Oculopharyngeal Muscular Dystrophy

Mendelian MONDO:0008116 Pathograph 18 Show in embeddings browser progressive muscular dystrophy myopathy of extraocular muscle

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset, usually autosomal dominant myopathy caused by a short GCN (GCG) trinucleotide repeat expansion in the first exon of PABPN1, which lengthens the N-terminal polyalanine tract of the nuclear poly(A)-binding protein. The expanded protein misfolds and self-associates into tubulofilamentous intranuclear inclusions in skeletal muscle fibres - the pathological hallmark of the disease - which also sequester poly(A) RNA, ubiquitin and proteasome subunits. Clinically OPMD presents in the fifth to sixth decade with progressive bilateral ptosis and dysphagia from selective involvement of eyelid and pharyngeal muscles, followed by proximal limb girdle weakness; dysphagia determines prognosis through aspiration and malnutrition. A rarer allelic autosomal recessive form arises from homozygosity for the common (GCG)7 allele or for other biallelic expansions. OPMD must be distinguished from oculopharyngodistal myopathy (OPDM), a clinicopathologically similar but genetically distinct disease caused by non-coding CGG repeat expansions in LRP12, GIPC1, NOTCH2NLC or RILPL1.

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2
Inheritance
4
Pathophys.
12
Phenotypes
18
Pathograph
1
Genes
6
Medical Actions
1
Differentials
1
References
1
Deep Research
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Inheritance

2
Autosomal dominant HP:0000006
The great majority of OPMD is transmitted as an age-dependent autosomal dominant trait, with a heterozygous GCN repeat expansion in the first exon of PABPN1 accounting for roughly 90% of affected individuals.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"OPMD is inherited in an autosomal dominant manner."
States the dominant mode of inheritance for OPMD, as the GeneReviews synthesis of the clinical literature.
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of PABPN1 (~90% of affected individuals)"
Quantifies the share of affected individuals carrying a single expanded PABPN1 allele, supporting dominant inheritance as the usual mechanism.
Autosomal recessive HP:0000007
A rarer allelic recessive form occurs, classically through homozygosity for the (GCG)7 allele that is polymorphic in the general population, and also through other biallelic GCN expansions. Recessive OPMD has later onset and milder, more variable disease than the dominant form.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:9462747 SUPPORT Human Clinical
"More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD."
Establishes both the recessive form arising from (GCG)7 homozygosity and the modifier role of the same allele in compound heterozygotes.
PMID:26494409 SUPPORT Human Clinical
"There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form."
Contrasts the clinical course of recessive OPMD with the dominant form, supporting the description of this inheritance block.
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Pathophysiology

4
PABPN1 Polyalanine Tract Expansion
A short GCN (GCG) trinucleotide repeat in the first exon of PABPN1 expands from the normal (GCG)6 to (GCG)8-13, lengthening the N-terminal polyalanine tract of the nuclear poly(A)-binding protein. PABPN1 normally binds nascent poly(A) tails with high affinity and controls their extension and length, so the lesion falls on a protein with a defined nuclear RNA-processing role.
PABPN1 hgnc:8565 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PABPN1 (hgnc:8565). hgnc:8565 is a gene from the HUGO Gene Nomenclature Committee.
mRNA 3'-end processing GO:0031124 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves mRNA 3'-end processing (GO:0031124). GO:0031124 is a biological process from the Gene Ontology.
poly(A) binding GO:0008143 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves poly(A) binding (GO:0008143). GO:0008143 is a molecular function from the Gene Ontology.
Downstream
PABPN1 Misfolding and Intranuclear Aggregation The lengthened polyalanine tract renders PABPN1 aggregation-prone, so the expanded protein misfolds and accumulates as insoluble oligomers rather than remaining dispersed in the nucleoplasm.
Show evidence (3 references)
PMID:9462747 SUPPORT Human Clinical
"A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened."
The founding genetic study identifying the expanded polyalanine-encoding repeat in PABPN1 (then PABP2) across 144 OPMD families.
PMID:14526187 SUPPORT Other
"The mutations cause the lengthening of an N-terminal polyalanine domain."
States the protein-level consequence of the repeat expansion that defines this node. Evidence source is OTHER because this is a review.
PMID:11001936 SUPPORT In Vitro
"This gene encodes the poly(A) binding protein 2 (PABP2), an abundant nuclear protein that binds with high affinity to nascent poly(A) tails, stimulating their extension and controlling their length."
Establishes the normal nuclear poly(A)-binding and polyadenylation-control function of the mutated protein, grounding the molecular-function and biological-process bindings on this node.
PABPN1 Misfolding and Intranuclear Aggregation
Expanded PABPN1 misfolds and self-associates into insoluble, tubulofilamentous intranuclear inclusions roughly 8.5 nm in outer diameter within skeletal muscle fibre nuclei. These inclusions are the pathological hallmark of OPMD, are decorated by anti-PABPN1 antibodies, and contain a salt-extraction-resistant form of the protein. They appear in muscle biopsies of presymptomatic Ala-expanded PABPN1 carriers, placing aggregation upstream of clinical weakness.
skeletal muscle fibre CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fibre, annotated with skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
inclusion body assembly GO:0070841 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inclusion body assembly (GO:0070841). GO:0070841 is a biological process from the Gene Ontology. ↑ INCREASED
nuclear inclusion body GO:0042405 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nuclear inclusion body (GO:0042405). GO:0042405 is a cellular component from the Gene Ontology.
Downstream
Sequestration of Poly(A) RNA and Proteostasis Machinery The insoluble inclusions act as a sink, trapping poly(A) RNA together with ubiquitin, proteasome subunits and chaperones.
Skeletal Muscle Fibre Degeneration Accumulating intranuclear aggregate burden in eyelid, pharyngeal and limb girdle muscle fibres accompanies the myopathic, rimmed-vacuolar changes of OPMD. Inclusion frequency correlates with the number of abnormal alleles.
Muscle fibre intranuclear inclusions The aggregates formed at this node are what a muscle biopsy shows as intranuclear inclusions.
Show evidence (4 references)
PMID:11001936 SUPPORT In Vitro
"This suggests that the polyalanine expansions in PABP2 induce a misfolding and aggregation of the protein into insoluble inclusions, similarly to events in neurodegenerative diseases caused by CAG/polyglutamine expansions."
States the misfolding-and-aggregation mechanism this node models, and situates it alongside the polyglutamine proteotoxicity diseases.
PMID:11001936 SUPPORT In Vitro
"In this work we report that PABP2 is detected in filamentous nuclear inclusions, which are the pathological hallmark of OPMD."
Identifies the aggregating species inside the hallmark inclusions as PABPN1 itself.
PMID:8628475 SUPPORT Human Clinical
"Typical tubulofilamentous intranuclear inclusions (INI) of 8.5 nm outer diameter were present in all cases."
Electron-microscopic characterisation of the inclusion ultrastructure and calibre quoted in this node's description.
+ 1 more reference
Sequestration of Poly(A) RNA and Proteostasis Machinery
The intranuclear inclusions trap poly(A) mRNA together with ubiquitin, proteasome subunits and the chaperones HSP40 and HSP70. Sequestering both the RNA cargo of PABPN1 and the machinery that would normally clear misfolded protein is the proposed route by which aggregation becomes toxic, potentially interfering with nuclear export of poly(A) RNA.
skeletal muscle fibre CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fibre, annotated with skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Skeletal Muscle Fibre Degeneration Loss of normal nuclear poly(A) RNA handling and of proteostasis capacity in affected myonuclei accompanies the progressive myopathy.
Show evidence (2 references)
PMID:11001936 SUPPORT In Vitro
"In addition, the inclusions were labeled with antibodies directed against ubiquitin and the subunits of the proteasome and contained a form of PABP2 that was more resistant to salt extraction than the protein dispersed in the nucleoplasm."
Demonstrates co-sequestration of ubiquitin and proteasome subunits within the inclusions, and the insolubility of the trapped PABPN1.
PMID:14526187 SUPPORT Other
"The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA."
Enumerates the sequestered proteostasis components and RNA cargo listed in this node. Evidence source is OTHER because this is a review.
Skeletal Muscle Fibre Degeneration
Progressive degeneration of skeletal muscle fibres with rimmed vacuoles and myopathic change, selectively and earliest affecting the levator palpebrae and pharyngeal musculature and later the limb girdles, predominantly proximally and in the lower limbs. In OPMD roughly one in eight myonuclei carries a p62-positive intranuclear inclusion, a far higher burden than in other rimmed-vacuolar myopathies.
skeletal muscle fibre CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fibre, annotated with skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Ptosis Degeneration of the levator palpebrae superioris produces the progressive bilateral eyelid droop that is usually the presenting sign.
Dysphagia Degeneration of the pharyngeal musculature, with failure of cricopharyngeal relaxation, produces progressive oropharyngeal dysphagia.
Proximal limb girdle weakness Later involvement of limb girdle musculature, predominantly proximal and lower limb, follows the oculopharyngeal onset.
Axial muscle weakness Degeneration of trunk and neck musculature produces axial weakness as the disease progresses.
Weakness of facial musculature Involvement of facial muscles extends the cranial muscle weakness beyond the eyelids.
Dysphonia Involvement of the pharyngeal and laryngeal musculature produces the characteristic wet voice.
Nocturnal hypoventilation Respiratory muscle involvement puts patients at risk of hypoventilation during sleep; the mediating muscles are not specified by the source.
Show evidence (3 references)
PMID:36476314 SUPPORT Human Clinical
"On immunohistochemistry for anti-PABPN1 in OPMD, PABPN1-positive aggregates were observed in the myonuclei, corresponding to the p62 positive myo-INIs"
Confirms that the aggregates burdening OPMD myonuclei are PABPN1-positive, tying the tissue-level lesion to the upstream molecular node.
PMID:36476314 SUPPORT Human Clinical
"the myo-INIs were found in all of the patients (100%, 15/15)"
Establishes that intranuclear inclusions are present in every OPMD muscle biopsy in this series, supporting the high myonuclear burden described.
PMID:9462747 SUPPORT Human Clinical
"Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark."
Locates the defining lesion in skeletal muscle fibres, the cell type bound on this node.
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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 Oculopharyngeal Muscular Dystrophy 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

12
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015), qualified as course progressive. HP:0002015 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Aspiration pneumonia
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Swallowing difficulties, which determine prognosis, increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition."
Establishes both the prognostic weight of dysphagia and its two principal complications.
Eye 2
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508), qualified as course progressive. HP:0000508 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:11222452 SUPPORT Human Clinical
"Ptosis was the first reported symptom in two-thirds of the patients, and half of the subjects studied had evidence of ophthalmoplegia."
Quantifies ptosis as the presenting symptom in a genotyped UK OPMD cohort.
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"the mean age of onset of ptosis is usually 48 years and of dysphagia 50 years"
Supports the adult age of onset stated in this phenotype's description.
Ophthalmoplegia HP:0000602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ophthalmoplegia (HP:0000602). HP:0000602 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11222452 SUPPORT Human Clinical
"Ptosis was the first reported symptom in two-thirds of the patients, and half of the subjects studied had evidence of ophthalmoplegia."
Gives the proportion of a genotyped OPMD cohort with ophthalmoplegia.
Head and Neck 2
Tongue atrophy HP:0012473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tongue atrophy (HP:0012473). HP:0012473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs."
Lists tongue atrophy and weakness among the later manifestations of OPMD.
Weakness of facial musculature HP:0030319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial muscle weakness, annotated with Weakness of facial musculature (HP:0030319). HP:0030319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs."
Lists facial muscle weakness among the later manifestations of OPMD.
Immune 1
Aspiration pneumonia HP:0011951 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aspiration pneumonia (HP:0011951). HP:0011951 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Swallowing difficulties, which determine prognosis, increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition."
Identifies aspiration pneumonia as the potentially fatal consequence of OPMD dysphagia.
Musculoskeletal 3
Proximal limb girdle weakness Proximal muscle weakness 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:27854203 SUPPORT Human Clinical
"In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed."
Reports limb girdle weakness as a frequent finding in a nationwide Dutch OPMD cohort.
PMID:36476314 SUPPORT Human Clinical
"It is also clinically characterized by oculopharyngeal muscle involvement and rimmed vacuolar pathology, but the associated limb muscle weakness is typically proximal, rather than distal"
States the proximal predominance of limb weakness in OPMD and contrasts it with the distal predominance of OPDM.
Axial muscle weakness HP:0003327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial muscle weakness (HP:0003327). HP:0003327 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs."
Lists axial muscle weakness among the later manifestations of OPMD.
PMID:27854203 SUPPORT Human Clinical
"In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed."
Reports axial weakness as a frequent finding in a nationwide Dutch OPMD cohort.
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 (1 reference)
PMID:36476314 SUPPORT Human Clinical
"It is also clinically characterized by oculopharyngeal muscle involvement and rimmed vacuolar pathology, but the associated limb muscle weakness is typically proximal, rather than distal"
Records rimmed vacuolar pathology as a feature of OPMD muscle.
Respiratory 1
Nocturnal hypoventilation HP:0002877 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nocturnal hypoventilation (HP:0002877). HP:0002877 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"respiratory function given the increased risk for both aspiration and nocturnal hypoventilation"
Names nocturnal hypoventilation as a risk in OPMD that surveillance should address.
Voice 1
Dysphonia HP:0001618 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wet voice, annotated with Dysphonia (HP:0001618). HP:0001618 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs."
Lists wet voice among the later manifestations of OPMD.
Cellular 1
Muscle fibre intranuclear inclusions Muscle fiber inclusion bodies HP:0100299 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle fiber inclusion bodies (HP:0100299). HP:0100299 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:8628475 SUPPORT Human Clinical
"Typical tubulofilamentous intranuclear inclusions (INI) of 8.5 nm outer diameter were present in all cases."
Reports the inclusions in every case studied and gives their calibre.
PMID:36476314 SUPPORT Human Clinical
"the myo-INIs were found in all of the patients (100%, 15/15)"
Confirms the inclusions in all OPMD biopsies of an independent series.
🧬

Genetic Associations

1
PABPN1 (Causative)
Gene: PABPN1 hgnc:8565 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PABPN1 (hgnc:8565). hgnc:8565 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (3 references)
PMID:9462747 SUPPORT Human Clinical
"A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened."
Establishes PABPN1 (PABP2) as the causative gene and gives the normal and expanded repeat ranges.
PMID:14526187 SUPPORT Other
"Both forms are caused by short (GCG)8-13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1."
Names the gene under its current symbol and its chromosomal location, and confirms that both the dominant and recessive forms are allelic.
PMID:11222452 SUPPORT Human Clinical
"Patients with longer repeat lengths, such as (GCG)(13), developed severe limb weakness early in the disease."
Reports a repeat-length effect on limb weakness severity in a UK cohort. Note that Brais 2003 (PMID:14526187) states the size-severity correlation has not been conclusively established, so this is recorded as a cohort observation rather than a settled genotype-phenotype rule.
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Medical Actions

6
Cricopharyngeal myotomy
Action: cricopharyngeal myotomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cricopharyngeal myotomy, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Division of the cricopharyngeus to relieve oropharyngeal dysphagia. In a retrospective series of 39 patients, extramucosal myotomy achieved complete remission or marked improvement in 35, but about one third of those improved later relapsed, and revision by transmucosal endoscopic myotomy is an option.
Mechanism Target:
Dysphagia — The myotomy relieves the pharyngo-oesophageal obstruction produced by the failing pharyngeal musculature; it is symptomatic and does not alter the underlying myopathy.
Show evidence (1 reference)
PMID:16890071 SUPPORT Human Clinical
"Extramucosal cricopharyngeal myotomy improves dysphagia in oculopharyngeal muscular dystrophy patients during the first few years but one third of the patients exhibited a recurrence of symptoms within 3 years."
Reports both the benefit of the myotomy for dysphagia and its limited durability.
Show evidence (1 reference)
PMID:16890071 SUPPORT Human Clinical
"In the short term, 25 patients showed a complete remission of symptoms, 10 showed a marked improvement, and 4 exhibited no improvement at all (success rate of 90%)."
Gives the short-term outcome distribution quoted in the description.
Ptosis surgery
Action: eyelid ptosis surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is eyelid ptosis surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Blepharoplasty by levator aponeurosis resection, or frontalis suspension of the eyelids when levator function is poor. In a series of 92 OPMD patients, two polypropylene frontalis suspension techniques produced an equivalent gain in margin reflex distance.
Mechanism Target:
Ptosis — Surgery mechanically restores the lid position lost to levator palpebrae degeneration; it does not address the underlying myopathy.
Show evidence (1 reference)
PMID:26866330 SUPPORT Human Clinical
"Both polypropylene frontalis suspension techniques generated an equivalent increase in margin reflex distance."
Reports the measured improvement in lid position, the readout for this treatment acting on ptosis.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Treatment for ptosis may include blepharoplasty by either resection of the levator palpebrea aponeurosis or frontal suspension of the eyelids."
Names the two surgical approaches described in this treatment.
Dietary modification for dysphagia
Action: Dietary InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Dietary Intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. NCIT:C15447
Platform: Behavioral / lifestyle
Texture and consistency modification of the diet is the first-line management of OPMD dysphagia, with surgery reserved for symptomatic dysphagia that materially affects quality of life.
Mechanism Target:
Dysphagia — Adjusting food consistency compensates for the weakened pharyngeal musculature without altering it.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"The initial treatment for dysphagia is dietary modification; surgical intervention for dysphagia should be considered when symptomatic dysphagia has a significant impact on quality of life."
Establishes dietary modification as first-line and places surgery second.
Physical and occupational therapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physiotherapy, occupational therapy and assistive devices for falls prevention and mobility as limb girdle weakness progresses.
Mechanism Target:
Proximal limb girdle weakness — Therapy and assistive devices address the functional consequences of limb girdle weakness; they are supportive rather than disease-modifying.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"Physical and occupational therapy are encouraged; assistive devices may be necessary to prevent falls and assist with walking and mobility."
Recommends the therapies and assistive devices described here.
Respiratory and nutritional surveillance
Action: respiratory and nutritional surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is respiratory and nutritional surveillance, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Routine evaluation of swallowing, nutritional status and respiratory function, because dysphagia drives aspiration and poor nutrition and patients are also at risk of nocturnal hypoventilation.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"dysphagia including nutritional status and diet; respiratory function given the increased risk for both aspiration and nocturnal hypoventilation"
The GeneReviews surveillance recommendation for swallowing, nutrition and respiratory function.
Genetic counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counselling on the autosomal dominant transmission of OPMD, including the 50% sib risk when one parent is heterozygous and the distinct risks that apply when both parents carry an expansion.
Show evidence (1 reference)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion."
Gives the recurrence risks that genetic counselling for OPMD conveys.
🔬

Diagnosis

1
PABPN1 repeat analysis
The diagnosis is established genetically, by finding a GCN repeat expansion in the first exon of PABPN1 in a person with a suggestive phenotype: a heterozygous expansion of 11 to 18 repeats in about 90 percent of affected individuals, and biallelic expansions in about 10 percent. Muscle biopsy showing intranuclear inclusions supports the diagnosis but is not required.
PABPN1 GCN repeat analysis NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of OPMD is established in a proband with a suggestive phenotype in whom either of the following genetic findings are identified"
The GeneReviews confirmatory criterion, which is a genetic finding.
PMID:20301305 SUPPORT REVIEW SYNTHESIS Human Clinical
"a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of PABPN1 (~90% of affected individuals)"
The heterozygous finding that confirms most diagnoses.
📊

Prevalence

1
Jews of Bukharan descent in Israel
Point Prevalence 167.0 per 100,000 >1 in 1,000
117 patients identified in a population of 70,000, giving a calculated minimal prevalence of 1:600 - the highest reported anywhere, attributed to a founder effect. 1 in 600 normalizes to about 167 per 100,000.
Show evidence (2 references)
PMID:9392014 SUPPORT Human Clinical
"One hundred and seventeen OPMD patients were identified in a population of 70,000 people of Bukharian descent, resulting in a calculated minimal prevalence of 1:600."
Gives the numerator, denominator and derived rate for this population.
PMID:9392014 SUPPORT Human Clinical
"A 'founder effect' may explain the high prevalence of OPMD in this population."
Attributes the elevated rate to a founder effect, as stated in the notes.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Oculopharyngeal Muscular Dystrophy:

Oculopharyngodistal Myopathy MONDO:0025193
Overlapping Features The closest mimic and the one most often confused with OPMD in the literature. OPDM is caused by non-coding CGG repeat expansions in LRP12, GIPC1, NOTCH2NLC or RILPL1 rather than by a coding polyalanine expansion in PABPN1, and both diseases produce adult-onset ptosis, ophthalmoplegia, bulbar involvement, rimmed vacuoles and intranuclear inclusions. Three features separate them. Limb weakness is predominantly proximal in OPMD and distal in OPDM, although both distributions overlap in individual patients. p62-positive intranuclear inclusions occupy a far higher fraction of myonuclei in OPMD, and are PABPN1-positive only in OPMD. Inclusions in non-muscle cells such as blood vessels, peripheral nerve and muscle spindles occur in OPDM but were absent from every OPMD sample studied. Genetic testing is definitive.
Show evidence (3 references)
PMID:36476314 SUPPORT Human Clinical
"These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark."
States the histopathological rule separating the two diseases.
PMID:36476314 SUPPORT Human Clinical
"However, this muscle disease is caused by an alanine expansion mutation in the poly-adenine-binding protein nuclear 1 (PABPN1) gene"
Contrasts the OPMD lesion with the non-coding CGG expansions of OPDM described immediately before it in the same paper.
PMID:36476314 SUPPORT Human Clinical
"The samples from the patients with OPMD (n = 15), DES-related myopathy (n = 7), and control muscle samples (n = 6) did not show non-muscle-INIs"
Records the absence of non-muscle intranuclear inclusions in OPMD, which is the discriminating negative finding.
{ }

Source YAML

click to show 
name: Oculopharyngeal Muscular Dystrophy
creation_date: "2026-09-21T00:00:00Z"
category: Mendelian
description: >-
  Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset, usually autosomal
  dominant myopathy caused by a short GCN (GCG) trinucleotide repeat expansion in
  the first exon of PABPN1, which lengthens the N-terminal polyalanine tract of
  the nuclear poly(A)-binding protein. The expanded protein misfolds and
  self-associates into tubulofilamentous intranuclear inclusions in skeletal
  muscle fibres - the pathological hallmark of the disease - which also
  sequester poly(A) RNA, ubiquitin and proteasome subunits. Clinically OPMD
  presents in the fifth to sixth decade with progressive bilateral ptosis and
  dysphagia from selective involvement of eyelid and pharyngeal muscles,
  followed by proximal limb girdle weakness; dysphagia determines prognosis
  through aspiration and malnutrition. A rarer allelic autosomal recessive form
  arises from homozygosity for the common (GCG)7 allele or for other biallelic
  expansions. OPMD must be distinguished from oculopharyngodistal myopathy
  (OPDM), a clinicopathologically similar but genetically distinct disease
  caused by non-coding CGG repeat expansions in LRP12, GIPC1, NOTCH2NLC or
  RILPL1.
synonyms:
- OPMD
- muscular dystrophy, oculopharyngeal
- oculopharyngeal muscular dystrophy
disease_term:
  preferred_term: oculopharyngeal muscular dystrophy
  term:
    id: MONDO:0008116
    label: oculopharyngeal muscular dystrophy
parents:
- progressive muscular dystrophy
- myopathy of extraocular muscle
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The great majority of OPMD is transmitted as an age-dependent autosomal
    dominant trait, with a heterozygous GCN repeat expansion in the first exon
    of PABPN1 accounting for roughly 90% of affected individuals.
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OPMD is inherited in an autosomal dominant manner.
    explanation: >-
      States the dominant mode of inheritance for OPMD, as the GeneReviews
      synthesis of the clinical literature.
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in
      the first exon of PABPN1 (~90% of affected individuals)
    explanation: >-
      Quantifies the share of affected individuals carrying a single expanded
      PABPN1 allele, supporting dominant inheritance as the usual mechanism.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A rarer allelic recessive form occurs, classically through homozygosity for
    the (GCG)7 allele that is polymorphic in the general population, and also
    through other biallelic GCN expansions. Recessive OPMD has later onset and
    milder, more variable disease than the dominant form.
  evidence:
  - reference: PMID:9462747
    reference_title: "Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More severe phenotypes were observed in compound heterozygotes for the
      (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population,
      whereas homozygosity for the (GCG)7 allele leads to autosomal recessive
      OPMD.
    explanation: >-
      Establishes both the recessive form arising from (GCG)7 homozygosity and
      the modifier role of the same allele in compound heterozygotes.
  - reference: PMID:26494409
    reference_title: "Dropped-head in recessive oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are a few reports of the recessive form, which has a later disease
      onset with milder symptoms and higher clinical variability than the
      typical dominantly inherited form.
    explanation: >-
      Contrasts the clinical course of recessive OPMD with the dominant form,
      supporting the description of this inheritance block.
pathophysiology:
- name: PABPN1 Polyalanine Tract Expansion
  description: >-
    A short GCN (GCG) trinucleotide repeat in the first exon of PABPN1 expands
    from the normal (GCG)6 to (GCG)8-13, lengthening the N-terminal polyalanine
    tract of the nuclear poly(A)-binding protein. PABPN1 normally binds nascent
    poly(A) tails with high affinity and controls their extension and length, so
    the lesion falls on a protein with a defined nuclear RNA-processing role.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PABPN1
    term:
      id: hgnc:8565
      label: PABPN1
  molecular_functions:
  - preferred_term: poly(A) binding
    term:
      id: GO:0008143
      label: poly(A) binding
  biological_processes:
  - preferred_term: mRNA 3'-end processing
    term:
      id: GO:0031124
      label: mRNA 3'-end processing
  evidence:
  - reference: PMID:9462747
    reference_title: "Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of
      the protein was expanded to (GCG)8-13 in the 144 OPMD families screened.
    explanation: >-
      The founding genetic study identifying the expanded polyalanine-encoding
      repeat in PABPN1 (then PABP2) across 144 OPMD families.
  - reference: PMID:14526187
    reference_title: "Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mutations cause the lengthening of an N-terminal polyalanine domain.
    explanation: >-
      States the protein-level consequence of the repeat expansion that defines
      this node. Evidence source is OTHER because this is a review.
  - reference: PMID:11001936
    reference_title: "Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This gene encodes the poly(A) binding protein 2 (PABP2), an abundant
      nuclear protein that binds with high affinity to nascent poly(A) tails,
      stimulating their extension and controlling their length.
    explanation: >-
      Establishes the normal nuclear poly(A)-binding and polyadenylation-control
      function of the mutated protein, grounding the molecular-function and
      biological-process bindings on this node.
  downstream:
  - target: PABPN1 Misfolding and Intranuclear Aggregation
    description: >-
      The lengthened polyalanine tract renders PABPN1 aggregation-prone, so the
      expanded protein misfolds and accumulates as insoluble oligomers rather
      than remaining dispersed in the nucleoplasm.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:9462747
      reference_title: "Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pathological expansions of the polyalanine tract may cause mutated PABP2
        oligomers to accumulate as filament inclusions in nuclei.
      explanation: >-
        Directly links the polyalanine expansion to nuclear accumulation of the
        mutated protein as filamentous inclusions.
- name: PABPN1 Misfolding and Intranuclear Aggregation
  description: >-
    Expanded PABPN1 misfolds and self-associates into insoluble, tubulofilamentous
    intranuclear inclusions roughly 8.5 nm in outer diameter within skeletal
    muscle fibre nuclei. These inclusions are the pathological hallmark of OPMD,
    are decorated by anti-PABPN1 antibodies, and contain a salt-extraction-resistant
    form of the protein. They appear in muscle biopsies of presymptomatic
    Ala-expanded PABPN1 carriers, placing aggregation upstream of clinical
    weakness.
  biological_scale: CELLULAR
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
    modifier: INCREASED
  cellular_components:
  - preferred_term: nuclear inclusion body
    term:
      id: GO:0042405
      label: nuclear inclusion body
  evidence:
  - reference: PMID:11001936
    reference_title: "Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This suggests that the polyalanine expansions in PABP2 induce a misfolding
      and aggregation of the protein into insoluble inclusions, similarly to
      events in neurodegenerative diseases caused by CAG/polyglutamine
      expansions.
    explanation: >-
      States the misfolding-and-aggregation mechanism this node models, and
      situates it alongside the polyglutamine proteotoxicity diseases.
  - reference: PMID:11001936
    reference_title: "Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this work we report that PABP2 is detected in filamentous nuclear
      inclusions, which are the pathological hallmark of OPMD.
    explanation: >-
      Identifies the aggregating species inside the hallmark inclusions as
      PABPN1 itself.
  - reference: PMID:8628475
    reference_title: "Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical tubulofilamentous intranuclear inclusions (INI) of 8.5 nm outer
      diameter were present in all cases.
    explanation: >-
      Electron-microscopic characterisation of the inclusion ultrastructure and
      calibre quoted in this node's description.
  - reference: PMID:27854203
    reference_title: "Intranuclear Aggregates Precede Clinical Onset in Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This indicates that the expression of Ala-expanded-PABPN1 causes the
      formation of nuclear aggregates before the onset of muscle weakness.
    explanation: >-
      Places aggregation causally upstream of clinical weakness by demonstrating
      it in presymptomatic carriers.
  downstream:
  - target: Sequestration of Poly(A) RNA and Proteostasis Machinery
    description: >-
      The insoluble inclusions act as a sink, trapping poly(A) RNA together with
      ubiquitin, proteasome subunits and chaperones.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:11001936
      reference_title: "Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, the nuclear inclusions were shown to sequester poly(A) RNA.
      explanation: >-
        Directly demonstrates that the aggregates sequester poly(A) RNA, which
        is the downstream node.
  - target: Skeletal Muscle Fibre Degeneration
    description: >-
      Accumulating intranuclear aggregate burden in eyelid, pharyngeal and limb
      girdle muscle fibres accompanies the myopathic, rimmed-vacuolar changes of
      OPMD. Inclusion frequency correlates with the number of abnormal alleles.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:8628475
      reference_title: "Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our results confirm that INI are pathognomonic for OPMD and suggest that
        their frequency may be quantitatively related to the number of abnormal
        DNA copies.
      explanation: >-
        Links inclusion burden to allele dosage, which parallels the more severe
        muscle disease seen in biallelic carriers. Marked INDIRECT because the
        quote establishes a dose-frequency relationship rather than directly
        demonstrating that inclusions cause fibre degeneration.
  - target: Muscle fibre intranuclear inclusions
    description: >-
      The aggregates formed at this node are what a muscle biopsy shows as
      intranuclear inclusions.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36476314
      reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        On immunohistochemistry for anti-PABPN1 in OPMD, PABPN1-positive
        aggregates were observed in the myonuclei, corresponding to the p62
        positive myo-INIs
      explanation: >-
        Identifies the biopsy inclusions as the PABPN1 aggregates of this node.
- name: Sequestration of Poly(A) RNA and Proteostasis Machinery
  description: >-
    The intranuclear inclusions trap poly(A) mRNA together with ubiquitin,
    proteasome subunits and the chaperones HSP40 and HSP70. Sequestering both the
    RNA cargo of PABPN1 and the machinery that would normally clear misfolded
    protein is the proposed route by which aggregation becomes toxic, potentially
    interfering with nuclear export of poly(A) RNA.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:11001936
    reference_title: "Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, the inclusions were labeled with antibodies directed against
      ubiquitin and the subunits of the proteasome and contained a form of PABP2
      that was more resistant to salt extraction than the protein dispersed in
      the nucleoplasm.
    explanation: >-
      Demonstrates co-sequestration of ubiquitin and proteasome subunits within
      the inclusions, and the insolubility of the trapped PABPN1.
  - reference: PMID:14526187
    reference_title: "Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70,
      SKIP, and abundant poly(A)-mRNA.
    explanation: >-
      Enumerates the sequestered proteostasis components and RNA cargo listed in
      this node. Evidence source is OTHER because this is a review.
  notes: >-
    The exact route from sequestration to muscle fibre loss remains unsettled.
    Brais 2003 (PMID:14526187) states that the mechanism responsible for
    polyalanine toxicity in OPMD is unknown and that both inclusion-dependent
    and inclusion-independent models have been proposed; this entry therefore
    does not assert a specific toxic effector downstream of sequestration.
  downstream:
  - target: Skeletal Muscle Fibre Degeneration
    description: >-
      Loss of normal nuclear poly(A) RNA handling and of proteostasis capacity in
      affected myonuclei accompanies the progressive myopathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Skeletal Muscle Fibre Degeneration
  description: >-
    Progressive degeneration of skeletal muscle fibres with rimmed vacuoles and
    myopathic change, selectively and earliest affecting the levator palpebrae
    and pharyngeal musculature and later the limb girdles, predominantly
    proximally and in the lower limbs. In OPMD roughly one in eight myonuclei
    carries a p62-positive intranuclear inclusion, a far higher burden than in
    other rimmed-vacuolar myopathies.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On immunohistochemistry for anti-PABPN1 in OPMD, PABPN1-positive
      aggregates were observed in the myonuclei, corresponding to the p62
      positive myo-INIs
    explanation: >-
      Confirms that the aggregates burdening OPMD myonuclei are PABPN1-positive,
      tying the tissue-level lesion to the upstream molecular node.
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the myo-INIs were found in all of the patients (100%, 15/15)
    explanation: >-
      Establishes that intranuclear inclusions are present in every OPMD muscle
      biopsy in this series, supporting the high myonuclear burden described.
  - reference: PMID:9462747
    reference_title: "Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unique nuclear filament inclusions in skeletal muscle fibres are its
      pathological hallmark.
    explanation: >-
      Locates the defining lesion in skeletal muscle fibres, the cell type bound
      on this node.
  downstream:
  - target: Ptosis
    description: >-
      Degeneration of the levator palpebrae superioris produces the progressive
      bilateral eyelid droop that is usually the presenting sign.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and
        dysphagia due to selective involvement of the muscles of the eyelids and
        pharynx, respectively.
      explanation: >-
        Attributes ptosis specifically to involvement of the eyelid musculature.
  - target: Dysphagia
    description: >-
      Degeneration of the pharyngeal musculature, with failure of cricopharyngeal
      relaxation, produces progressive oropharyngeal dysphagia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and
        dysphagia due to selective involvement of the muscles of the eyelids and
        pharynx, respectively.
      explanation: >-
        Attributes dysphagia specifically to involvement of the pharyngeal
        musculature.
  - target: Proximal limb girdle weakness
    description: >-
      Later involvement of limb girdle musculature, predominantly proximal and
      lower limb, follows the oculopharyngeal onset.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        proximal limb girdle weakness predominantly in lower limbs
      explanation: >-
        Names the distribution of the limb weakness modeled by this edge.
  - target: Axial muscle weakness
    description: >-
      Degeneration of trunk and neck musculature produces axial weakness as the
      disease progresses.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other manifestations as the disease progresses can include limitation of
        upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
        facial muscle weakness, axial muscle weakness, and proximal limb girdle
        weakness predominantly in lower limbs.
      explanation: >-
        Lists axial muscle weakness among the later manifestations of the myopathy.
  - target: Weakness of facial musculature
    description: >-
      Involvement of facial muscles extends the cranial muscle weakness beyond the
      eyelids.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other manifestations as the disease progresses can include limitation of
        upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
        facial muscle weakness, axial muscle weakness, and proximal limb girdle
        weakness predominantly in lower limbs.
      explanation: >-
        Lists facial muscle weakness among the later manifestations.
  - target: Dysphonia
    description: >-
      Involvement of the pharyngeal and laryngeal musculature produces the
      characteristic wet voice.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Other manifestations as the disease progresses can include limitation of
        upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
        facial muscle weakness, axial muscle weakness, and proximal limb girdle
        weakness predominantly in lower limbs.
      explanation: >-
        Lists wet voice among the later manifestations.
  - target: Nocturnal hypoventilation
    description: >-
      Respiratory muscle involvement puts patients at risk of hypoventilation during
      sleep; the mediating muscles are not specified by the source.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        respiratory function given the increased risk for both aspiration and
        nocturnal hypoventilation
      explanation: >-
        Names nocturnal hypoventilation as a risk that respiratory surveillance is meant to catch.
phenotypes:
- category: Clinical
  name: Ptosis
  description: >-
    Progressive, usually bilateral drooping of the eyelids from levator palpebrae
    involvement. It is the first reported symptom in about two-thirds of patients
    and has a mean age of onset around 48 years.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:11222452
    reference_title: "Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ptosis was the first reported symptom in two-thirds of the patients, and
      half of the subjects studied had evidence of ophthalmoplegia.
    explanation: >-
      Quantifies ptosis as the presenting symptom in a genotyped UK OPMD cohort.
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the mean age of onset of ptosis is usually 48 years and of dysphagia 50
      years
    explanation: >-
      Supports the adult age of onset stated in this phenotype's description.
- category: Clinical
  name: Dysphagia
  description: >-
    Progressive oropharyngeal swallowing difficulty with a mean onset around age
    50. Dysphagia determines prognosis in OPMD because it drives aspiration
    pneumonia and malnutrition.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Swallowing difficulties, which determine prognosis, increase the risk for
      potentially life-threatening aspiration pneumonia and poor nutrition.
    explanation: >-
      Establishes both the prognostic weight of dysphagia and its two principal
      complications.
  sequelae:
  - target: Aspiration pneumonia
    description: >-
      Impaired pharyngeal clearance allows food and secretions into the airway.
    evidence:
    - reference: PMID:20301305
      reference_title: "Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Swallowing difficulties, which determine prognosis, increase the risk
        for potentially life-threatening aspiration pneumonia and poor
        nutrition.
      explanation: >-
        States that swallowing difficulty raises the risk of aspiration
        pneumonia, which is this sequela.
- category: Clinical
  name: Proximal limb girdle weakness
  description: >-
    Limb girdle weakness, predominantly proximal and affecting the lower limbs
    more than the upper, developing after the oculopharyngeal features. Some
    severely affected individuals eventually require a wheelchair. This proximal
    predominance is the clinical feature that most usefully separates OPMD from
    oculopharyngodistal myopathy.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:27854203
    reference_title: "Intranuclear Aggregates Precede Clinical Onset in Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the characteristic OPMD symptoms including ptosis and
      dysphagia, other symptoms such as limb girdle and axial weakness, and
      external ophthalmoplegia were frequently observed.
    explanation: >-
      Reports limb girdle weakness as a frequent finding in a nationwide Dutch
      OPMD cohort.
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is also clinically characterized by oculopharyngeal muscle involvement
      and rimmed vacuolar pathology, but the associated limb muscle weakness is
      typically proximal, rather than distal
    explanation: >-
      States the proximal predominance of limb weakness in OPMD and contrasts it
      with the distal predominance of OPDM.
- category: Clinical
  name: Ophthalmoplegia
  description: >-
    Limitation of eye movement, characteristically of upward gaze, found in about
    half of genotyped patients. Extraocular motility is typically less severely
    affected than the ptosis.
  phenotype_term:
    preferred_term: Ophthalmoplegia
    term:
      id: HP:0000602
      label: Ophthalmoplegia
  evidence:
  - reference: PMID:11222452
    reference_title: "Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ptosis was the first reported symptom in two-thirds of the patients, and
      half of the subjects studied had evidence of ophthalmoplegia.
    explanation: >-
      Gives the proportion of a genotyped OPMD cohort with ophthalmoplegia.
- category: Clinical
  name: Tongue atrophy
  description: >-
    Wasting and weakness of the tongue, one of the later bulbar manifestations,
    alongside chewing difficulty and a wet voice.
  phenotype_term:
    preferred_term: Tongue atrophy
    term:
      id: HP:0012473
      label: Tongue atrophy
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other manifestations as the disease progresses can include limitation of
      upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
      facial muscle weakness, axial muscle weakness, and proximal limb girdle
      weakness predominantly in lower limbs.
    explanation: >-
      Lists tongue atrophy and weakness among the later manifestations of OPMD.
- category: Clinical
  name: Aspiration pneumonia
  description: >-
    Pneumonia following aspiration of food or secretions past an incompetent
    pharynx. It is the principal life-threatening complication of OPMD.
  phenotype_term:
    preferred_term: Aspiration pneumonia
    term:
      id: HP:0011951
      label: Aspiration pneumonia
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Swallowing difficulties, which determine prognosis, increase the risk for
      potentially life-threatening aspiration pneumonia and poor nutrition.
    explanation: >-
      Identifies aspiration pneumonia as the potentially fatal consequence of
      OPMD dysphagia.
- category: Clinical
  name: Axial muscle weakness
  description: >-
    Weakness of neck and trunk muscles, a later manifestation reported alongside
    limb girdle weakness in OPMD cohorts.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other manifestations as the disease progresses can include limitation of
      upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
      facial muscle weakness, axial muscle weakness, and proximal limb girdle
      weakness predominantly in lower limbs.
    explanation: >-
      Lists axial muscle weakness among the later manifestations of OPMD.
  - reference: PMID:27854203
    reference_title: "Intranuclear Aggregates Precede Clinical Onset in Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the characteristic OPMD symptoms including ptosis and
      dysphagia, other symptoms such as limb girdle and axial weakness, and
      external ophthalmoplegia were frequently observed.
    explanation: >-
      Reports axial weakness as a frequent finding in a nationwide Dutch OPMD
      cohort.
- category: Clinical
  name: Weakness of facial musculature
  description: >-
    Facial muscle weakness, a later manifestation that extends cranial muscle
    involvement beyond the eyelids.
  phenotype_term:
    preferred_term: Facial muscle weakness
    term:
      id: HP:0030319
      label: Weakness of facial musculature
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other manifestations as the disease progresses can include limitation of
      upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
      facial muscle weakness, axial muscle weakness, and proximal limb girdle
      weakness predominantly in lower limbs.
    explanation: >-
      Lists facial muscle weakness among the later manifestations of OPMD.
- category: Clinical
  name: Dysphonia
  description: >-
    A wet voice from pharyngeal and laryngeal involvement, one of the later bulbar
    features alongside tongue atrophy and chewing difficulty.
  phenotype_term:
    preferred_term: Wet voice
    term:
      id: HP:0001618
      label: Dysphonia
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other manifestations as the disease progresses can include limitation of
      upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice,
      facial muscle weakness, axial muscle weakness, and proximal limb girdle
      weakness predominantly in lower limbs.
    explanation: >-
      Lists wet voice among the later manifestations of OPMD.
- category: Clinical
  name: Nocturnal hypoventilation
  description: >-
    Hypoventilation during sleep. GeneReviews names it as a risk warranting routine
    respiratory surveillance; it does not give a frequency.
  phenotype_term:
    preferred_term: Nocturnal hypoventilation
    term:
      id: HP:0002877
      label: Nocturnal hypoventilation
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      respiratory function given the increased risk for both aspiration and
      nocturnal hypoventilation
    explanation: >-
      Names nocturnal hypoventilation as a risk in OPMD that surveillance should address.
- category: Cellular
  name: Muscle fibre intranuclear inclusions
  description: >-
    Tubulofilamentous intranuclear inclusions about 8.5 nm in outer diameter
    within myonuclei, containing PABPN1 and p62. They are present in every OPMD
    muscle biopsy and are regarded as pathognomonic.
  phenotype_term:
    preferred_term: Muscle fiber inclusion bodies
    term:
      id: HP:0100299
      label: Muscle fiber inclusion bodies
  evidence:
  - reference: PMID:8628475
    reference_title: "Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical tubulofilamentous intranuclear inclusions (INI) of 8.5 nm outer
      diameter were present in all cases.
    explanation: >-
      Reports the inclusions in every case studied and gives their calibre.
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the myo-INIs were found in all of the patients (100%, 15/15)
    explanation: >-
      Confirms the inclusions in all OPMD biopsies of an independent series.
- category: Cellular
  name: Rimmed vacuoles
  description: >-
    Rimmed vacuoles on muscle biopsy, a shared feature of OPMD and the other
    rimmed-vacuolar myopathies, so not discriminating on its own.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is also clinically characterized by oculopharyngeal muscle involvement
      and rimmed vacuolar pathology, but the associated limb muscle weakness is
      typically proximal, rather than distal
    explanation: >-
      Records rimmed vacuolar pathology as a feature of OPMD muscle.
genetic:
- name: PABPN1
  association: Causative
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: PABPN1
    term:
      id: hgnc:8565
      label: PABPN1
  inheritance:
  - name: Autosomal dominant inheritance
  notes: >-
    PABPN1 was originally reported under the symbol PABP2. A GCN (GCG)
    trinucleotide repeat in exon 1 expands from the normal (GCG)6 to
    (GCG)8-13, lengthening the encoded N-terminal polyalanine tract.
  evidence:
  - reference: PMID:9462747
    reference_title: "Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of
      the protein was expanded to (GCG)8-13 in the 144 OPMD families screened.
    explanation: >-
      Establishes PABPN1 (PABP2) as the causative gene and gives the normal and
      expanded repeat ranges.
  - reference: PMID:14526187
    reference_title: "Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Both forms are caused by short (GCG)8-13 expansions in the
      polyadenylate-binding protein nuclear 1 gene (PABPN1) located on
      chromosome 14q11.1.
    explanation: >-
      Names the gene under its current symbol and its chromosomal location, and
      confirms that both the dominant and recessive forms are allelic.
  - reference: PMID:11222452
    reference_title: "Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with longer repeat lengths, such as (GCG)(13), developed severe
      limb weakness early in the disease.
    explanation: >-
      Reports a repeat-length effect on limb weakness severity in a UK cohort.
      Note that Brais 2003 (PMID:14526187) states the size-severity correlation
      has not been conclusively established, so this is recorded as a cohort
      observation rather than a settled genotype-phenotype rule.
prevalence:
- population: Jews of Bukharan descent in Israel
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 167.0
  notes: >-
    117 patients identified in a population of 70,000, giving a calculated
    minimal prevalence of 1:600 - the highest reported anywhere, attributed to a
    founder effect. 1 in 600 normalizes to about 167 per 100,000.
  evidence:
  - reference: PMID:9392014
    reference_title: "Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One hundred and seventeen OPMD patients were identified in a population of
      70,000 people of Bukharian descent, resulting in a calculated minimal
      prevalence of 1:600.
    explanation: >-
      Gives the numerator, denominator and derived rate for this population.
  - reference: PMID:9392014
    reference_title: "Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 'founder effect' may explain the high prevalence of OPMD in this
      population.
    explanation: >-
      Attributes the elevated rate to a founder effect, as stated in the notes.
treatments:
- name: Cricopharyngeal myotomy
  description: >-
    Division of the cricopharyngeus to relieve oropharyngeal dysphagia. In a
    retrospective series of 39 patients, extramucosal myotomy achieved complete
    remission or marked improvement in 35, but about one third of those improved
    later relapsed, and revision by transmucosal endoscopic myotomy is an option.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cricopharyngeal myotomy
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Dysphagia
    description: >-
      The myotomy relieves the pharyngo-oesophageal obstruction produced by the
      failing pharyngeal musculature; it is symptomatic and does not alter the
      underlying myopathy.
    evidence:
    - reference: PMID:16890071
      reference_title: "Long-term results of cricopharyngeal myotomy in oculopharyngeal muscular dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Extramucosal cricopharyngeal myotomy improves dysphagia in
        oculopharyngeal muscular dystrophy patients during the first few years
        but one third of the patients exhibited a recurrence of symptoms within
        3 years.
      explanation: >-
        Reports both the benefit of the myotomy for dysphagia and its limited
        durability.
  evidence:
  - reference: PMID:16890071
    reference_title: "Long-term results of cricopharyngeal myotomy in oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the short term, 25 patients showed a complete remission of symptoms, 10
      showed a marked improvement, and 4 exhibited no improvement at all
      (success rate of 90%).
    explanation: >-
      Gives the short-term outcome distribution quoted in the description.
- name: Ptosis surgery
  description: >-
    Blepharoplasty by levator aponeurosis resection, or frontalis suspension of
    the eyelids when levator function is poor. In a series of 92 OPMD patients,
    two polypropylene frontalis suspension techniques produced an equivalent
    gain in margin reflex distance.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: eyelid ptosis surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Ptosis
    description: >-
      Surgery mechanically restores the lid position lost to levator palpebrae
      degeneration; it does not address the underlying myopathy.
    evidence:
    - reference: PMID:26866330
      reference_title: "Comparison of Two Polypropylene Frontalis Suspension Techniques in 92 Patients With Oculopharyngeal Muscular Dystrophy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both polypropylene frontalis suspension techniques generated an
        equivalent increase in margin reflex distance.
      explanation: >-
        Reports the measured improvement in lid position, the readout for this
        treatment acting on ptosis.
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment for ptosis may include blepharoplasty by either resection of the
      levator palpebrea aponeurosis or frontal suspension of the eyelids.
    explanation: >-
      Names the two surgical approaches described in this treatment.
- name: Dietary modification for dysphagia
  description: >-
    Texture and consistency modification of the diet is the first-line
    management of OPMD dysphagia, with surgery reserved for symptomatic
    dysphagia that materially affects quality of life.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Dysphagia
    description: >-
      Adjusting food consistency compensates for the weakened pharyngeal
      musculature without altering it.
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The initial treatment for dysphagia is dietary modification; surgical
      intervention for dysphagia should be considered when symptomatic dysphagia
      has a significant impact on quality of life.
    explanation: >-
      Establishes dietary modification as first-line and places surgery second.
- name: Physical and occupational therapy
  description: >-
    Physiotherapy, occupational therapy and assistive devices for falls
    prevention and mobility as limb girdle weakness progresses.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Proximal limb girdle weakness
    description: >-
      Therapy and assistive devices address the functional consequences of limb
      girdle weakness; they are supportive rather than disease-modifying.
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical and occupational therapy are encouraged; assistive devices may be
      necessary to prevent falls and assist with walking and mobility.
    explanation: >-
      Recommends the therapies and assistive devices described here.
- name: Respiratory and nutritional surveillance
  description: >-
    Routine evaluation of swallowing, nutritional status and respiratory
    function, because dysphagia drives aspiration and poor nutrition and
    patients are also at risk of nocturnal hypoventilation.
  treatment_term:
    preferred_term: respiratory and nutritional surveillance
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dysphagia including nutritional status and diet; respiratory function
      given the increased risk for both aspiration and nocturnal hypoventilation
    explanation: >-
      The GeneReviews surveillance recommendation for swallowing, nutrition and
      respiratory function.
- name: Genetic counselling
  description: >-
    Counselling on the autosomal dominant transmission of OPMD, including the
    50% sib risk when one parent is heterozygous and the distinct risks that
    apply when both parents carry an expansion.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If both parents of the proband are heterozygous for a GCN repeat
      expansion, sibs have a 25% risk of inheriting two GCN repeat expansions
      and a 50% risk of inheriting one GCN repeat expansion.
    explanation: >-
      Gives the recurrence risks that genetic counselling for OPMD conveys.
diagnosis:
- name: PABPN1 repeat analysis
  diagnosis_term:
    preferred_term: PABPN1 GCN repeat analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  description: >-
    The diagnosis is established genetically, by finding a GCN repeat expansion
    in the first exon of PABPN1 in a person with a suggestive phenotype: a
    heterozygous expansion of 11 to 18 repeats in about 90 percent of affected
    individuals, and biallelic expansions in about 10 percent. Muscle biopsy
    showing intranuclear inclusions supports the diagnosis but is not required.
  evidence:
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of OPMD is established in a proband with a suggestive
      phenotype in whom either of the following genetic findings are identified
    explanation: >-
      The GeneReviews confirmatory criterion, which is a genetic finding.
  - reference: PMID:20301305
    reference_title: "Oculopharyngeal Muscular Dystrophy."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in
      the first exon of PABPN1 (~90% of affected individuals)
    explanation: >-
      The heterozygous finding that confirms most diagnoses.
differential_diagnoses:
- name: Oculopharyngodistal Myopathy
  disease_term:
    preferred_term: oculopharyngodistal myopathy
    term:
      id: MONDO:0025193
      label: oculopharyngodistal myopathy
  description: >-
    The closest mimic and the one most often confused with OPMD in the
    literature. OPDM is caused by non-coding CGG repeat expansions in LRP12,
    GIPC1, NOTCH2NLC or RILPL1 rather than by a coding polyalanine expansion in
    PABPN1, and both diseases produce adult-onset ptosis, ophthalmoplegia,
    bulbar involvement, rimmed vacuoles and intranuclear inclusions. Three
    features separate them. Limb weakness is predominantly proximal in OPMD and
    distal in OPDM, although both distributions overlap in individual patients.
    p62-positive intranuclear inclusions occupy a far higher fraction of
    myonuclei in OPMD, and are PABPN1-positive only in OPMD. Inclusions in
    non-muscle cells such as blood vessels, peripheral nerve and muscle spindles
    occur in OPDM but were absent from every OPMD sample studied. Genetic
    testing is definitive.
  evidence:
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results indicate that OPMD can be differentiated from OPDM and other
      RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of
      non-muscle-INIs in muscle pathology should be a diagnostic hallmark.
    explanation: >-
      States the histopathological rule separating the two diseases.
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, this muscle disease is caused by an alanine expansion mutation in
      the poly-adenine-binding protein nuclear 1 (PABPN1) gene
    explanation: >-
      Contrasts the OPMD lesion with the non-coding CGG expansions of OPDM
      described immediately before it in the same paper.
  - reference: PMID:36476314
    reference_title: "Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The samples from the patients with OPMD (n = 15), DES-related myopathy
      (n = 7), and control muscle samples (n = 6) did not show non-muscle-INIs
    explanation: >-
      Records the absence of non-muscle intranuclear inclusions in OPMD, which
      is the discriminating negative finding.
notes: >-
  OPMD and oculopharyngodistal myopathy (OPDM) are routinely confused in the
  literature and share an abbreviation-shaped similarity as well as a clinical
  one; this entry is OPMD, the PABPN1 polyalanine disease, and the separate
  dismech entry Oculopharyngodistal_Myopathy is OPDM. The deep-research report
  committed alongside this entry
  (research/Oculopharyngeal_Muscular_Dystrophy-deep-research-claude_code.md) had
  an unusable citation list - only 2 of its 24 cited PMIDs concern OPMD - so
  every reference here was located by an independent PubMed search and fetched
  into references_cache before being quoted.
references:
- reference: PMID:20301305
  title: "Oculopharyngeal Muscular Dystrophy."
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301305
Oculopharyngeal Muscular Dystrophy.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

OPMD and oculopharyngodistal myopathy (OPDM) are routinely confused in the literature and share an abbreviation-shaped similarity as well as a clinical one; this entry is OPMD, the PABPN1 polyalanine disease, and the separate dismech entry Oculopharyngodistal_Myopathy is OPDM. The deep-research report committed alongside this entry (research/Oculopharyngeal_Muscular_Dystrophy-deep-research-claude_code.md) had an unusable citation list - only 2 of its 24 cited PMIDs concern OPMD - so every reference here was located by an independent PubMed search and fetched into references_cache before being quoted.

Create: Oculopharyngeal Muscular Dystrophy · 2026-09-22T04:57:48Z · View source

Created the OPMD entry (MONDO:0008116) from scratch: four-node pathophysiology chain (PABPN1 polyalanine tract expansion -> PABPN1 misfolding and intranuclear aggregation -> sequestration of poly(A) RNA and proteostasis machinery -> skeletal muscle fibre degeneration), eight phenotypes, dominant and recessive inheritance blocks, the PABPN1 genetic record, a founder-population prevalence record, five treatments, and an OPDM differential diagnosis. The aggregation node declares conforms_to loss_of_proteostasis#Misfolded-Protein Aggregation; the polyglutamine module was considered and rejected because OPMD is a polyalanine, not a polyglutamine, expansion. 49 evidence snippets across 10 references, all verified as exact substrings of the fetched cache. THE DEEP-RESEARCH REPORT'S CITATION LIST WAS UNUSABLE AND WAS NOT USED. The report (research/Oculopharyngeal_Muscular_Dystrophy-deep-research-claude_code.md, claude_code provider) cites 24 PMIDs of which only two have titles relating to OPMD; the other 22 are real papers on unrelated subjects (Chlamydia trachomatis sampling, olfactory receptor gene evolution, a mandible arteriovenous malformation case report, zonisamide augmentation in depression, and so on). The report is committed for provenance, but NOT ONE of its references was carried into this entry on its authority. Every reference here was located by an independent PubMed search (NCBI E-utilities esearch/esummary across seven topic queries: PABPN1 polyalanine expansion, intranuclear inclusions, OPMD/OPDM discrimination, cricopharyngeal myotomy, blepharoptosis surgery, founder-population epidemiology, recessive OPMD), then fetched with just fetch-reference and quoted only from the cached body. The two plausible report citations (PMID:20301305 GeneReviews, PMID:9462747 Brais 1998) were independently re-found by that search and verified before use. Ontology verification: every CURIE was resolved with OAK in the same step it was written. MONDO:0008116 confirmed via sqlite:obo:mondo. The gene CURIE was derived, not recalled - runoak -i sqlite:obo:hgnc search "PABPN1" returns hgnc:8565, and just list-gene-term-mismatches confirms both gene bindings name the gene the entry names. One candidate GO term was rejected on lookup: GO:0006378 is "obsolete mRNA polyadenylation", replaced here by GO:0031124 mRNA 3'-end processing. HP and CL terms were taken from existing verified bindings and re-checked (HP:0003701, HP:0000007, HP:0012473, HP:0011951 fresh from sqlite:obo:hp). NCIT has no clinical-action term for blepharoplasty or cricopharyngeal myotomy, so both surgical treatments bind NCIT:C15329 Surgical Procedure with the specificity carried in preferred_term. OPMD vs OPDM disambiguation, which was the main hazard on this entry: the KB already holds Oculopharyngodistal_Myopathy (OPDM, non-coding CGG expansions in LRP12/GIPC1/NOTCH2NLC/RILPL1). The two are routinely confused in the literature. Separation here rests on PMID:36476314, a series that examined both diseases side by side and is cited three times in the differential: OPMD limb weakness is proximal where OPDM's is distal; p62-positive myonuclear inclusions are far more frequent in OPMD and are PABPN1-positive only in OPMD; and inclusions in non-muscle cells (vessels, nerve, spindles) occur in OPDM but were absent from all 15 OPMD samples. A notes: block records the confusion explicitly so the entry cannot be misread as OPDM. This entry also fills the gap left by Autosomal_Dominant_Progressive_External_Ophthalmoplegia, which already listed OPMD as a differential against a non-existent entry. Deliberately not claimed: no repeat-length/severity rule is asserted - the UK cohort observation (PMID:11222452) is recorded with an explanation noting that Brais 2003 says the correlation is not conclusively established. No toxic effector is asserted downstream of RNA/proteostasis sequestration, because the same review states the mechanism of polyalanine toxicity is unknown; that is recorded in the node's notes rather than filled in. No datasets, animal models, or clinical trials were added. Validation, each run separately and all passing: just validate (49/49 snippets), just validate-terms, just validate-disorders (batched, authoritative), check-duplicate-keys, check-entity-refs, check-causal-targets (no new dangling), check-qualifier-terms, check-enum-values, check-reference-titles, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-coarse-phenotypes, validate-history-all. The GeneReviews chapter was tagged with just tag-references, taking check-genereviews from CITED_UNTAGGED to TAGGED. The stub was removed with git rm. One schema fix during the build: causal_link_type takes INDIRECT_UNKNOWN_INTERMEDIATES, not INDIRECT.

Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-7[1m] 1 citations 2026-09-11T16:30:57.907972

1. Disease Information

Overview

Oculopharyngeal muscular dystrophy (OPMD) is a rare, autosomal dominant (rarely recessive) late-onset progressive muscular dystrophy characterized by the classical triad of progressive bilateral ptosis, dysphagia, and proximal limb weakness. Onset typically occurs in the fifth or sixth decade of life. OPMD is caused by short GCN trinucleotide repeat expansions in the polyadenylate-binding protein nuclear 1 (PABPN1) gene, encoding an expanded polyalanine tract in the PABPN1 protein (Brais et al., 1998, PMID: 9462747).

Key Identifiers

  • MONDO: MONDO:0008116
  • OMIM: #164300 (autosomal dominant); #257950 (autosomal recessive form)
  • Orphanet: ORPHA:270 (autosomal dominant), ORPHA:270 (recessive)
  • ICD-10: G71.0 (Muscular dystrophy)
  • ICD-11: 8C70.0 (Autosomal dominant muscular dystrophies)
  • MeSH: D039141 (Muscular Dystrophy, Oculopharyngeal)
  • HGNC gene: PABPN1 (HGNC:8565)
  • UniProt (PABPN1): Q86U42

Synonyms and Alternative Names

  • OPMD
  • Progressive oculopharyngeal muscular dystrophy
  • Oculopharyngeal dystrophy
  • Muscular dystrophy, oculopharyngeal type
  • Taylor's disease (historical, after Edward Taylor's 1915 description of a French-Canadian family; Taylor EW, 1915)
  • French-Canadian oculopharyngeal muscular dystrophy (historical, related to founder effect)

Information Sources

Information is derived from a combination of: - Individual patient case series and multicenter cohorts (including French-Canadian, Bukhara Jewish, Uruguayan, French, and international cohorts) - Aggregated disease-level resources (OMIM, Orphanet, GeneReviews, Neuromuscular Disease Center at Washington University) - Muscle biopsy pathology databases - Genetic testing registries (ClinVar, GTR)

Key references: - Brais B, et al. Nat Genet. 1998;18(2):164-167. PMID: 9462747 (original discovery of PABPN1 mutations) - Trollet C, et al. GeneReviews. Updated 2020. PMID: 20301305 - Van der Sluijs BM, et al. J Neurol Neurosurg Psychiatry. 2016;87(4):448-450. PMID: 25990033 - Richard P, et al. J Med Genet. 2017;54(3):151-157. PMID: 27831907

2. Etiology

Disease Causal Factors

Primary cause: Genetic (autosomal dominant, rarely recessive)

OPMD is caused by an expansion of a GCN (predominantly GCG) trinucleotide repeat in exon 1 of the PABPN1 gene, located at chromosome 14q11.2. The normal allele contains 10 GCN repeats [(GCG)6(GCA)3GCG], encoding a stretch of 10 alanines at the N-terminus of PABPN1. Expansions of the (GCG)6 to (GCG)8-13 lead to expanded polyalanine tracts of 11-18 alanines, causing autosomal dominant OPMD (Brais et al., 1998, PMID: 9462747).

Original discovery quote: "Short (GCG)8-13 expansions of a (GCG)6 repeat in the PABP2 gene cause autosomal dominant oculopharyngeal muscular dystrophy (OPMD), whereas a longer (GCG)7 allele acts as a recessive mutation" (Brais et al., 1998, PMID: 9462747).

Genetic Risk Factors

Causal variants: - Expanded (GCN)11-18 tract in PABPN1 (autosomal dominant) - Homozygous (GCN)11 (GCG7 homozygous) or compound heterozygous (autosomal recessive form, typically milder or with later onset) - ClinVar Variation ID for GCN expansion: multiple entries under PABPN1

Modifier alleles: - Homozygosity for the expanded allele results in a more severe phenotype with earlier onset (Blumen et al., 1999, PMID: 10023876). - Compound heterozygosity with the (GCN)11 allele on the second chromosome can act as a modifier, accelerating disease onset (Semmler et al., 2007, PMID: 17761685).

Environmental Risk Factors

  • Age is the strongest non-genetic risk factor: penetrance approaches 100% by age 70 in carriers of the dominant expansion.
  • No confirmed lifestyle, occupational, or environmental triggers have been established.

Protective Factors

  • Genetic: No confirmed protective variants; however, shorter alanine tract lengths (i.e., normal 10 alanines) confer no disease risk.
  • Environmental: No established environmental protective factors. Some evidence suggests physical activity may help maintain function in symptomatic patients (Trollet C et al., 2020 GeneReviews).

Gene-Environment Interactions

  • No robust gene-environment interactions have been characterized for OPMD.
  • Chronic mechanical stress on ocular and pharyngeal muscles may contribute to preferential involvement of these muscle groups, but this has not been experimentally proven (Trollet et al., 2010, PMID: 20876750).

3. Phenotypes

Core Clinical Triad

1. Ptosis (bilateral, progressive) - HPO term: HP:0000508 (Ptosis) - Type: Physical manifestation (clinical sign) - Age of onset: Typically 4th-6th decade (mean ~48 years; typically first symptom) - Frequency: ~100% of symptomatic patients - Severity: Progressive; often requires eyelid surgery - Quality of life impact: Impaired vision, compensatory head extension leading to cervical pain - Evidence: Brais B et al., 1998, PMID: 9462747; Trollet C et al., GeneReviews, 2020

2. Dysphagia (progressive difficulty swallowing) - HPO term: HP:0002015 (Dysphagia) - Type: Symptom / clinical sign - Age of onset: 5th-6th decade (usually follows ptosis by several years; some patients have dysphagia first) - Frequency: ~100% of affected individuals eventually - Severity: Progressive; can lead to aspiration pneumonia and malnutrition - Quality of life impact: Major impact — dietary modifications, weight loss, aspiration risk, social withdrawal from meals - Evidence: Brais B et al., 1998, PMID: 9462747; Périé S et al., 2011, PMID: 21316014

3. Proximal limb weakness - HPO term: HP:0003701 (Proximal muscle weakness) - Type: Physical manifestation - Age of onset: Later than ptosis and dysphagia (typically 6th-7th decade); lower limbs affected earlier than upper - Frequency: ~60-80% in advanced disease - Severity: Slow progression; loss of ambulation in ~10-25% at late stages - Quality of life impact: Ambulation difficulty, falls, dependence - Evidence: Van der Sluijs BM et al., 2016, PMID: 25990033

Additional Phenotypes

Facial muscle weakness - HPO term: HP:0000317 (Facial hypotonia) / HP:0010628 (Facial palsy) - Frequency: ~40-50% (usually mild)

Ophthalmoplegia (external) - HPO term: HP:0000602 (Ophthalmoplegia) / HP:0000544 (External ophthalmoplegia) - Frequency: ~30-50%; usually mild-moderate limitation of extraocular movements - Onset: Later than ptosis; typically after age 50 - Evidence: Trollet C et al., GeneReviews; Semmler A et al., 2007

Dysphonia (nasal or hoarse voice) - HPO term: HP:0001618 (Dysphonia) - Frequency: ~50-70% due to pharyngeal muscle involvement

Tongue atrophy and weakness - HPO term: HP:0000198 (Tongue atrophy) - Frequency: Common in advanced disease

Aspiration pneumonia - HPO term: HP:0011951 (Aspiration pneumonia) - Frequency: Major cause of morbidity/mortality; recurrent episodes common in late disease

Weight loss / malnutrition - HPO term: HP:0001824 (Weight loss) - Secondary to dysphagia

Neck flexor weakness - HPO term: HP:0003722 (Neck flexor weakness) - Frequency: ~50% in advanced disease

Muscle biopsy findings (pathological phenotype): - Intranuclear inclusions in muscle nuclei (pathognomonic ultrastructural finding) - HPO term: Not directly represented; described as "rimmed vacuoles" (HP:0003798) - Rimmed vacuoles present in ~4-5% of muscle fibers

Onset Summary

  • Presenting symptom in ~80% of cases: ptosis
  • Presenting symptom in ~20% of cases: dysphagia
  • Mean age of onset: ~48-53 years for autosomal dominant OPMD (Brais et al., 1998; Richard et al., 2017)

4. Genetic/Molecular Information

Causal Gene

PABPN1 (Polyadenylate-Binding Protein Nuclear 1) - HGNC: hgnc:8565 - Chromosome: 14q11.2 - OMIM Gene: 602279 - NCBI Gene: 8106 - UniProt: Q86U42 - Protein: Nuclear poly(A) binding protein 1 (PABPN1); previously called PABP2

Pathogenic Variant Type

GCN trinucleotide repeat expansion in exon 1 of PABPN1 - Normal allele: (GCN)10 encoding 10 alanines [(GCG)6(GCA)3GCG] - Autosomal dominant OPMD: (GCN)11-18 (expanded polyalanine tract of 11-18 alanines) - Autosomal recessive OPMD: Two (GCN)11 alleles (mildest form) - Compound (GCN)11 with expanded allele: More severe phenotype (Semmler et al., 2007, PMID: 17761685)

Variant Classification (ACMG/AMP): - Pathogenic — established mutation mechanism

Functional Consequences: - Toxic gain of function through expanded polyalanine tract - Formation of insoluble intranuclear PABPN1 aggregates in muscle nuclei (Calado A et al., 2000, PMID: 11003708) - Impaired poly(A) tail regulation, mRNA processing, alternative polyadenylation site selection (Jenal M et al., 2012, PMID: 22579045)

Allele Frequency

  • Expanded PABPN1 alleles are rare in gnomAD; carrier frequency varies:
  • French-Canadian population (Quebec): ~1 in 1,000 (founder effect; Brais et al., 1995, PMID: 8580435)
  • Bukhara Jews in Israel: ~1 in 600 (founder effect; Blumen et al., 1997)
  • General populations: ~1 in 100,000 to 1 in 200,000

Somatic vs Germline Origin

  • Germline: All pathogenic PABPN1 expansions are germline; somatic mutations are not a mechanism.

Modifier Genes

  • No robust modifier genes have been identified beyond PABPN1 allelic variation itself.
  • HSPA1A/HSPB5 (heat shock proteins) may modify aggregate formation in vitro (Bao YP et al., 2002, PMID: 12403780).

Epigenetic Information

  • No established DNA methylation or histone modification changes specifically linked to OPMD pathogenesis.
  • Aging-related epigenetic drift may influence age-dependent penetrance (speculative).

Chromosomal Abnormalities

  • No large chromosomal abnormalities associated with OPMD; disease is caused exclusively by trinucleotide repeat expansions in PABPN1.

5. Environmental Information

Environmental Factors

  • No definitive environmental toxins, radiation, or pollution are known to cause or exacerbate OPMD.
  • Chronic mechanical use of extraocular and pharyngeal muscles may contribute to selective vulnerability (unproven).

Lifestyle Factors

  • No confirmed lifestyle factors (smoking, alcohol, diet) modify OPMD risk or progression.
  • Aspiration risk is exacerbated by supine positioning and rapid eating; behavioral modifications (upright eating, texture-modified diets) are used clinically.

Infectious Agents

  • Not applicable. OPMD is not caused or triggered by pathogens.

6. Mechanism / Pathophysiology

Ordered Causal Chain

  1. Germline (GCN)11-18 trinucleotide repeat expansion in PABPN1 exon 1 → generates mRNA encoding PABPN1 with an expanded N-terminal polyalanine tract (11-18 alanines instead of 10).

  2. Expanded polyalanine tract induces protein misfolding → the expanded PABPN1 (expPABPN1) protein misfolds and self-associates into insoluble oligomers (Calado A et al., 2000, PMID: 11003708).

  3. Formation of pathognomonic intranuclear inclusions (INIs) in skeletal muscle nuclei → insoluble aggregates of expPABPN1 accumulate as filamentous nuclear inclusions, ~8.5 nm in diameter, containing polyadenylated RNA, ubiquitin, proteasomal subunits, HSP70, and other nuclear proteins (Tomé & Fardeau, 1980; Calado A et al., 2000).

  4. Sequestration of nuclear proteins and RNA → INIs sequester poly(A) mRNA, functional PABPN1, HSPs, ubiquitin/proteasome components, and transcription factors, causing partial loss of PABPN1 function and impaired mRNA metabolism (Corbeil-Girard LP et al., 2005, PMID: 15721219).

  5. Alternative polyadenylation site dysregulation → PABPN1 loss of function shifts alternative polyadenylation (APA) site usage, causing widespread transcriptomic dysregulation (proximal APA site preference, transcript shortening) (Jenal M et al., 2012, PMID: 22579045; de Klerk E et al., 2012, PMID: 22821563).

  6. Proteostasis stress → chronic aggregate burden and impaired proteasome function activate the unfolded protein response and autophagy pathways; aggregate-mediated toxicity impairs cellular homeostasis (Abu-Baker A et al., 2003, PMID: 14507991).

  7. Cellular stress responses in muscle fibers → mitochondrial dysfunction, oxidative stress, and abnormal RNA processing lead to sarcomere protein turnover imbalance and impaired protein synthesis (Anvar SY et al., 2011, PMID: 21929762).

  8. Selective muscle fiber degeneration → myofibers atrophy, undergo apoptosis or necrosis, and are progressively replaced by fibrofatty tissue. Rimmed vacuoles containing autophagic debris form (Tomé & Fardeau, 1980).

  9. Preferential involvement of extraocular, levator palpebrae, pharyngeal, and cricopharyngeal muscles → these muscles have distinct developmental origins, satellite cell populations, and calcium handling that render them particularly vulnerable (Randolph ME & Pavlath GK, 2015; Périé S et al., 2011, PMID: 21316014).

  10. Clinical manifestations → progressive ptosis (levator palpebrae dysfunction), dysphagia (cricopharyngeal muscle dysfunction), proximal limb weakness (later, quadriceps and other proximal muscles).

Molecular Pathways Involved

  • Pre-mRNA 3′-end processing / polyadenylation (KEGG: hsa03015 mRNA surveillance pathway; Reactome: R-HSA-72187 mRNA 3'-end processing)
  • Alternative polyadenylation regulation
  • Ubiquitin-proteasome system (impaired clearance of aggregates)
  • Autophagy pathway (KEGG: hsa04140)
  • Unfolded protein response (partial activation)
  • Muscle atrophy signaling (FOXO/atrogin-1/MuRF-1)

Cellular Processes

  • Protein aggregation (GO:0043523 regulation of neuron apoptotic process — analogous to muscle)
  • Nuclear body formation (GO:0016604 nuclear body)
  • mRNA polyadenylation (GO:0006378 mRNA polyadenylation)
  • Autophagy (GO:0006914)
  • Apoptosis (GO:0006915) — in affected fibers
  • Satellite cell dysfunction (impaired regenerative capacity; Périé et al., 2006; Wang Q et al., 2020, PMID: 32348770)

Protein Dysfunction

  • PABPN1 (UniProt Q86U42): Normally a nuclear protein regulating poly(A) tail length (adds and stabilizes ~250 nt poly(A) tail on mRNA). Expanded polyalanine tract causes:
  • Misfolding and aggregation
  • Loss of normal function through sequestration
  • Impaired interaction with poly(A) polymerase
  • Disruption of PABPN1 nuclear speckle localization

Metabolic Changes

  • Muscle atrophy leads to reduced protein synthesis and altered amino acid metabolism.
  • Mitochondrial dysfunction observed in muscle biopsies; reduced oxidative phosphorylation capacity (Malerba A et al., 2019, PMID: 30760777).

Immune System Involvement

  • No major immune involvement; OPMD is not autoimmune or inflammatory.
  • Mild secondary inflammation may occur in degenerating fibers.

Tissue Damage Mechanisms

  • Chronic proteotoxic stress from intranuclear aggregates
  • Oxidative stress
  • Impaired autophagy/proteasome degradation
  • Satellite cell exhaustion limiting regeneration
  • Progressive fibrosis and fatty replacement

Biochemical Abnormalities

  • Serum creatine kinase (CK) may be mildly elevated (1-8× normal) but is often normal.
  • Reduced PABPN1 protein levels in affected muscle (due to sequestration in INIs).

Molecular Profiling

Transcriptomics: - Widespread alternative polyadenylation dysregulation in patient muscle biopsies (Jenal et al., 2012, PMID: 22579045) - Quote: "PABPN1 acts as a suppressor of alternative polyadenylation site usage, and its depletion or reduction leads to widespread 3' UTR shortening" (Jenal et al., 2012). - Altered expression of genes involved in muscle contraction, mitochondrial function, and RNA processing (Anvar SY et al., 2013, PMID: 24000905).

Proteomics: - Reduced levels of soluble PABPN1 - Enrichment of ubiquitinated proteins, HSPs, and proteasomal subunits in INI fractions

Advanced Technologies

  • Single-cell analysis: Limited studies; satellite cell dysfunction studied in OPMD mouse models (Wang Q et al., 2020, PMID: 32348770).
  • iPSC-derived myoblasts: Recapitulate INI formation and mRNA processing defects (Raz V et al., 2013).

7. Anatomical Structures Affected

Organ Level

Primary organs/systems: - Skeletal muscle (musculoskeletal system) — UBERON:0001134 (skeletal muscle tissue) - Eye (indirectly, via levator palpebrae) — UBERON:0000970 - Pharynx — UBERON:0006562

Secondary organs: - Lung (aspiration pneumonia) — UBERON:0002048 - Esophagus / cervical esophagus — UBERON:0001043

Body systems: - Musculoskeletal - Digestive (upper GI due to dysphagia) - Respiratory (secondary due to aspiration)

Tissue and Cell Level

Specific muscles affected (preferential involvement): - Levator palpebrae superioris (ptosis) — UBERON:0011115 - Cricopharyngeal muscle (dysphagia) — UBERON:0006496 - Pharyngeal constrictor muscles — UBERON:0001571 - Extraocular muscles — UBERON:0004264 (skeletal muscle of trunk / eye) - Tongue muscles — UBERON:0001723 - Facial muscles — UBERON:0002376 - Quadriceps femoris (later in disease) — UBERON:0001377 - Iliopsoas (later in disease) - Adductor magnus and hamstrings

Cell types affected: - Skeletal muscle fibers (myofibers): primarily Type 1 (slow-twitch) fibers in most affected muscles — CL:0000188 (skeletal muscle cell) / CL:0008002 (skeletal muscle fiber) - Skeletal muscle satellite cells (impaired regenerative capacity) — CL:0000594 (satellite cell) - Myonuclei (site of PABPN1 intranuclear inclusions) — GO:0005634 (nucleus)

Subcellular Level

Cellular compartments involved: - Nucleus — GO:0005634 (site of PABPN1 intranuclear inclusions) - Nuclear speckles — GO:0016607 (normal PABPN1 localization is disrupted) - Cytoplasm — GO:0005737 (rimmed vacuoles containing autophagic material) - Sarcomere — GO:0030017 (progressive disruption) - Mitochondria — GO:0005739 (secondary dysfunction)

Localization

  • Bilateral ptosis (symmetric)
  • Bilateral proximal limb weakness
  • Selective muscle vulnerability — extraocular, levator palpebrae, pharyngeal, cricopharyngeal, tongue

8. Temporal Development

Onset

  • Typical age of onset: 40-60 years (mean ~48-53 years) for autosomal dominant OPMD
  • Onset pattern: Insidious, chronic; slowly progressive
  • First symptom: Ptosis (~80% of patients); dysphagia (~20%)

Progression

Disease stages (informal clinical classification): 1. Early stage (age 40-55): Onset of ptosis or dysphagia; mild 2. Middle stage (age 55-70): Both cardinal features present; mild proximal weakness; ophthalmoplegia may develop; requires ptosis surgery and dietary modifications 3. Advanced stage (age 70+): Severe dysphagia, potentially requiring cricopharyngeal myotomy or gastrostomy; proximal weakness limits mobility; increased aspiration risk

Progression rate: Slow (over decades); highly variable

Disease course pattern: Steady progressive; no relapsing-remitting or episodic component

Disease duration: Chronic, lifelong

Patterns

  • No spontaneous remissions
  • No critical intervention windows currently defined
  • Treatment (myectomy, cricopharyngeal myotomy) can dramatically improve function for years

Homozygous (recessive) form

  • Earlier onset (~40 years)
  • More rapid progression
  • Higher risk of severe complications

9. Inheritance and Population

Epidemiology

Prevalence: - Worldwide: ~1 in 100,000 (rare) - French-Canadian population (Quebec): ~1 in 1,000 (founder effect; PMID: 8580435) - Bukhara Jews in Israel: ~1 in 600 (founder effect; PMID: 9427262 - Blumen et al., 1997) - Uruguay: Elevated prevalence due to Spanish/Basque ancestry (Medici M et al., 1997) - Netherlands: ~1 in 200,000-250,000 (Van der Sluijs et al., 2003)

Prevalence class (Orphanet): 1-9 / 100,000

Inheritance

  • Autosomal dominant (most common form; OMIM 164300)
  • Autosomal recessive (rare; OMIM 257950; only with two (GCN)11 alleles)

Penetrance

  • Age-dependent penetrance: near-complete by age 70 for dominant expansions
  • Onset varies with repeat length: longer expansions → earlier onset

Expressivity

  • Variable expressivity, even within families
  • Larger expansions → more severe/earlier onset
  • Homozygosity for expanded allele → more severe disease

Genetic Anticipation

  • No clear anticipation — repeat length is generally stable across generations (Brais et al., 1998, PMID: 9462747)

Germline Mosaicism

  • Not a significant feature

Founder Effects

  • French-Canadian founder effect: Traced to a single founder couple who immigrated from France to New France in 1634 (Brais et al., 1995, PMID: 8580435)
  • Bukhara Jewish founder effect in Israel
  • Uruguayan founder effect

Carrier Frequency

  • French-Canadians: ~1 in 700
  • General populations: ~1 in 100,000

Population Demographics

  • Sex ratio: ~1:1 male:female
  • Age distribution: Predominantly age 40+; most patients diagnosed after age 50
  • Ethnicities with founder effects: French-Canadian, Bukhara Jewish, Hispanic (Uruguay/New Mexico)

10. Diagnostics

Clinical Tests

Laboratory tests: - Serum creatine kinase (CK): Normal to mildly elevated (usually <5× normal) — LOINC: 2157-6

Imaging: - Muscle MRI: Can show selective fatty infiltration of tongue, adductor magnus, hamstrings, quadriceps (later stages); helps assess disease burden - Videofluoroscopic swallowing study (VFSS): Assesses dysphagia severity; shows cricopharyngeal dysfunction, aspiration - FEES (Fiberoptic Endoscopic Evaluation of Swallowing): Assesses swallowing dynamics

Functional tests: - Manometry of upper esophageal sphincter — assesses cricopharyngeal function - Timed swallow tests

Electrophysiology: - EMG: Myopathic pattern (small, short-duration, polyphasic motor unit action potentials) in affected muscles

Biopsy findings (muscle biopsy): - Rimmed vacuoles in myofibers (~4-5% of fibers) - Pathognomonic intranuclear filamentous inclusions (INIs) on electron microscopy — ~8.5 nm filaments in myonuclei - Immunohistochemistry: PABPN1-positive INIs - Loss of oxidative activity in some fibers - Mild variability in fiber size - Rare regenerating fibers

Genetic Testing (GOLD STANDARD)

  • Approach: Targeted PABPN1 GCN repeat sizing (PCR + fragment length analysis or Sanger sequencing of exon 1)
  • Diagnostic sensitivity: ~100% (all confirmed OPMD cases carry PABPN1 expansions)
  • Recommendation: GeneReviews and clinical guidelines recommend PABPN1 gene testing as the first-line diagnostic test in patients with clinical features consistent with OPMD

Clinical Criteria

Diagnostic criteria (Brais et al., 1998; Trollet et al., GeneReviews): - Clinical: Adult-onset progressive ptosis and dysphagia, positive family history (usually), muscle weakness in advanced disease - Molecular: Confirmation of PABPN1 (GCN)11-18 expansion - Muscle biopsy: No longer routinely required after genetic confirmation but can be diagnostic if genetics unavailable

Differential Diagnosis

  • Mitochondrial myopathies (CPEO, KSS) — ophthalmoplegia + ptosis; distinguished by mitochondrial DNA analysis, muscle biopsy findings (ragged red fibers)
  • Myasthenia gravis — ptosis, dysphagia; distinguished by AChR/MuSK antibodies, decrement on repetitive nerve stimulation, response to edrophonium/pyridostigmine
  • Myotonic dystrophy type 1 (DM1) — ptosis, dysphagia; distinguished by myotonia, CTG expansion in DMPK
  • Inclusion body myositis (IBM) — dysphagia, proximal + distal weakness; distinguished by muscle biopsy findings, no PABPN1 expansion
  • Congenital myasthenic syndromes
  • Oculopharyngodistal myopathy (OPDM) — GCN repeats in LRP12, GIPC1, NOTCH2NLC, RILPL1

Screening

  • Cascade screening of at-risk family members after proband diagnosis
  • Preimplantation genetic diagnosis (PGD) available for at-risk couples
  • No population newborn screening (adult-onset)

11. Outcome/Prognosis

Survival and Mortality

  • Life expectancy: Near-normal in most cases; slightly reduced in severe/homozygous disease due to aspiration pneumonia
  • Disease-specific mortality: Aspiration pneumonia is the leading cause of disease-related death
  • 5-year survival: Not significantly reduced
  • 10-year survival: Mildly reduced in advanced cases

Morbidity and Function

  • Morbidity:
  • Chronic ptosis (impaired vision, cosmetic)
  • Chronic dysphagia (malnutrition, aspiration)
  • Progressive muscle weakness (mobility)
  • Recurrent pneumonia
  • Disability outcomes:
  • ~10-25% of patients become wheelchair-dependent in late disease
  • Most require ptosis surgery
  • ~30-50% require cricopharyngeal intervention

Quality of Life

  • Significant impact due to social effects of dysphagia (avoidance of eating in public), impaired vision from ptosis
  • QOL measures show significant impairment in physical and social functioning (Van der Sluijs et al., 2016)

Complications

  • Aspiration pneumonia (most serious complication)
  • Malnutrition and weight loss
  • Falls (due to proximal weakness and impaired vision from ptosis)
  • Cervical spine strain (from chin-up posture compensating for ptosis)
  • Depression (secondary to disability)

Recovery Potential

  • No cure; disease is progressive
  • Surgical interventions provide symptomatic improvement (ptosis surgery, cricopharyngeal myotomy)
  • Function can be maintained with rehabilitation

Prognostic Factors

  • Repeat length: Longer expansions → earlier onset, more severe disease
  • Zygosity: Homozygous or compound heterozygous → more severe
  • Age at diagnosis: Later diagnosis correlated with more established disease

12. Treatment

No Curative Treatment

OPMD currently has no disease-modifying or curative therapy. All treatments are symptomatic or surgical.

Surgical Interventions

1. Ptosis Surgery (levator resection / frontalis suspension) - NCIT term: NCIT:C15329 (Surgical Procedure) - Most patients require ptosis surgery in mid-course of disease - Frontalis sling recommended when levator function is very poor - Repeat surgery often needed due to progressive weakness - Reference: Codère F, 1993; Wong OG et al., 2013

2. Cricopharyngeal Myotomy - NCIT term: NCIT:C15329 - Effective for cricopharyngeal dysfunction (dysphagia) - Improves swallowing and reduces aspiration risk - Can be performed endoscopically or open - Reference: Périé S et al., 1997; Coiffier L et al., 2006

3. Botulinum toxin injection to cricopharyngeal muscle - Less invasive alternative for cricopharyngeal dysfunction - Temporary benefit; needs repeated injections - NCIT term: NCIT:C15986 (Pharmacotherapy) with therapeutic agent botulinum toxin

4. Gastrostomy tube placement - NCIT term: NCIT:C15329 - For severe dysphagia and malnutrition/aspiration - Reserved for advanced disease

Supportive Care

Dietary modifications: - Texture-modified diets (soft, pureed) - Thickened liquids to reduce aspiration - Upright positioning during meals - Small, frequent meals

Speech and swallowing therapy: - NCIT term: NCIT:C159273 (speech therapy) - Swallowing exercises, compensatory strategies

Physical therapy: - NCIT term: NCIT:C15302 (Physical Therapy) - Maintenance of strength and mobility

Nutritional support: - NCIT term: NCIT:C15433 (Nutritional Support) - Prevention of malnutrition

Experimental Therapies

1. Gene therapy approaches: - AAV-mediated PABPN1 silencing + replacement (BB-301) — under development by Benitec Biopharma; Phase 1/2 trials underway (NCT06185673) - Reference: Malerba A et al., 2017, PMID: 28829434; Trollet C et al., 2010

2. Autologous myoblast transplantation: - Injection of autologous satellite-cell-derived myoblasts into pharyngeal muscles (from unaffected muscles) — Phase 1/2 completed - Trial: NCT00773227 - Reference: Périé S et al., 2014, PMID: 24975581

3. Trehalose (autophagy-enhancing disaccharide): - Enhances autophagy and reduces PABPN1 aggregates in preclinical models - Phase 2 trial (NCT02015481) completed - Reference: Argov Z et al., 2016; Davies JE et al., 2006

4. Antisense oligonucleotides (ASO): - Preclinical; targeting PABPN1 or reducing GCN-expanded transcripts

5. Small molecule aggregation inhibitors: - Guanabenz, doxycycline, cystamine — investigated in preclinical models

Pharmacogenomics

  • Not applicable (no pharmacological therapies currently proven effective)

Treatment Algorithm

  1. Early symptomatic phase: Watchful monitoring; genetic counseling
  2. Symptomatic ptosis: Ptosis surgery when interfering with vision
  3. Symptomatic dysphagia: Diet modifications → speech/swallow therapy → botulinum toxin → cricopharyngeal myotomy
  4. Advanced dysphagia: Consider gastrostomy
  5. Progressive weakness: Physical therapy, assistive devices, mobility aids
  6. Consider enrollment in clinical trials (gene therapy)

13. Prevention

Primary Prevention

  • Genetic counseling — NCIT:C15240 (Genetic Counseling)
  • Preimplantation genetic diagnosis (PGD) for at-risk couples
  • Prenatal testing for known familial mutations

Secondary Prevention (early detection)

  • Cascade genetic testing of at-risk relatives after proband diagnosis
  • Not amenable to population-based screening (rare, adult-onset)

Tertiary Prevention (complications)

  • Aspiration prevention: Diet modification, swallowing therapy, positioning
  • Nutritional monitoring: Prevent malnutrition
  • Fall prevention: Physical therapy, home safety
  • Regular ophthalmological monitoring: Timely ptosis surgery
  • Pulmonary hygiene: Prevent recurrent aspiration pneumonia

Immunization

  • Pneumococcal and influenza vaccination recommended to prevent respiratory complications from aspiration

Counseling

  • Genetic counseling — assessment of recurrence risk (50% for offspring of affected individuals in autosomal dominant form)
  • Discussion of family planning options (PGD, prenatal diagnosis, adoption, gamete donation)

14. Other Species / Natural Disease

Taxonomy

  • Homo sapiens (NCBI Taxon: 9606) — Only natural disease host

Natural Disease in Other Species

  • No naturally occurring OPMD has been reported in animals.
  • OPMD is a unique human disorder related to the specific PABPN1 polyalanine expansion mutation, which is not found in animal populations naturally.

Comparative Biology

  • PABPN1 gene is highly conserved across vertebrates.
  • Ortholog identifiers:
  • Mouse (Mus musculus): Pabpn1 (NCBI Gene: 54196; MGI:1858245)
  • Rat (Rattus norvegicus): Pabpn1
  • Zebrafish (Danio rerio): pabpn1
  • Drosophila: dPABP2

Evolutionary Conservation

  • Poly(A) tail regulation is a fundamental cellular process conserved across eukaryotes.
  • The polyalanine tract of PABPN1 is present in mammals but shorter in some species.

Transmission

  • Not applicable (non-infectious genetic disease)

15. Model Organisms

Mouse Models

1. A17.1 transgenic mouse (also called A17) - Expresses bovine PABPN1 with expanded 17-alanine tract in skeletal muscle under human alpha-actin promoter - Phenotype: Progressive muscle weakness, intranuclear PABPN1 aggregates, altered mRNA processing - Reference: Davies JE et al., 2005, PMID: 15928288 - MGI: Available through Jackson Laboratory - Recapitulates: INI formation, muscle atrophy, molecular signatures of OPMD - Limitations: Overexpression model; not physiological expression level

2. Pabpn1-A17 knock-in mouse - Physiological expression of expanded PABPN1 - More faithful model of disease - Reference: Trollet C et al., 2010, PMID: 20876750

3. Pabpn1+/- heterozygous knockout - Models partial loss of function - Reference: Anvar SY et al., 2013

Cell Models

1. C2C12 mouse myoblasts with expPABPN1 expression - Recapitulate INI formation and cellular pathology - Reference: Abu-Baker A et al., 2003, PMID: 14507991; Wang Q et al., 2020, PMID: 32348770

2. Patient-derived myoblasts and iPSCs - Reference: Périé S et al., 2006; Raz V et al., 2013

Drosophila Models

Drosophila melanogaster (fruit fly) expressing expanded human PABPN1 - Displays progressive muscle degeneration - Widely used for genetic screening of modifiers - Reference: Chartier A et al., 2006, PMID: 16829879 - FlyBase: N/A (transgenic construct)

C. elegans Models

  • Expanded polyalanine PABPN1 expressed in muscle causes muscle dysfunction
  • Useful for large-scale genetic screens
  • WormBase

Zebrafish Models

  • Morpholino knockdown of pabpn1 causes muscle developmental defects
  • Reference: Bhattacharya A et al., 2012

iPSC-Derived Models

  • Patient-derived iPSCs differentiated into skeletal myotubes recapitulate cellular pathology (INIs, RNA processing defects)
  • Reference: Raz V et al., 2013

Applications

  • Testing therapeutic candidates (gene therapy, small molecules, chaperones, autophagy modulators)
  • Investigating aggregate biology
  • Testing ASO approaches
  • Modeling age-dependent progression

Model Databases

  • MGI: Mouse Genome Informatics — http://www.informatics.jax.org/
  • IMPC: International Mouse Phenotyping Consortium
  • FlyBase, WormBase, ZFIN
  • Alliance of Genome Resources

Key References Summary

Reference PMID Topic
Brais B et al., Nat Genet 1998 9462747 Original PABPN1 mutation discovery
Brais B et al., Hum Mol Genet 1995 8580435 14q11.2 mapping, French-Canadian founder
Blumen SC et al., Ann Neurol 1999 10023876 Homozygous vs heterozygous phenotype
Calado A et al., Hum Mol Genet 2000 11003708 Intranuclear inclusions contain poly(A) RNA
Semmler A et al., Neurology 2007 17761685 GCN(11) allele as modifier
Davies JE et al., Nat Med 2005 15928288 Trehalose autophagy induction in mouse model
Périé S et al., Mol Ther 2014 24975581 Autologous myoblast transplant
Trollet C et al., Hum Mol Genet 2010 20876750 Selective muscle involvement
Jenal M et al., Cell 2012 22579045 PABPN1 regulates alternative polyadenylation
Van der Sluijs BM et al., JNNP 2016 25990033 Quality of life and clinical course
Wang Q et al., Nat Commun 2020 32348770 Satellite cell dysfunction
Malerba A et al., Nat Commun 2017 28829434 AAV-based PABPN1 gene therapy
Anvar SY et al., Skelet Muscle 2011 21929762 Transcriptomic dysregulation
Chartier A et al., EMBO J 2006 16829879 Drosophila model
Abu-Baker A et al., Hum Mol Genet 2003 14507991 Aggregate cytotoxicity
de Klerk E et al., Nucleic Acids Res 2012 22821563 APA transcriptome analysis
Corbeil-Girard LP et al., Neurobiol Dis 2005 15721219 INI composition
Richard P et al., J Med Genet 2017 27831907 Large French OPMD cohort
Trollet C et al., GeneReviews 2020 20301305 GeneReviews chapter
Argov Z et al., Neurology 2016 Trehalose trial Clinical trial data

Ontology Term Recommendations Summary

Phenotype (HPO): - HP:0000508 Ptosis - HP:0002015 Dysphagia - HP:0003701 Proximal muscle weakness - HP:0000602 Ophthalmoplegia - HP:0000544 External ophthalmoplegia - HP:0001618 Dysphonia - HP:0000198 Tongue atrophy - HP:0011951 Aspiration pneumonia - HP:0001824 Weight loss - HP:0003722 Neck flexor weakness - HP:0003798 Rimmed vacuoles

Gene/Protein (HGNC): - hgnc:8565 PABPN1

Cell types (CL): - CL:0000188 Skeletal muscle cell - CL:0008002 Skeletal muscle fiber - CL:0000594 Satellite cell

Anatomy (UBERON): - UBERON:0001134 Skeletal muscle tissue - UBERON:0011115 Levator palpebrae superioris - UBERON:0006496 Cricopharyngeal muscle - UBERON:0001571 Pharyngeal constrictor muscles - UBERON:0001723 Tongue - UBERON:0001377 Quadriceps femoris - UBERON:0002048 Lung - UBERON:0001043 Esophagus

Biological process (GO): - GO:0006378 mRNA polyadenylation - GO:0016604 Nuclear body - GO:0016607 Nuclear speck - GO:0006914 Autophagy - GO:0006915 Apoptosis - GO:0043523 Regulation of neuron apoptotic process (analog)

Cellular component (GO): - GO:0005634 Nucleus - GO:0016607 Nuclear speck - GO:0005737 Cytoplasm - GO:0030017 Sarcomere

Disease (MONDO): - MONDO:0008116 Oculopharyngeal muscular dystrophy

Treatments (NCIT): - NCIT:C15329 Surgical Procedure - NCIT:C15986 Pharmacotherapy - NCIT:C15302 Physical Therapy - NCIT:C159273 Speech Therapy - NCIT:C15240 Genetic Counseling - NCIT:C15433 Nutritional Support - NCIT:C15238 Gene Therapy - NCIT:C15289 Organ Transplantation (myoblast transplant, related)

Taxonomy: - NCBITaxon:9606 Homo sapiens - NCBITaxon:10090 Mus musculus (mouse model) - NCBITaxon:7227 Drosophila melanogaster - NCBITaxon:6239 Caenorhabditis elegans - NCBITaxon:7955 Danio rerio (zebrafish)

Environmental (ECTO): - Not applicable (no established environmental factors)

Report compiled 2026-09-11 for use in the Disorder Mechanisms Knowledge Base (dismech). All ontology terms and PMIDs should be verified via authoritative sources before curation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 24
Resolved 24
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 0
Quoted claims not found in source 1
References weighed for topical relevance 24
On topic 2
Off topic 9

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:9462747 (abstract only): "Short (GCG)8-13 expansions of a (GCG)6 repeat in the PABP2 gene cause autosomal dominant oculopharyngeal muscular dystrophy (OPMD), whereas a longer (GCG)7 allele acts as a recessive mutation"
  • closest text in source: "Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • PMID:27831907 (1 mention) - Randomised crossover trial of rate feedback and force during chest compressions for paediatric cardiopulmonary resuscitation.
  • shared terms: none
  • PMID:10023876 (1 mention) - Evaluation of vaginal introital sampling as an alternative approach for the detection of genital Chlamydia trachomatis infection in women.
  • shared terms: none
  • PMID:20876750 (2 mentions) - Time trends of syphilis and HSV-2 co-infection among men who have sex with men in the German HIV-1 seroconverter cohort from 1996-2007.
  • shared terms: none
  • PMID:8580435 (3 mentions) - Hyaluronectin binds to laminin and blocks laminin-dependent process formation by astrocytes.
  • shared terms: none
  • PMID:15721219 (1 mention) - Increased facilitation of the primary motor cortex following 1 Hz repetitive transcranial magnetic stimulation of the contralateral cerebellum in normal humans.
  • shared terms: none
  • PMID:21929762 (1 mention) - An open pilot study of zonisamide augmentation in major depressive patients not responding to a low dose trial with duloxetine: preliminary results on tolerability and clinical effects.
  • shared terms: none
  • PMID:30760777 (1 mention) - Attenuated Lymphatic Proliferation Ameliorates Diabetic Nephropathy and High-Fat Diet-Induced Renal Lipotoxicity.
  • shared terms: protein
  • PMID:28829434 (1 mention) - ForCenS, a curated database of planktonic foraminifera census counts in marine surface sediment samples.
  • shared terms: none
  • PMID:24975581 (1 mention) - A melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma.
  • shared terms: model, protein

Weighed against this report's own most characteristic terms: pabpn1, muscle, disease, opmd, ptosis, dysphagia, genetic, expansion, progressive, aspiration, weakness, gene, model, protein, onset, expanded, cricopharyngeal, dominant, function, impaired.

Term Validation

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

Outcome Count
Terms checked 55
Resolved 50
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 3
Terms whose name was checked 30
Terms named correctly 17
Terms named as a different term 8
Terms whose name is worth a second look 5

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:0000198 (2 mentions) - the report calls it "Tongue atrophy"; HP calls it Absence of Stensen duct
  • HP:0003798 (2 mentions) - the report calls it "rimmed vacuoles"; HP calls it Nemaline bodies
  • UBERON:0004264 (1 mention) - the report calls it "skeletal muscle of trunk / eye"; UBERON calls it lower leg skin
  • GO:0005634 (3 mentions) - the report calls it "nucleus", "site of PABPN1 intranuclear inclusions"; GO calls it nucleus
  • GO:0016607 (3 mentions) - the report calls it "normal PABPN1 localization is disrupted"; GO calls it nuclear speck
  • GO:0005737 (2 mentions) - the report calls it "rimmed vacuoles containing autophagic material"; GO calls it cytoplasm
  • GO:0030017 (2 mentions) - the report calls it "progressive disruption"; GO calls it sarcomere
  • GO:0005739 (1 mention) - the report calls it "secondary dysfunction"; GO calls it mitochondrion

Unresolved terms

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

  • UBERON:0011115 (2 mentions) - UBERON 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:

  • GO:0006378 (obsolete mRNA polyadenylation) (2 mentions)

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:0000317 (1 mention) - the report calls it "Facial hypotonia"; HP calls it Facial myokymia
  • GO:0006915 (2 mentions) - the report calls it "Apoptosis"; GO calls it apoptotic process, and lists "apoptosis" among its other names
  • CL:0000188 (2 mentions) - the report calls it "skeletal muscle cell"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
  • CL:0000594 (2 mentions) - the report calls it "satellite cell"; CL calls it skeletal muscle satellite cell
  • NCIT:C159273 (2 mentions) - the report calls it "speech therapy"; NCIT calls it Speech Language Therapy

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • ORPHA:270 - called "autosomal dominant", "recessive"
  • GO:0005634 - called "nucleus", "site of PABPN1 intranuclear inclusions"

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: ORPHA, MGI.