3][4][5][7][9] Limb-girdle and proximal muscle weakness, sometimes preceded by transient congenital joint contractures (arthrogryposis), constitutes the major systemic manifestation, and muscle biopsy reveals characteristic alterations of fiber type composition and structure, which differ between dominant and recessive forms.[3][4][7][14][15]

Early reports adopted the term “hereditary inclusion-body myopathy type 3” (IBM3) for the dominantly inherited form associated with the E706K MYH2 mutation, because muscle biopsies showed dystrophic changes, rimmed vacuoles, and intranuclear and cytoplasmic inclusions reminiscent of inclusion body myositis.[12][14] Darin and colleagues first mapped the disease locus to chromosome 17p13.1 and later studies identified the MYH2 missense mutation as causative, renaming the condition as “MyHC IIa myopathy.”[2][5][7][12] Subsequent series from Tajsharghi, Lossos, and others described recessively inherited MYH2 myopathy with external ophthalmoplegia, mild to moderate generalized weakness, and complete absence of type 2A fibers, thereby establishing that both dominant negative and loss-of-function mechanisms affecting the same fast myosin isoform can produce overlapping yet distinguishable clinical entities.[3][15][16] ClinGen has curated MYH2 as a gene with definitive evidence for autosomal recessive proximal myopathy and ophthalmoplegia (MONDO:0011577), and notes separate evidence for autosomal dominant disease via distinct mutational mechanisms.[15][16]

1.2 Key Identifiers and Classification

The key identifiers for MYH2-related myopathy span multiple clinical and ontological databases. OMIM assigns the disease entry #605637, “congenital myopathy 6 with ophthalmoplegia,” and links it to the gene entry 160740 for “MYOSIN, HEAVY CHAIN 2, SKELETAL MUSCLE,” located at cytogenetic band 17p13.1.[2][5] The gene itself is designated MYH2 by HGNC (HGNC:7572) and is annotated in NCBI Gene (Gene ID: 4620) as “myosin heavy chain 2,” described as a conventional class II myosin heavy chain that functions in skeletal muscle contraction and resides within a cluster of myosin heavy chain genes on chromosome 17.[1][2] The MONDO ontology assigns MONDO:0011577 to “myopathy, proximal, and ophthalmoplegia,” a concept used in ClinVar and ClinGen to capture MYH2-associated disease.[15][17] Orphanet recognizes MYH2-related conditions within the group of congenital myopathies and links them to the same OMIM identifier, though detailed Orphanet entries are not fully represented in the provided search results.[5][17]

In clinical taxonomies, MYH2-related myopathy falls within the category of congenital myopathies and hereditary myosin myopathies, and more broadly under neuromuscular diseases involving skeletal muscle.[4][7] ICD-10 and ICD-11 do not provide a fully specific code for MYH2-related disease, and affected individuals are generally coded under categories such as “other specified myopathies” (e.g., ICD-10 G72.8) or “hereditary progressive muscular dystrophies” depending on local coding practices. The Human Phenotype Ontology (HPO) maps key clinical manifestations such as proximal muscle weakness (HP:0003690), external ophthalmoplegia (HP:0000622), ptosis (HP:0000508), arthrogryposis (HP:0002829), and rimmed vacuoles on muscle biopsy (HP:0003483), providing standardized phenotype terms that can be linked to the disease concept MONDO:0011577.[5][7][14][15][16]

The gene and disease are also represented in specialty resources. PanelApp (Australia) includes MYH2 on the “Muscular dystrophy and myopathy – Paediatric” panel, describing both monoallelic and biallelic variants causing proximal myopathy and ophthalmoplegia and summarizing more than ten families with bi-allelic variants and at least two missense variants with monoallelic disease.[16] ClinVar lists multiple variants in MYH2 associated with “myopathy, proximal, and ophthalmoplegia,” including pathogenic splice-site and truncating mutations as well as variants of uncertain significance (VUS) such as NM_017534.6(MYH2):c.1266+5G>C.[17] ClinVarMiner and related tools catalog benign MYH2 variants with relatively high allele frequencies in gnomAD, underscoring the importance of variant-level interpretation for this gene.[11][13] Collectively, these identifiers and classifications confirm that MYH2-related myopathy is recognized as a distinct Mendelian neuromuscular disease entity in major biomedical ontologies and databases.[2][5][7][15][16][17]

1.3 Nomenclature and Synonyms

MYH2-related myopathy has accumulated several synonyms and alternative names over the course of its characterization, reflecting evolving understanding of its pathology and genetics. OMIM uses the term “congenital myopathy 6 with ophthalmoplegia” (CMYO6) to describe the unified phenotype associated with MYH2 mutations, noting that both autosomal dominant and autosomal recessive forms share a broadly similar clinical picture of childhood-onset muscle weakness with ophthalmoplegia.[5] The dominant form originally received the designation “hereditary inclusion body myopathy type 3” (IBM3) or “inclusion body myopathy-3,” due to the presence of rimmed vacuoles and inclusion bodies on muscle biopsy that resembled inclusion body myositis.[2][5][7][12][14] ClinVar and MedGen list synonyms such as “MYOPATHY WITH CONGENITAL JOINT CONTRACTURES, OPHTHALMOPLEGIA, AND RIMMED VACUOLES,” “inclusion body myopathy autosomal dominant,” and “myopathy, proximal, and ophthalmoplegia,” integrating both clinical and pathological descriptors.[5][17]

In specialist literature, the dominant phenotype is often referred to as “MyHC IIa myopathy” or “MYH2 myopathy,” emphasizing the specific isoform and gene.[4][7][12] Tajsharghi and colleagues introduced the term “recessive myosin myopathy with external ophthalmoplegia” for bi-allelic MYH2 loss-of-function variants, highlighting the recessive nature and the myosin basis of disease.[3] More recently, the JND report by Baskar et al. used “MYH2-related myopathy” in the context of chronic progressive external ophthalmoplegia (CPEO), and stressed that “MYH2 myopathy has to be considered in adult patients with CPEO,” thereby integrating the disease into the wider CPEO spectrum.[9] Cassini et al. likewise used “MYH2-associated myopathy” for a family with a novel splice-site variant and atypical phenotype lacking ophthalmoplegia, indicating that the MYH2 term can encompass diverse clinical presentations linked by the underlying gene defect.[10]

These various names map onto the same underlying gene–disease relationship. For the purposes of knowledge-base integration, “MYH2-related myopathy” and “myopathy, proximal, and ophthalmoplegia (MONDO:0011577)” can be treated as umbrella terms encompassing autosomal dominant MyHC IIa myopathy (IBM3), autosomal recessive myosin myopathy with external ophthalmoplegia, and emerging atypical presentations such as MYH2-associated CPEO without skeletal abnormalities.[3][4][5][7][9][10][14][15][16]

1.4 Data Sources and Evidence Types

Information on MYH2-related myopathy is largely derived from aggregated disease-level resources and case-series in the published literature rather than from large-scale individual EHR datasets, reflecting the rarity of the condition. OMIM summarizes clinical, genetic, and mapping data from family studies and linkage analyses, including the mapping of IBM3 to chromosome 17p13.1 and subsequent identification of MYH2 mutations.[2][5] ClinGen curations synthesize evidence from multiple probands and families with bi-allelic MYH2 variants, citing key publications such as Tajsharghi et al. (2010, PMID: 20418530), Lossos et al. (2013, PMID: 23388406), and Tajsharghi et al. (2014, PMID: 24193343), and rate the gene–disease relationship as “definitive” for autosomal recessive proximal myopathy and ophthalmoplegia.[15]

Primary clinical data are provided by human case reports and series describing individuals and kindreds with specific MYH2 variants, supported by detailed clinical examination, neurophysiology, imaging, and histopathology.[3][4][9][10][12][14] For example, Tajsharghi et al. reported families with homozygous or compound heterozygous truncating MYH2 mutations, documenting muscle biopsies with small or absent type 2A fibers and reduced MyHC IIa expression, and concluded that “mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.”[3] Cassini et al. presented three affected individuals from a four-generation family with a novel splice-site variant c.5673+1G>C, demonstrating segregation of the variant with disease and functional evidence of abnormal splicing.[10]

Experimental evidence arises from model systems and in vitro studies examining the IBM3 mutation and other MYH2 variants. A notable example is the expression of the inclusion-body myopathy 3 E706K mutation in myosin heavy chain IIa, which was shown to cause misfolding, myofibrillar disorganization, and inclusion-body formation in cellular models.[12] ClinGen highlights expression evidence of MyHC IIa in type IIa muscle fibers (PMID: 7545970) and a Caenorhabditis elegans model (PMID: 16130113) supporting the biological role of MYH2 orthologs in fast muscle function.[15] Together, these aggregated resources and primary studies provide a robust evidence base for articulating the disease characteristics of MYH2-related myopathy.

2. Etiology

2.1 Primary Causal Factors: Genetic Basis

The primary causal factor in MYH2-related myopathy is germline mutation in the MYH2 gene, which encodes the myosin heavy chain isoform expressed in fast type 2A muscle fibers and, in some species, also in 2B fibers.[2][4][7][15] OMIM explains that “The MYH2 gene encodes the myosin heavy chain isoform that is expressed in fast type 2A muscle fibers,” and notes that heterozygous, compound heterozygous, or homozygous mutations can cause CMYO6.[2][5] ClinGen’s gene–disease curation explicitly concludes that “MYH2 is definitively associated with autosomal recessive proximal myopathy and ophthalmoplegia” and separately acknowledges autosomal dominant MYH2 myopathy with a proposed dominant-negative mechanism.[15]

Dominant disease is primarily linked to missense mutations in highly conserved regions of the myosin motor domain, most famously the E706K substitution in the SH1 helix.[2][7][12][14] This mutation replaces a negatively charged glutamate at position 706 with a positively charged lysine, and is located in the core of the motor domain, a region highly conserved through evolution.[2][7] Martinsson et al. (2000) identified E706K in affected members of a Swedish family with autosomal dominant congenital myopathy-6 with ophthalmoplegia, confirming its pathogenic role.[2] Subsequent functional work showed that expression of E706K MyHC IIa in muscle cells produces misfolded myosin, myofibrillar disarray, rimmed vacuoles, and cytoplasmic inclusions, justifying the original label “hereditary inclusion body myopathy 3.”[12]

Recessive disease is typically caused by truncating or severe missense variants that result in loss of fast IIa myosin heavy chain function.[3][4][15] Tajsharghi et al. (2010; PMID: 20418530) described homozygous or compound heterozygous truncating MYH2 mutations as causing recessive myopathy with external ophthalmoplegia, mild-to-moderate muscle weakness, and complete lack of type 2A fibers, and emphasized the loss-of-function mechanism.[3][15] Lossos et al. (2013; PMID: 23388406) identified MYH2 mutations in recessive myopathy with external ophthalmoplegia in Arab families linked to chromosome 17p13.1-p12, further supporting the causal role of biallelic variants.[15] Tajsharghi et al. (2014; PMID: 24193343) expanded the series of recessive cases and reinforced the characterization of recessive MYH2 myopathy as an early-onset, largely nonprogressive disease with absent type 2A fibers.[3][15]

Newer reports have added splice-site and frameshift variants to the pathogenic spectrum. Cassini et al. reported a novel splice-site variant c.5673+1G>C in intron 32, which was shown to affect splicing and generate abnormal transcripts, and segregation analysis in the family supported causality.[10] Baskar et al. documented two adult patients with CPEO due to novel homozygous MYH2 mutations: a 5′ splice variation in intron 4 (c.348+2dup) and a frameshift in exon 32 (p.Ala1480ProfsTer11), both consistent with loss of MyHC IIa.[9] Taken together, MYH2-related myopathy is unequivocally a genetically determined condition with a clear single-gene etiology, and environmental or infectious causation has not been implicated.[2][3][4][5][7][9][10][14][15][16]

2.2 Genetic Risk Factors and Variant Spectrum

Within the etiological framework, specific genetic variants in MYH2 constitute both causal and risk factors for developing disease. Dominant missense variants in the motor domain, especially E706K, have high penetrance for MyHC IIa myopathy in carriers.[2][7][12][14] Myosinopathies reviews note that “The disease was mapped to chromosome 17p13.1 and later demonstrated to be caused by a heterozygous missense mutation in MYH2 encoding MyHC IIa,” underscoring the strength of linkage and segregation evidence.[7] PanelApp summarizes that more than ten families with bi-allelic variants and at least two missense variants with monoallelic disease have been reported, providing a minimal count of known pathogenic alleles.[16]

Recessive pathogenic variants include nonsense mutations, frameshifts, splice-site changes, in-frame deletions, and severe missense substitutions in functional domains.[3][4][15] Tajsharghi et al. catalogued multiple truncating mutations and showed that they abolish expression of MyHC IIa protein in muscle, leading to absence of type 2A fibers.[3] Lossos et al. and subsequent authors added additional alleles, including variants affecting the rod region and tailpiece of the myosin heavy chain.[3][15] Baskar et al. identified a homozygous intronic duplication at c.348+2 and a homozygous frameshift at p.Ala1480ProfsTer11, both predicted to disrupt proper splicing or protein coding sequence.[9]

Population databases highlight many MYH2 variants that are benign and relatively common, indicating that not all sequence changes in this gene confer disease risk. ClinVarMiner’s list of variants reported as benign for inclusion body myositis includes several MYH2 variants such as NM_017534.6(MYH2):c.324A>G (p.Glu108=; rs12600539) with a gnomAD frequency of 0.43843, c.742-30A>C (rs11078849; 0.41970), and c.2697+25A>G (rs3744565; 0.41121), among others, many of which are synonymous or deep intronic.[13] These high-frequency benign variants illustrate that only specific changes, typically affecting conserved residues or splice motifs, act as pathogenic risk factors. ClinVar also lists variants of uncertain significance, such as c.1266+5G>C, which are present in population databases at low frequency (0.03%) and have at least one homozygous carrier but lack clear evidence of disease association, underscoring ongoing challenges in variant interpretation.[17]

To date, no susceptibility loci outside MYH2 have been robustly associated with MYH2-related myopathy, and there is no evidence for polygenic or multifactorial risk in this condition. The gene appears to act in a highly penetrant Mendelian fashion, with disease risk closely tied to specific pathogenic alleles. The concept of modifier genes—including other myosin isoforms or fiber-type regulatory genes—remains hypothetical, and data supporting genetic modifiers of severity are limited, although phenotypic variability among carriers of the same mutation suggests that additional genetic or environmental factors may influence expressivity.[4][7][10][14][15]

2.3 Environmental and Lifestyle Risk Factors

Current evidence does not implicate environmental, occupational, or lifestyle factors as primary causes or strong modifiers of MYH2-related myopathy. The disease has been consistently observed in familial clusters with segregation of MYH2 variants, and no case series have reported toxin exposures, infections, or lifestyle elements such as smoking or physical activity patterns as triggers or determinants of disease occurrence.[3][4][5][7][9][10][14][15][16] Neuromuscular clinicians generally recognize MYH2-related myopathy as a hereditary disorder, and diagnostic workup focuses on genetic testing rather than on environmental epidemiology.

Nevertheless, general principles of muscle physiology suggest that environmental factors could influence disease course or symptom severity without altering underlying risk. For example, disuse atrophy due to sedentary lifestyle or immobilization might exacerbate weakness in individuals with MYH2 myopathy, while regular tailored exercise might help preserve function, as is true for other congenital myopathies. Similarly, intercurrent illnesses or malnutrition could transiently worsen strength and fatigue. However, these influences are not disease-specific and have not been systematically studied in MYH2 cohorts, so they cannot be considered established risk factors. There is no evidence that chemical exposures, radiation, or specific infections precipitate MYH2-related myopathy in genetically susceptible individuals.[3][4][7][9][10][14][15][16]

2.4 Protective Factors

Protective factors specific to MYH2-related myopathy have not been identified. Population-level data from gnomAD and ClinVarMiner show many benign MYH2 variants at appreciable frequencies, implying that neutral variation in this gene is common, but there is no indication that any particular allele confers protection against disease in the presence of a pathogenic variant.[11][13] For example, rs12600539 (p.Glu108=) is a synonymous variant with a gnomAD frequency of 0.43843, but it is classified as benign and simply represents normal variation rather than a protective modifier.[13]

At a broader level, general health-promoting behaviors such as balanced nutrition, avoidance of extreme muscle overuse or injury, and maintenance of cardiovascular fitness may help individuals with MYH2-related myopathy optimize their functional status and delay secondary complications such as contractures or respiratory compromise. However, these measures are nonspecific and apply to many neuromuscular diseases. There are no data indicating that any pharmacological agents, nutraceuticals, or dietary patterns reduce the risk of developing MYH2 myopathy in carriers of pathogenic variants. Thus, etiological protective factors are best regarded as absent or unknown in this disease context.[3][4][7][9][10][14][15][16]

2.5 Gene–Environment Interactions

Given the strong Mendelian nature of MYH2-related myopathy, gene–environment (GxE) interactions have not been a major focus of research, and no specific interactions have been documented. Case reports do not mention environmental triggers preceding onset of weakness or ophthalmoplegia, and there is no evidence that environmental exposures modulate penetrance or expressivity of MYH2 mutations to a clinically significant degree.[3][4][5][7][9][10][14][15][16]

In theory, gene–environment interactions could influence aspects such as muscle fiber-type plasticity, proteostasis capacity, or mitochondrial function, thereby shaping the tissue response to MYH2 dysfunction. Factors such as physical training, hormonal milieu, or nutritional status can affect fiber-type composition and contractile properties, which might modulate the impact of losing type IIa fibers or expressing dysfunctional myosin. Yet such hypotheses remain speculative, and no mechanistic or epidemiologic studies have directly addressed them in MYH2 disease. Accordingly, the etiology of MYH2-related myopathy is best characterized as monogenic, with minimal or unproven gene–environment interaction.

3. Phenotypes

3.1 Core Neuromuscular Phenotype: Proximal Weakness and Muscle Involvement

The cardinal systemic manifestation of MYH2-related myopathy is proximal muscle weakness, predominantly affecting limb-girdle muscles of the shoulder and hip.[3][4][5][7][9][10][14][15][16] OMIM describes CMYO6 as “a relatively mild muscle disorder characterized by childhood onset of symptoms,” noting that affected individuals retain ambulation but exhibit mild to moderate weakness, especially in proximal muscle groups.[5] Myosinopathies reviews state that autosomal dominant MyHC IIa myopathy features “Mild proximal muscle weakness in childhood” with a progressive course in some adults affecting ambulation, and that recessive myopathy presents with “mild to moderate muscle weakness, usually mild facial involvement.”[7] Cassini et al. reported an autosomal dominant family with a slowly progressive, predominantly proximal myopathy, without congenital contractures or ophthalmoplegia, illustrating the core limb involvement.[10]

Clinically, patients often report difficulty climbing stairs, rising from a seated position, or lifting objects overhead, consistent with involvement of hip and shoulder girdle muscles. Weakness may be symmetric and insidiously progressive over years, though some recessive cases appear stable or minimally progressive.[3][5][7][15][16] Distal muscles are generally less affected, though some individuals exhibit mild distal weakness or atrophy, particularly in dominant forms with longer disease duration.[4][7][10][14] Fasciculations are not typical, and tendon reflexes may be preserved or reduced depending on severity.

Muscle bulk is often mildly reduced in affected regions, with possible scapular winging or lordotic posture reflecting core muscle involvement. EMG studies typically demonstrate a myopathic pattern with low-amplitude, short-duration motor unit potentials and early recruitment, without significant neurogenic changes, supporting primary muscle pathology.[4][7][10][14] Imaging studies such as muscle MRI reveal variable fatty infiltration of proximal muscles, occasionally with selective involvement patterns that can aid diagnosis.[10] The HPO term HP:0003690 (Proximal muscle weakness) captures this phenotype, and associated terms such as HP:0001769 (Scapular winging) and HP:0003723 (Gait disturbance) may be relevant in some cases.

3.2 Ocular Phenotype: Ptosis and External Ophthalmoplegia

External ophthalmoplegia is the most consistent and distinctive clinical feature across MYH2-related myopathy subtypes. OMIM and multiple case reports highlight ophthalmoplegia as an important clinical finding, often accompanied by ptosis.[3][4][5][7][9][14][15][16] Tajsharghi et al. concluded that “mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations,” emphasizing the diagnostic value of ocular involvement.[3] Myosinopathies reviews describe autosomal dominant MyHC IIa myopathy with “Ophthalmoplegia” as a major characteristic, and recessive myopathy similarly with “Ophthalmoplegia” as a consistent feature.[7]

Clinically, patients present with bilateral, symmetric limitation of extraocular movements, often starting in adolescence or early adulthood, and sometimes preceded or accompanied by ptosis.[4][5][7][9][14][15][16] The condition may initially be subtle, with impaired upgaze or mild diplopia, but typically progresses to chronic progressive external ophthalmoplegia (CPEO) with near-complete fixation of the globe and prominent ptosis.[9] Baskar et al. studied two adult patients with MYH2 myopathy presenting with CPEO and muscle weakness, noting novel “features such as adult onset, isolated CPEO, proptosis, esophageal reflux disease and absence of skeletal abnormalities,” and argued that “MYH2 myopathy has to be considered in adult patients with CPEO.”[9] This expands the phenotype towards isolated ocular disease in some individuals.

The HPO terms HP:0000622 (External ophthalmoplegia) and HP:0000508 (Ptosis) accurately capture these ocular manifestations. Quality of life impact is considerable, as severe ptosis can interfere with vision and external ophthalmoplegia restricts eye movements, often causing cosmetic concerns and functional impairment in activities requiring rapid gaze shifts such as driving or reading. Surgical interventions for ptosis may be required, and prism glasses or other aids may be helpful to manage diplopia, though in many cases diplopia decreases as ocular motility becomes severely restricted.[4][7][9][14][15]

3.3 Congenital and Joint Phenotypes: Arthrogryposis and Contractures

In the autosomal dominant form, congenital joint contractures are a characteristic but transient feature. Myosinopathies reviews note that dominant MyHC IIa myopathy is characterized by “Congenital, reversible joint contractures,” and OMIM similarly mentions congenital joint contractures that resolve with time.[5][7] Darin et al. and Martinsson et al. described affected individuals with arthrogryposis—multiple joint contractures at birth—who later experienced resolution of contractures but developed proximal weakness and ophthalmoplegia in adolescence.[2][7][14] The HPO term HP:0002829 (Arthrogryposis) or HP:0001371 (Joint contracture) reflects this aspect of the phenotype.

The presence of congenital contractures suggests intrauterine or early postnatal muscle dysfunction, perhaps reflecting impaired fast-twitch muscle development due to dominant-negative MYH2 mutations. Over time, as muscle growth continues and neuromuscular adaptation occurs, these contractures may diminish, but underlying muscle weakness remains.[2][7][14] Not all dominant cases show arthrogryposis; Cassini et al.’s family with a splice-site variant c.5673+1G>C had no congenital contractures, indicating phenotypic variability even within the dominant category.[10] Recessive cases generally do not feature prominent congenital contractures but may have mild facial weakness and subtle craniofacial features.[3][15]

Quality of life impact of congenital contractures includes difficulty with neonatal care, delayed motor milestones, and potential need for orthopedic interventions. However, because contractures are often reversible in MyHC IIa myopathy, long-term disability from joint deformities is limited, and proximal muscle weakness and ophthalmoplegia represent the more enduring sources of morbidity.[5][7][14]

3.4 Histopathological Phenotypes: Fiber-Type Changes, Rimmed Vacuoles, and Inclusions

Histopathological findings on muscle biopsy are central to the characterization and diagnosis of MYH2-related myopathy, and they differ markedly between autosomal dominant and autosomal recessive forms. In dominant MyHC IIa myopathy, muscle biopsies from adults often show dystrophic changes, rimmed vacuoles, and intranuclear and cytoplasmic inclusions, prompting the original designation of hereditary inclusion body myopathy 3.[4][7][12][14] Myosinopathies reviews describe “Rimmed vacuoles with protein aggregates, composed of 15–20 nm tubulofilaments, in adults with progressive course and dystrophic muscle changes,” as well as “Structural alterations with minicores in type 2 fibers in childhood and in mildly affected muscles of adults,” and “Reduced number and small type 2 fibers in some cases.”[7]

Experimental expression of the E706K IBM3 mutation confirmed its propensity to cause myofibrillar disorganization and inclusion-body formation. In the PMC3364171 article, the authors state that “Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments,” when describing IBM3.[12] These features closely resemble inclusion body myositis, with tubulofilamentous inclusions and rimmed vacuoles, but the pattern of fiber-type involvement and genetic basis distinguish MYH2 myopathy as a separate entity.[7][12][14] The HPO term HP:0003483 (Rimmed vacuoles on muscle biopsy) and HP:0007340 (Cytoplasmic inclusion bodies in muscle fibers) are appropriate phenotype descriptors.

In recessive MYH2 myopathy, the hallmark biopsy finding is near-complete absence of type 2A fibers and reduced or absent expression of MyHC IIa transcript and protein.[3][4][7][15] Tajsharghi et al. reported that “Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein,” and concluded that this pattern is the hallmark of recessive MYH2 disease.[3] Myosinopathies reviews summarize recessive pathology as “Complete absence of type 2A muscle fibers. Variable, unspecific myopathic changes with fatty infiltration. Type 2B fibers may be lacking,” reflecting a fiber-type–specific and noninflammatory myopathic process.[7] Rimmed vacuoles and inclusions are notably absent in recessive cases, distinguishing them from dominant IBM3.[3][4][7][14][15]

These histopathological phenotypes have significant diagnostic and mechanistic implications. They provide direct evidence of MYH2 protein dysfunction, fiber-type specificity, and downstream proteostasis changes, and correlate with clinical features such as ophthalmoplegia and proximal weakness. The absence of inflammatory infiltrates or significant necrosis suggests that MYH2-related myopathy is primarily a structural and fiber-type disease rather than an inflammatory myositis.[4][7][12][14]

3.5 Imaging, Electrophysiology, and Laboratory Phenotypes

Beyond histology, MYH2-related myopathy manifests in characteristic radiological and electrophysiological patterns. Muscle MRI in affected individuals often shows fatty infiltration of proximal muscles, with variable severity and muscle group involvement. Cassini et al. noted that “This is radiographically characterized by fatty infiltration of variable severity and muscle group involvement,” referring to MYH2 variants.[10] The distribution pattern may highlight selective involvement of thigh and pelvic girdle muscles while sparing distal muscles, akin to other congenital myopathies, although systematic MRI studies remain limited.[4][7][10]

Electromyography (EMG) usually demonstrates a myopathic pattern. In the series summarized by Tajsharghi and others, EMG showed low-amplitude, short-duration motor unit potentials, early recruitment, and absence of neurogenic changes, consistent with primary muscle disease.[3][4][7][14][15] Baskar et al. emphasized that in their CPEO patients, the absence of decremental response in repetitive nerve stimulation (RNS) helped differentiate MYH2 myopathy from congenital myasthenic syndromes.[9] Nerve conduction studies are typically normal, further supporting a myopathic rather than neuropathic etiology.[4][7][10][14]

Routine laboratory tests such as serum creatine kinase (CK) may be normal or mildly elevated, reflecting the relatively nondystrophic nature of many MYH2 cases. In Tajsharghi’s recessive series, CK levels were often within the normal range or only modestly raised, and myopathic changes were subtle.[3][4][15] In some dominant IBM3 cases with progressive degeneration, CK may be more elevated, but data are variable.[4][7][12][14] Pulmonary function tests and cardiac evaluations are usually normal, as MYH2 myopathy primarily affects skeletal muscle and extraocular muscles, with minimal involvement of respiratory or cardiac muscle.[4][7][15][16]

The HPO terms HP:0003457 (Myopathic EMG pattern) and HP:0003215 (Abnormal muscle MRI) capture these diagnostic phenotypes. Together, imaging, electrophysiology, and laboratory findings contextualize the clinical picture and help differentiate MYH2-related myopathy from inflammatory myopathies, neuropathies, and mitochondrial myopathies.[4][7][9][10][14][15][16]

3.6 Quality of Life Impact

The cumulative impact of proximal muscle weakness, chronic external ophthalmoplegia, and, in some cases, congenital contractures contributes to notable but often moderate impairment in quality of life for individuals with MYH2-related myopathy. OMIM notes that CMYO6 is generally mild and that affected individuals retain ambulation, suggesting that many patients can perform basic activities of daily living, though with limitations in strenuous tasks.[5] Proximal weakness can restrict mobility, reduce endurance, and complicate employment in physically demanding occupations, thereby affecting social and economic participation. Ophthalmoplegia and ptosis impose visual and cosmetic burdens, with potential psychosocial consequences due to altered appearance and gaze.[4][7][9][14][15]

The early onset and chronic nature of symptoms mean that patients must adapt over the lifespan, potentially requiring assistive devices, orthotics, or surgical interventions. Children with congenital contractures may need orthopedic care and physical therapy to achieve optimal motor development, while adults may require muscle-strengthening programs and occupational therapy to maintain independence.[4][7][14][15][16] Despite these challenges, many individuals have stable or slowly progressive disease and can live full lives with appropriate supportive care. In the absence of large QoL survey studies specifically targeting MYH2 myopathy, the impact can be inferred from common neuromuscular outcome measures such as SF-36 or EQ-5D, which typically show moderate reductions in physical functioning but relatively preserved mental health domains.

From an ontological perspective, quality-of-life aspects may be captured using terms such as HP:0001324 (Fatigue), HP:0002355 (Reduced activity tolerance), and WHOQOL categories of physical health, psychological health, social relationships, and environment. Research gaps remain in quantifying these aspects systematically in MYH2 cohorts and understanding how interventions can optimize quality of life.

4. Genetic and Molecular Information

4.1 Causal Gene: MYH2

MYH2 is the sole gene currently implicated as a causal locus in MYH2-related myopathy. NCBI Gene describes MYH2 (Gene ID: 4620) as encoding “a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction,” located in a cluster of myosin heavy chain genes on chromosome 17.[1] OMIM gene entry 160740 notes that MYH2 encodes the myosin heavy chain isoform expressed in fast type 2A muscle fibers and summarizes mapping and mutation data linking it to congenital myopathy 6 with ophthalmoplegia.[2][5] Cytogenetically, MYH2 is situated at 17p13.1, and genomic coordinates (GRCh38) are 17:10,521,148–10,549,658, reflecting a ~28.5 kb locus with multiple exons.[2]

At the protein level, MYH2 encodes the myosin heavy chain IIa (MyHC IIa), a ~2,000 amino acid motor protein comprising an N-terminal head (motor) domain responsible for ATP hydrolysis and actin binding, a neck region that binds light chains, and a long C-terminal coiled-coil rod that forms the backbone of thick filaments.[2][4][7] MyHC IIa partners with regulatory and essential light chains to form the myosin II hexamer, and the heavy chain head domain undergoes conformational changes that translate chemical energy from ATP hydrolysis into mechanical movement along actin filaments.[4][7] The SH1 helix within the motor domain is crucial for coupling nucleotide state to lever arm rotation, and mutations such as E706K in this region have profound effects on motor function.[2][7][12]

In human skeletal muscle, MYH2 is predominantly expressed in fast type 2A fibers, which exhibit intermediate contraction speeds and oxidative capacity, and in some species also in 2B fibers.[4][7] ClinGen cites expression evidence (PMID: 7545970) showing MyHC IIa localization to type IIa muscle fibers, and notes a C. elegans ortholog with similar functional roles.[15] The gene cluster on chromosome 17 also includes MYH1 and MYH3, indicating coordinated regulation of myosin isoforms during development and in adult muscle.[2][7]

4.2 Pathogenic Variant Classes and ACMG Classification

Pathogenic variants in MYH2 span multiple ACMG/AMP classes and include missense, nonsense, frameshift, splice-site, and in-frame deletions. Dominant variants are typically missense changes in highly conserved residues of the motor domain, with strong functional and segregation evidence, fulfilling criteria for “pathogenic” or “likely pathogenic” classification under ACMG guidelines.[2][7][12][14][15][16] The E706K substitution is the prototypical dominant pathogenic variant, with clear causality demonstrated by co-segregation in families, absence in controls, location in a critical functional region, and mechanistic studies showing deleterious effects.[2][7][12][14] Other reported dominant missense mutations include variants in adjacent helices or loops that affect motor performance, though fewer families have been described.[7][16]

Recessive pathogenic variants include truncating mutations (nonsense and frameshift), essential splice-site changes, and severe missense or in-frame deletions that abolish or markedly reduce MyHC IIa expression.[3][4][15] Tajsharghi et al. and Lossos et al. documented multiple such variants and provided evidence of loss of MyHC IIa protein in muscle, satisfying ACMG criteria for loss-of-function in a gene where LoF is a known disease mechanism.[3][15] ClinGen lists ten unique variants across eight probands in three key publications, including missense, in-frame deletions, frameshifts, and splice-site variants, and explicitly notes a loss-of-function mechanism for recessive disease.[15] Baskar et al.’s splice-site and frameshift variants and Cassini’s c.5673+1G>C splice-site variant further expand the LoF variant catalog.[9][10]

ClinVar hosts numerous MYH2 entries with varying significance. For instance, RCV000809069.5 describes NM_017534.6(MYH2):c.1266+5G>C in intron 13 as a single nucleotide variant affecting a consensus splice-site nucleotide, present in gnomAD at 0.03% including homozygotes, but with in silico predictions suggesting it is not likely to affect splicing and no reported affected individuals, leading to classification as a variant of uncertain significance (VUS).[17] ClinVarMiner’s benign variant table lists several synonymous and intronic MYH2 variants with high allele frequencies, reflecting their non-pathogenic nature.[13] These resources highlight the need for careful ACMG interpretation incorporating population data, computational predictions, functional assays, and segregation analyses when assessing MYH2 variants.

4.3 Allele Frequency and Population Distribution

Population allele frequency data from gnomAD and related databases, as summarized by ClinVarMiner, show that many MYH2 variants are common and benign, while pathogenic variants are rare.[11][13][17] For example, rs12600539 (p.Glu108=) has a gnomAD frequency of 0.43843, rs11078849 (c.742-30A>C) 0.41970, and rs3744565 (c.2697+25A>G) 0.41121, all classified as benign in the context of inclusion body myositis and MYH2-related conditions.[13] Several other synonymous and splice-region variants have frequencies in the 0.01–0.2 range and are also benign, indicating that MYH2 tolerates considerable variation outside critical domains.[13]

In contrast, pathogenic MYH2 variants described in families with myopathy are usually absent or extremely rare in population databases, reflecting their deleterious nature. Baskar et al.’s homozygous c.348+2dup and p.Ala1480ProfsTer11 variants were novel and not present in public databases.[9] Cassini’s c.5673+1G>C splice-site variant, while present in the proband’s family, was not reported as common in the general population.[10] ClinGen’s recessive variant catalog underscores that most LoF alleles are family-specific or very rare.[15]

Geographically, MYH2 pathogenic variants have been reported in Swedish, Arab, Indian, and other populations, suggesting broad distribution without a strong founder effect, although small series may reflect local genetic backgrounds.[2][3][9][15][16] The overall carrier frequency of pathogenic MYH2 variants is expected to be extremely low, consistent with the rarity of clinically manifest MYH2 myopathy, but precise carrier estimates are not available.

4.4 Somatic versus Germline Origin

All documented MYH2-related myopathy cases are associated with germline variants, present in constitutional DNA and segregating within families according to autosomal dominant or recessive patterns.[2][3][4][5][7][9][10][14][15][16] There is no evidence that somatic mutations in MYH2 cause acquired muscle disease, nor has MYH2 emerged as a recurrent somatic driver in cancer or other contexts in databases such as COSMIC. Muscle biopsies in MYH2 myopathy reveal structural pathology but not somatic mosaicism of MYH2 expression that would suggest acquired gene lesions.[4][7][12][14]

Germline origin is confirmed by sequencing of blood DNA from probands and relatives, with consistent detection of the same variant in affected individuals and absence in unaffected family members, supporting Mendelian inheritance.[2][3][9][10][14][15] Thus, MYH2-related myopathy should be considered a purely hereditary disorder, and somatic mutation data are largely irrelevant to its pathogenesis.

4.5 Functional Consequences: Loss of Function and Dominant Negative

Mechanistically, MYH2 pathogenic variants fall into two broad categories: loss-of-function (LoF) variants causing recessive disease and dominant-negative missense variants causing dominant disease with inclusion-body pathology.[3][4][7][12][14][15][16] Tajsharghi et al. and ClinGen emphasize that recessive MYH2 myopathy results from loss of fast IIa myosin heavy chain due to truncating or disruptive mutations, leading to complete absence of type 2A fibers.[3][15] Functional studies show reduced or absent MYH2 transcript and protein in muscle biopsies, and immunohistochemistry confirms the lack of MyHC IIa.[3] In recessive disease, heterozygous carriers generally remain asymptomatic, consistent with haplosufficiency of MYH2 in most tissues.[3][15]

In dominant MyHC IIa myopathy (IBM3), missense mutations such as E706K in the SH1 helix cause structural perturbation of the myosin motor domain that exerts a dominant-negative effect. The mutated myosin heavy chain integrates into thick filaments but impairs motor function and promotes misfolding, leading to aggregation and inclusion formation.[7][12][14] The location of E706K in a highly conserved, functionally critical helix supports a significant impact on ATPase activity and actin interaction. Expression studies of E706K MYH2 demonstrate misfolded protein, disorganized myofilaments, dystrophic changes, rimmed vacuoles, and cytoplasmic inclusions, providing direct evidence of dominant-negative behavior.[12]

Some splice-site variants, such as Cassini’s c.5673+1G>C, may produce aberrant transcripts that encode altered carboxy-terminal regions of MyHC IIa or lead to nonsense-mediated decay, and the precise functional consequence may lie between pure LoF and dominant-negative effects depending on the nature of transcripts and protein expression.[10] Cassini et al. observed novel transcripts and histologic hallmarks of MYH2 myopathy (small, paucity of type 2A fibers, rimmed vacuoles), suggesting that their variant had pathogenic impact consistent with dominant disease even in the absence of classic ophthalmoplegia.[10]

Overall, the functional landscape of MYH2 mutations illustrates how different classes of variants can perturb the same protein in distinct ways, producing overlapping yet differentiable phenotypes. Dominant-negative motor domain mutations lead to toxic gain-of-function at the level of protein misfolding and inclusion formation, while recessive LoF variants cause developmental absence of MyHC IIa and fiber-type defects without inclusion pathology.[3][4][7][12][14][15][16]

4.6 Modifier Genes and Epigenetic Information

At present, no specific modifier genes have been convincingly shown to alter the severity or expression of MYH2-related myopathy. It is plausible that genes controlling muscle fiber-type specification (e.g., transcription factors regulating fast versus slow fiber differentiation) or proteostasis (e.g., autophagy and ubiquitin–proteasome pathway components) could modulate disease phenotype, but such modifiers remain hypothetical in the absence of genetic or functional data.[4][7][12][14] Similarly, epigenetic mechanisms such as DNA methylation or histone modifications that influence MYH2 expression have not been systematically studied in this disease context.

ENCODE and Roadmap Epigenomics data characterize chromatin states in skeletal muscle tissue, including regulatory elements that may govern MYH2 transcription, but these resources have not yet been integrated into MYH2 myopathy-specific research. MGI notes that the mouse Myh2 locus is regulated by several regulatory regions (Rr194, Rr195, Rr196), including a locus control region, suggesting complex regulation of fast myosin expression.[8] Whether analogous regulatory structures exist in human MYH2 and whether epigenetic changes at these sites contribute to variability in disease expression is unknown. For now, epigenetic information should be considered a research frontier rather than a defined component of MYH2 myopathy etiology.

4.7 Chromosomal Abnormalities

Chromosomal abnormalities such as large deletions, duplications, translocations, or aneuploidy involving the MYH2 locus have not been reported as causes of MYH2-related myopathy. Linkage and mapping studies localized IBM3 and recessive myopathy loci to 17p13.1–p12, but subsequent fine mapping identified point mutations and small-scale sequence variants within MYH2 rather than structural rearrangements.[2][5][15] Genomewide linkage analyses by Lossos et al. found significant linkage to a 12-cM region on chromosome 17p13.1–p12 between markers D17S1812 and D17S947, but the disease locus was ultimately attributed to MYH2 sequence variants rather than copy number changes.[5][15]

ClinVar and DECIPHER do not highlight recurrent chromosomal syndromes involving MYH2 linked to congenital myopathy 6, and karyotyping in affected individuals is generally normal.[2][3][5][15][16][17] Therefore, MYH2-related myopathy is best conceptualized as a single-gene sequence variant disorder, and chromosomal abnormalities are not part of its typical genetic architecture.

5. Environmental Information

5.1 Environmental Factors

As noted earlier, there is no current evidence that environmental exposures play a causal role in MYH2-related myopathy. The disease consistently arises in individuals carrying germline MYH2 mutations, and no reports implicate specific toxins, pollutants, radiation, or occupational hazards in precipitating or exacerbating the condition.[3][4][5][7][9][10][14][15][16] Comparative toxicogenomics databases like CTD do not list MYH2 as a common target of environmental toxicants in muscle disease, and myosinopathies reviews solely discuss genetic mechanisms.

Experimental exposures could, in principle, modulate myosin function or muscle proteostasis, but any such effects would be nonspecific and not recognized as MYH2-specific environmental factors. For example, oxidative stress from toxins might exacerbate protein aggregation in dominant MYH2 myopathy, or endocrine disruptors might alter fiber-type ratios, but these hypotheses lack empirical support. Thus, the environmental factor dimension in MYH2-related myopathy is minimal and largely limited to generic considerations of muscle health.

5.2 Lifestyle Factors

Lifestyle factors such as physical activity, diet, and substance use have not been systematically studied in relation to MYH2 myopathy risk or progression. In clinical practice, neuromuscular specialists advise patients with congenital myopathies to maintain moderate, non-excessive exercise, avoid extreme overuse or immobilization, and follow balanced nutrition, but these recommendations are not disease-specific.[4][7][15][16] Smoking, alcohol consumption, and obesity can influence overall health and comorbidities but have not been linked to specific changes in MYH2 disease course.

Given the rarity of MYH2 myopathy, large-scale epidemiologic studies exploring lifestyle correlates are unlikely in the near term. For now, lifestyle should be considered an adjunct to supportive care rather than an etiological or major phenotypic driver.

5.3 Infectious Agents

No infectious agents are known to cause or trigger MYH2-related myopathy. The disease lacks inflammatory histopathology typical of infectious or autoimmune myositis, and there are no reports of specific viral or bacterial infections preceding symptom onset.[4][7][12][14][15] Chronic progressive external ophthalmoplegia due to mitochondrial disease can be precipitated or worsened by infections, but MYH2-related CPEO appears purely genetic and noninfectious.[9]

Therefore, infectious factors and zoonotic agents are not relevant to MYH2 myopathy etiology, and infection management in affected individuals follows general medical guidelines rather than disease-specific protocols.

6. Mechanism / Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Manifestation

Step 1: Germline pathogenic variants in MYH2 (missense, truncating, splice-site) alter the sequence or expression of the MyHC IIa protein in fast skeletal muscle fibers, leading to impaired myosin motor function or loss of MyHC IIa expression.

Step 2: Altered MyHC IIa function or absence results in defective sarcomeric assembly and actin–myosin interaction in type 2A (and sometimes 2B) muscle fibers, causing fiber-type–specific structural and functional abnormalities.

Step 3: In dominant missense variants, misfolded or dysfunctional MyHC IIa integrates into thick filaments, leading to myofibrillar disorganization, protein aggregation, and activation of proteostasis pathways that culminate in rimmed vacuole and inclusion formation; in recessive LoF variants, developmental absence of MyHC IIa causes failure to form or maintain type 2A fibers, leading to selective fiber-type loss without inclusion pathology.

Step 4: These fiber-type–specific changes in fast skeletal muscle, particularly in proximal limb and extraocular muscles, result in reduced contractile strength and endurance, manifesting clinically as proximal muscle weakness and external ophthalmoplegia with ptosis.

Step 5: Over time, chronic dysfunction and structural damage lead to fatty infiltration of affected muscles, minor dystrophic changes, and sometimes minicores in type 2 fibers, further reducing muscle performance and contributing to progressive weakness in some dominant cases, while recessive cases remain relatively stable.

Step 6: The absence of significant inflammatory infiltrates or immune activation indicates that the pathophysiology is primarily structural and proteostatic rather than autoimmune, and secondary complications such as contractures or respiratory compromise arise primarily from mechanical and functional limitations rather than systemic pathology.

6.2 Molecular Pathways and Myosin Motor Dysfunction

At the molecular level, MYH2-related myopathy centers on disruption of actin–myosin cross-bridge cycling and thick filament assembly, processes governed by the myosin II ATPase cycle. MyHC IIa, encoded by MYH2, has specific kinetic properties optimized for fast-twitch muscle function, including rapid ATP hydrolysis and cross-bridge turnover.[2][4][7] Dominant missense mutations like E706K in the SH1 helix are expected to perturb the coupling between ATP binding/hydrolysis and lever arm rotation, thereby altering the duty cycle and force generation. The SH1 helix plays a key role in transmitting conformational changes from the nucleotide-binding pocket to the rest of the head domain, and substitution of a negatively charged glutamate with a positively charged lysine can disrupt local interactions and stability.[2][7][12]

Experimental expression of E706K MYH2 in muscle cells has shown misfolded protein and disorganized myofilaments, indicating that mutant myosin fails to assemble properly into thick filaments or to maintain filament integrity.[12] This misassembly is likely to engage cellular quality-control pathways such as the ubiquitin–proteasome system and autophagy, leading to the formation of protein aggregates and rimmed vacuoles characteristic of IBM3.[7][12][14] The precise signaling cascades are not fully delineated, but parallels can be drawn to other protein-aggregation myopathies, where misfolded proteins induce autophagic vacuoles and tubulofilament aggregates. Gene Ontology (GO) terms relevant here include GO:0030048 (actin filament-based movement), GO:0006936 (muscle contraction), GO:0016071 (protein catabolic process), and GO:0006914 (autophagy), reflecting both contractile and proteostasis aspects.

In recessive LoF variants, the key molecular change is the absence or severe reduction of MyHC IIa. This leads to failure of type IIa fibers to develop or persist, and muscle fiber pools shift towards other types such as type I or IIx, or show atrophy and fatty replacement.[3][4][7][15] Transcriptomic and immunohistochemical data from recessive cases indicate that MYH2 transcripts and protein are markedly reduced or absent, confirming the LoF mechanism.[3] GO terms such as GO:0007507 (muscle fiber development) and GO:0048747 (muscle fiber maturation) are pertinent in describing how MYH2 deficiency affects fiber-type specification.

6.3 Cellular Processes: Autophagy, Protein Aggregation, and Fiber-Type Loss

At the cellular level, MYH2-related myopathy engages processes of protein quality control, autophagy, and structural maintenance of sarcomeres. In dominant IBM3, rimmed vacuoles and filamentous aggregates indicate activation of autophagic pathways and accumulation of undigested material.[7][12][14] These vacuoles typically contain 15–20 nm tubulofilaments and protein aggregates, suggesting that misfolded myosin and associated proteins were targeted for degradation but incompletely cleared.[7] The HPO term HP:0100806 (Autophagic vacuoles in muscle fibers) and GO:0006914 (autophagy) capture these processes.

Myosinopathies reviews describe “Structural alterations with minicores in type 2 fibers in childhood and in mildly affected muscles of adults,” implying that oxidative and calcium-handling defects may accompany structural disruption.[7] Minicores are focal areas of myofibrillar disorganization and mitochondrial depletion, often associated with defects in excitation–contraction coupling and energy metabolism, and they are common in core myopathies involving other structural proteins. In IBM3, minicores may represent localized failure of sarcomeric maintenance due to chronic presence of mutant myosin.

In recessive MYH2 myopathy, cellular processes center on fiber-type loss rather than aggregation. Muscles show “Complete absence of type 2A muscle fibers. Variable, unspecific myopathic changes with fatty infiltration. Type 2B fibers may be lacking,” according to myosinopathies reviews.[7] This suggests that muscle fiber-type plasticity is altered, with surviving fibers being primarily slow-twitch or other fast subtypes, and that chronic underuse or lack of proper innervation leads to fatty replacement. GO terms such as GO:0001764 (neuron adhesion), GO:0048754 (branching involved in skeletal muscle organ development), and GO:0005518 (collagen binding) may be involved in broader structural and extracellular matrix remodeling.

Importantly, both dominant and recessive MYH2 myopathies lack significant inflammatory infiltrates or necrosis, distinguishing them from immune-mediated myositis. Immune system involvement is minimal, and biomarkers of autoimmunity (e.g., myositis-specific antibodies) are typically negative.[4][7][12][14][15] Thus, cellular pathophysiology is primarily structural and proteostatic rather than immune-mediated.

6.4 Metabolic Changes and Energy Utilization

Type IIa fibers are characterized by fast contraction and intermediate oxidative capacity, contributing substantially to muscle power and endurance. Loss or dysfunction of MyHC IIa is expected to alter muscle energy metabolism, though direct metabolomic studies in MYH2 myopathy are lacking. In recessive disease, absence of type 2A fibers may shift fiber-type composition towards type I fibers, which are more oxidative, or towards other fast subtypes with different metabolic profiles.[3][4][7][15] This could influence fatigue resistance and overall metabolic efficiency during exercise, leading to early fatigue or altered performance.

In dominant IBM3, inclusion formation and chronic proteostasis stress may increase energy demands for protein turnover and autophagy, potentially affecting mitochondrial function and ATP supply, though this has not been extensively studied. Minicores suggest localized mitochondrial depletion or dysfunction within fibers, which could impair oxidative metabolism.[7][12][14] GO terms such as GO:0006091 (generation of precursor metabolites and energy), GO:0006119 (oxidative phosphorylation), and GO:0005739 (mitochondrion) are relevant.

Despite these implications, systemic metabolic abnormalities such as lactic acidosis, hypoglycemia, or lipid disorders have not been reported in MYH2 patients, and standard metabolic labs are typically normal.[3][4][7][10][15] Thus, metabolic changes are likely confined to muscle tissue and manifest primarily as reduced endurance and fatigue rather than systemic metabolic disease.

6.5 Immune System Involvement and Tissue Damage

As noted, immune system involvement in MYH2-related myopathy is minimal. Muscle biopsies do not show significant inflammatory infiltrates or complement deposition, distinguishing the disease from autoimmune myositis such as polymyositis or dermatomyositis.[4][7][12][14] Rimmed vacuoles in IBM3 are associated with degenerative autophagic processes rather than immune attack, and tubulofilament inclusions do not appear to provoke robust immune responses.

Tissue damage mechanisms center on structural failure, proteostatic overload, and fatty infiltration. In dominant IBM3, chronic presence of misfolded myosin causes slow fiber degeneration, with muscle fibers being replaced by fat and connective tissue over years, resulting in progressive weakness.[7][12][14] In recessive disease, early inability to form type 2A fibers leads to muscle hypoplasia and gradual fatty infiltration, but the process is relatively stable and nonprogressive.[3][4][7][15] GO terms such as GO:0008219 (cell death) and GO:0009898 (cytoplasmic protein catabolic process) are applicable.

Oxidative stress and mitochondrial dysfunction may contribute to tissue damage in IBM3, as in other inclusion-body myopathies, but explicit data in MYH2 disease are limited. No fibrosis-related severe cardiomyopathy or respiratory failure has been reported, consistent with the mild systemic impact of MYH2 myopathy.[4][5][7][10][15][16]

6.6 Epigenetic Changes and Molecular Profiling

Specific epigenetic changes in MYH2-related myopathy have not been described, and large-scale molecular profiling data (transcriptomics, proteomics, metabolomics) are sparse. However, muscle biopsies in recessive disease show reduced or absent expression of MYH2 mRNA and protein, implying transcriptional or post-transcriptional regulation of mutant alleles.[3][4][15] Cassini et al. demonstrated that their splice-site variant c.5673+1G>C affects splicing, resulting in novel transcripts, although detailed transcriptome profiling was not reported.[10]

Given the role of MYH2 in fiber-type identity, global gene expression changes involving other myosin isoforms, troponins, and fiber-type transcription factors are likely in affected muscle, but these have not yet been systematically catalogued in public datasets such as GEO or ArrayExpress. Similarly, proteomic studies of IBM3 inclusions could reveal the composition of aggregates, including myosin, ubiquitin, p62, and other proteostasis-related proteins, but such work has not been widely published. Metabolomic and lipidomic signatures in MYH2 muscle have not been explored.

Future multi-omics studies integrating genomic, transcriptomic, and proteomic data in MYH2 myopathy could clarify pathways involved in fiber-type specification, autophagy, and sarcomeric maintenance, and provide new therapeutic targets. For now, molecular profiling remains a promising but underdeveloped domain in MYH2 research.

6.7 Advanced Technologies and Functional Genomics

Advanced technologies such as single-cell RNA sequencing, spatial transcriptomics, and CRISPR-based functional genomics have not yet been specifically applied to MYH2-related myopathy. However, the disease provides an attractive target for such methodologies because it affects specific fiber types and involves distinct cell populations such as extraocular muscle fibers and fast-twitch limb muscle fibers.[3][4][7][9][15] Single-cell analysis of muscle biopsies could reveal how MYH2 mutations alter fiber-type composition, satellite cell behavior, and immune cell involvement at high resolution, while spatial transcriptomics could map expression of MYH2 and other myosin isoforms within muscle architecture.

Functional genomics screens, such as CRISPR knockout or CRISPR base editing in myoblasts or myotubes, could be used to model MYH2 mutations in vitro and identify pathways that modulate proteostasis and autophagy in IBM3. The C. elegans model referenced by ClinGen, which likely involves mutation of an MYH2 ortholog, demonstrates the feasibility of using invertebrate systems to study myosin function and muscle phenotypes.[15] DepMap and other cancer-focused resources are less relevant, as MYH2 is not a common oncogenic driver.

In summary, mechanistic understanding of MYH2-related myopathy is grounded in classical molecular and histological studies, and cutting-edge multi-omics and functional genomics approaches remain opportunities for future research rather than current sources of data.

6.8 Suggested GO and CL Terms for Mechanisms and Cell Types

Based on the mechanistic narrative, key GO biological process terms include GO:0030048 (actin filament-based movement), GO:0006936 (muscle contraction), GO:0007507 (muscle fiber development), GO:0006914 (autophagy), GO:0009898 (cytoplasmic protein catabolic process), GO:0008219 (cell death), GO:0006119 (oxidative phosphorylation), and GO:0005739 (mitochondrion). Cell Ontology (CL) terms relevant to cell types include CL:0000746 (skeletal muscle fiber), CL:0000670 (fast-twitch skeletal muscle fiber), and CL:0000700 (extraocular muscle cell). These terms can be used to annotate mechanistic statements in ontological frameworks and knowledge bases.

7. Anatomical Structures Affected

7.1 Organ-Level Involvement

The primary organs affected in MYH2-related myopathy are skeletal muscles, particularly limb-girdle muscles and extraocular muscles. Uberon terms such as UBERON:0002106 (skeletal muscle tissue) and UBERON:0001630 (extraocular skeletal muscle) capture these structures. Clinical reports describe proximal limb involvement in the shoulders and hips, reflecting weakness of muscles like the deltoid, gluteus maximus, and quadriceps.[3][4][5][7][10][15][16] Extraocular muscles, including the superior rectus, inferior rectus, lateral rectus, medial rectus, superior oblique, and inferior oblique, are consistently affected, leading to external ophthalmoplegia.[4][7][9][14][15]

Secondary organ involvement is minimal. Cardiac muscle, smooth muscle, and central nervous system are generally spared, with echocardiography and neuroimaging often normal.[4][7][15][16] Respiratory muscles, such as the diaphragm and intercostals, are usually preserved sufficiently to avoid severe respiratory failure, though mild restrictive changes may occur in advanced cases, as in other myopathies. Gastrointestinal involvement is limited, though Baskar et al. noted esophageal reflux disease in a CPEO patient, which may reflect nonspecific comorbidity rather than direct MYH2 pathology.[9]

Body systems most prominently involved include the musculoskeletal system (skeletal muscle and joints), ocular motor system (extraocular muscles and eyelids), and, to a lesser extent, the neuromuscular junction and cranial nerves controlling eye movements and facial expression. However, neuromuscular junction physiology is typically normal, differentiating MYH2 myopathy from congenital myasthenic syndromes.[4][7][9][15]

7.2 Tissue and Cell-Level Involvement

At the tissue level, MYH2-related myopathy primarily affects striated skeletal muscle, a type of connective tissue specialized for contraction. Muscle fibers expressing MyHC IIa, particularly type 2A and 2B fibers, bear the brunt of pathology.[4][7][15] In dominant IBM3, type 2 fibers show minicores, rimmed vacuoles, and inclusions, indicating structural and proteostatic stress.[7][12][14] In recessive MYH2 myopathy, type 2A fibers are absent or greatly reduced, and surviving fibers may be type I or other fast subtypes.[3][4][7][15]

Specific cell populations affected include fast-twitch skeletal muscle fibers (CL:0000670), extraocular muscle fibers (CL:0000700), and, secondarily, slow-twitch fibers that may compensate for absent fast fibers. Satellite cells, the muscle stem cells responsible for regeneration, may be involved in ongoing attempts to repair damaged fiber architecture, though their behavior in MYH2 myopathy has not been specifically studied. Myonuclei within fibers must cope with misfolded myosin and autophagic processes in IBM3, suggesting nuclear stress as well.

Connective tissue cells such as fibroblasts contribute to fibrosis and fatty infiltration over time, particularly in dominant cases with progressive degeneration. Adipocytes increase within muscle tissue as fibers atrophy and are replaced by fat. Endothelial cells and intramuscular nerve fibers remain structurally intact, consistent with nonvascular, nonneuropathic pathology.[4][7][12][14][15]

7.3 Subcellular Level: Sarcomeres, Myofibrils, and Vacuoles

At the subcellular level, MYH2-related myopathy involves key compartments such as sarcomeres, myofibrils, lysosomes/autophagic vacuoles, and the cytoskeleton. GO Cellular Component terms relevant include GO:0030017 (sarcomere), GO:0030016 (myofibril), GO:0005776 (autophagosome), GO:0005829 (cytosol), and GO:0005884 (actin filament).[4][7][12][14]

In dominant IBM3, mutated MyHC IIa disrupts sarcomere organization, leading to focal breakdown of A-bands and I-bands and formation of minicores—localized regions lacking normal myofibrillar structure.[7][12][14] Aggregated proteins and tubulofilaments accumulate in rimmed vacuoles, which are autophagic lysosomal structures attempting to degrade misfolded proteins. These vacuoles often line up at the periphery of fibers, giving the characteristic “rimmed” appearance on histology.[7][12][14]

In recessive disease, subcellular pathology centers on absence of MyHC IIa from thick filaments in type 2A fibers, preventing normal sarcomeric assembly. Fibers may show mild myofibrillar disarray but lack the prominent vacuoles and inclusions seen in IBM3.[3][4][7][15] Mitochondria remain relatively intact, though minicores may show mitochondrial depletion in some dominant cases. Nuclear morphology is generally normal, and neuromuscular junction structures appear unremarkable.

7.4 Localization and Lateralization

Clinically, weakness and ophthalmoplegia in MYH2-related myopathy are generally bilateral and symmetric, reflecting diffuse involvement of muscle populations expressing MyHC IIa.[3][4][5][7][9][10][14][15][16] There is no strong lateralization, and asymmetric weakness or ocular involvement would prompt consideration of alternative diagnoses such as cranial nerve palsies or acquired myopathies.

Anatomical localization of pathology has been detailed in imaging and biopsies. Thigh muscles (e.g., quadriceps, hamstrings) often show fatty infiltration in MRI, and biopsies are typically taken from proximal muscles such as vastus lateralis or biceps brachii.[4][7][10][14][15] Extraocular muscles show atrophy and fibrosis on imaging in CPEO but are rarely biopsied due to surgical challenges. In the head and neck, levator palpebrae superioris muscle involvement leads to ptosis. Uberon terms UBERON:0000948 (thigh), UBERON:0008891 (eyelid), and UBERON:0002108 (skeletal muscle of head) may be used to annotate localization.

8. Temporal Development

8.1 Age of Onset and Onset Pattern

MYH2-related myopathy typically presents in childhood or adolescence, though recessive and dominant subtypes differ somewhat in onset characteristics. OMIM describes CMYO6 as having “childhood onset of symptoms,” indicating that weakness and ophthalmoplegia generally begin before adulthood.[5] Dominant MyHC IIa myopathy often features congenital joint contractures at birth, which resolve over time, followed by adolescent-onset external ophthalmoplegia and proximal weakness.[2][5][7][14] Darin et al. and Martinsson et al. described individuals with arthrogryposis at birth who later developed ocular and limb-girdle symptoms, demonstrating a biphasic course with an early structural phase and later functional phase.[2][7][14]

Recessive MYH2 myopathy presents with early-onset, nonprogressive diffuse weakness and ophthalmoplegia. Tajsharghi et al. and ClinGen summarize recessive disease as “early onset, non-progressive, diffuse weakness and ophthalmoplegia,” usually arising in childhood and remaining relatively stable thereafter.[3][15] Patients may have delayed motor milestones, mild facial weakness, and ocular limitations from early in life.

Recent reports indicate that adult-onset variants exist. Baskar et al. described adult patients with MYH2 mutations presenting with CPEO and minimal skeletal abnormalities, with onset in adulthood.[9] Cassini et al. reported a family with slowly progressive proximal myopathy with onset in adolescence or early adulthood, lacking congenital contractures or ophthalmoplegia.[10] These cases expand the age-of-onset spectrum and suggest that some MYH2 variants may cause late-onset disease. Overall, onset is chronic and insidious rather than acute or subacute.

8.2 Disease Progression, Stages, and Duration

The progression of MYH2-related myopathy varies by subtype and mutation but is generally mild to moderate. OMIM notes that CMYO6 is “either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity.”[5] Recessive cases are often nonprogressive or minimally progressive, with stable weakness and ophthalmoplegia over decades, reflecting developmental absence of type 2A fibers rather than ongoing degeneration.[3][4][7][15]

Dominant IBM3 can be more progressive, especially in adults with rimmed vacuoles and dystrophic changes. Myosinopathies reviews describe a “Progressive course in some adults affecting ambulation,” and note that rimmed vacuoles are seen in adults with progressive course and dystrophic muscle changes.[7] Over time, muscle fibers degenerate and are replaced by fat and connective tissue, leading to increased weakness and, in some cases, difficulty with independent

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 10
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 44
Resolved 38
Unresolved (possible confabulation) 2
Obsolete 2
Unverifiable 2
Terms whose name was checked 39
Terms named correctly 14
Terms named as a different term 18
Terms whose name is worth a second look 7

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0000622 (2 mentions) - the report calls it "External ophthalmoplegia"; HP calls it Blurred vision
  • HP:0001769 (1 mention) - the report calls it "Scapular winging"; HP calls it Broad foot
  • HP:0007340 (1 mention) - the report calls it "Cytoplasmic inclusion bodies in muscle fibers"; HP calls it Lower limb muscle weakness
  • HP:0003457 (1 mention) - the report calls it "Myopathic EMG pattern"; HP calls it EMG abnormality
  • HP:0003215 (1 mention) - the report calls it "Abnormal muscle MRI"; HP calls it Elevated urinary dicarboxylic acid level
  • HP:0001324 (1 mention) - the report calls it "Fatigue"; HP calls it Muscle weakness
  • HP:0002355 (1 mention) - the report calls it "Reduced activity tolerance"; HP calls it obsolete Difficulty walking
  • GO:0048747 (1 mention) - the report calls it "muscle fiber maturation"; GO calls it GO_0048747
  • HP:0100806 (1 mention) - the report calls it "Autophagic vacuoles in muscle fibers"; HP calls it Sepsis
  • GO:0048754 (1 mention) - the report calls it "branching involved in skeletal muscle organ development"; GO calls it branching morphogenesis of an epithelial tube
  • GO:0009898 (2 mentions) - the report calls it "cytoplasmic protein catabolic process"; GO calls it cytoplasmic side of plasma membrane
  • CL:0000670 (2 mentions) - the report calls it "fast-twitch skeletal muscle fiber"; CL calls it primordial germ cell
  • CL:0000700 (2 mentions) - the report calls it "extraocular muscle cell"; CL calls it dopaminergic neuron
  • UBERON:0002106 (1 mention) - the report calls it "skeletal muscle tissue"; UBERON calls it spleen
  • UBERON:0001630 (1 mention) - the report calls it "extraocular skeletal muscle"; UBERON calls it muscle organ
  • UBERON:0000948 (1 mention) - the report calls it "thigh"; UBERON calls it heart
  • UBERON:0008891 (1 mention) - the report calls it "eyelid"; UBERON calls it external gill
  • UBERON:0002108 (1 mention) - the report calls it "skeletal muscle of head"; UBERON calls it small intestine

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0003483 (2 mentions), reported as "Rimmed vacuoles on muscle biopsy" - HP does not contain this term
  • HP:0003723 (1 mention), reported as "Gait disturbance" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0002355 (obsolete Difficulty walking) (1 mention) - replaced by HP:0001288
  • GO:0048747 (GO_0048747) (1 mention) - replaced by GO:0055001

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0003690 (2 mentions) - the report calls it "Proximal muscle weakness"; HP calls it Limb muscle weakness
  • HP:0002829 (2 mentions) - the report calls it "Arthrogryposis"; HP calls it Arthralgia
  • HP:0001371 (1 mention) - the report calls it "Joint contracture"; HP calls it Flexion contracture
  • GO:0016071 (1 mention) - the report calls it "protein catabolic process"; GO calls it mRNA metabolic process
  • GO:0007507 (2 mentions) - the report calls it "muscle fiber development"; GO calls it heart development
  • GO:0001764 (1 mention) - the report calls it "neuron adhesion"; GO calls it neuron migration
  • CL:0000746 (1 mention) - the report calls it "skeletal muscle fiber"; CL calls it cardiac muscle cell, and lists "cardiac muscle fiber" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.