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Oculopharyngeal Muscular Dystrophy

Synonym: OPMD

, PhD, , MD, PhD, , MSc, , MD, PhD, , PhD, and , MD.

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Initial Posting: ; Last Update: February 20, 2014.

Estimated reading time: 29 minutes


Clinical characteristics.

Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and swallowing difficulties due to selective involvement of the muscles of the eyelid and pharynx, respectively. The mean age of onset of ptosis is usually 48 years and onset of dysphagia is 50 years. Early symptoms of dysphagia are increased time needed to consume a meal and an acquired avoidance of dry foods. Swallowing difficulties determine prognosis, and increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition. Other signs observed as the disease progresses are tongue weakness (82%), proximal lower-extremity weakness (71%), wet voice due to pooling of saliva (67%), limitation of upward gaze (61%), facial muscle weakness (43%), and proximal upper extremity weakness (38%). Involvement of the nervous system occurs on occasion. Severe OPMD, representing 5% to 10% of all OPMD, is characterized by onset of ptosis and dysphagia before age 45 years and incapacitating proximal leg weakness that starts before age 60 years. Some individuals with severe involvement eventually need a wheelchair.


OPMD is suspected based on clinical criteria; the diagnosis is confirmed by molecular genetic testing of PABPN1. Ptosis is defined as vertical separation of at least one palpebral fissure that measures less than 8 mm at rest. Dysphagia is determined by physical examination, a videoendoscopic swallowing study (VESS), videofluoroscopic swallowing study (VFSS), and a swallowing time greater than seven seconds when drinking 80 mL of ice-cold water. Confirmatory diagnosis depends on detection of an expansion of a GCN trinucleotide repeat in the first exon of PABPN1. Normal alleles contain ten GCN trinucleotide repeats. Autosomal dominant alleles range in size from 12 to 17 GCN repeats; autosomal recessive alleles comprise 11 GCN repeats. Muscle biopsy is warranted only in individuals with suspected OPMD who have two normal PABPN1 alleles.


Treatment of manifestations: Treatment for ptosis may include blepharoplasty by either resection of the levator palpebrea aponeurosis or frontal suspension of the eyelids. The common treatment for dysphagia is cricopharyngeal myotomy. However, despite the high rate of immediate improvement in swallowing with relief of dysphagia, in a very high proportion of patients progressive dysphagia recurs in the next few years.

Prevention of secondary complications: To reduce the risk for the most common complications of OPMD (aspiration pneumonia, weight loss, and social withdrawal) the following are recommended: annual flu vaccination for the elderly; prompt evaluation of a productive cough; dietary supplements as needed to maintain weight gain; and when socializing with others, diet restricted to foods that are easily swallowed.

Surveillance: The frequency of follow-up neurologic evaluations depends on the degree of ptosis, dysphagia, and muscle weakness; routine ophthalmologic evaluation to monitor degree of ptosis and need for surgical intervention; routine reevaluation for functional signs of dysphagia through videoscopy and fiberoscopy.

Genetic counseling.

OPMD is inherited in either an autosomal dominant (AD) or an autosomal recessive (AR) manner.

  • AD OPMD. The proportion of OPMD caused by a de novo pathogenic variant is unknown, but appears to be small. Each child of an individual with AD OPMD (i.e., who is heterozygous for one expanded allele in the normal range [GCN 12-17]) has a 50% chance of inheriting the expanded allele and being affected.
  • AR OPMD. Each sib of an affected individual has 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. The offspring of an individual with AR OPMD are obligate heterozygotes (carriers) for a mutated allele causing OPMD; their risk of being affected is less than 1%.

Prenatal testing for pregnancies at increased risk for autosomal dominant or autosomal recessive OPMD is technically possible if the expanded PABPN1 GCN repeat has been identified in an affected family member. However, requests for prenatal testing for adult-onset conditions that do not affect intellect or life span and result in relatively mild physical limitations are not common.


Clinical Criteria

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD). The following three criteria are required for a diagnosis of autosomal dominant OPMD:

  • A positive family history with involvement of two or more generations
  • The presence of ptosis defined as EITHER vertical separation of at least one palpebral fissure that measures less than 8 mm at rest OR previous corrective surgery for ptosis
  • The presence of dysphagia, defined as a swallowing time greater than seven seconds when drinking 80 mL of ice-cold water [Bouchard et al 1992]. A videoendoscopic swallowing study (VESS) and videofluoroscopic swallowing study (VFSS) are essential to document the dysfunction of the pharyngeal muscles and upper esophageal sphincter (UES) [Dodds et al 1990, Langmore et al 1991, St Guily et al 1995, Périé et al 1998].

Autosomal recessive OPMD

Molecular Genetic Testing

Molecular genetic testing of PABPN1 is used to confirm the diagnosis in individuals known or suspected to have OPMD (see Figure 1). A pathogenic variant is defined as a larger than normal "GCN" trinucleotide repeat in the first exon of PABPN1 (previously called PABP2) [Brais et al 1998] (Table 1).

Figure 1.

Figure 1.

Diagnostic evaluation of dysphagia and ptosis

Note: Because four different codons ‒ GCA, GCT, GCC, and GCG ‒ encode the amino acid alanine, GCN, where N represents any A/C/G/T nucleotide, is a generic designation for these four possible codons. A recent European Neuromuscular Center (ENMC) workshop on OPMD [Raz et al 2013] suggested the following nomenclature for number of triplet repeats/number of alanine of PABPN1 variants:

  • Normal allele: (GCN)10 / Ala10
  • Pathogenic alleles: (GCN)11-17 and Ala11–17, where the range of triplet repeats/alanines is 11-17

When available, the full sequence of normal and pathogenic alleles should be reported; for example, an Ala13 allele may have a sequence of (GCG)10(GCA)(GCG)2.

The nomenclature of the Human Genome Variation Society for these alleles is summarized in Molecular Genetics.

Normal alleles have ten GCN repeats (GCN)10 (previously referred to as the (GCG)6 normal allele) encoding ten alanines (Ala10).

Note: PABPN1 variants were first described as pure (GCG) expansions of a (GCG)6 stretch coding for six alanines in the first exon [Brais et al 1998]. However, approximately 25% of these variants consist of (GCN) repeats [Nakamoto et al 2002], each encoding alanine.

Autosomal dominant alleles have 12 to 17 GCN repeats. In one study [Brais et al 1998], probands had allele frequencies of

  • 5% (GCN)12/Ala12
  • 40% (GCN)13/Ala13
  • 26% (GCN)14/Ala14
  • 21% (GCN)15/Ala15
  • 7% (GCN)16/Ala16
  • 1% (GCN)17/Ala17

Autosomal recessive alleles have 11 GCN repeats (GCN)11/Ala11 (i.e., previously referred to as (GCN)7). Autosomal recessive inheritance has only been observed in one instance in an individual homozygous for (GCN)11 alleles [Brais et al 1998].

Table 1.

Molecular Genetic Testing Used in Oculopharyngeal Muscular Dystrophy

Gene 1MethodPathogenic VariantProportion of Probands with a Pathogenic Variant Detectable by Method
PABPN1Targeted analysis for pathogenic variants 2Heterozygosity for (GCN)12-17>99%, autosomal dominant 3
Homozygosity for (GCN)11>99%, recessive 4

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants.


Testing to determine the size of the GCN trinucleotide repeat in the first exon of PABPN1 is more than 99% sensitive and 100% specific.


Growing evidence indicates that >99% of individuals with a severe autosomal dominant OPMD-like phenotype have a PABPN1 (GCN) expansion.


One case reported [Brais et al 1998]

Additional Testing

Muscle biopsy. Previously the diagnosis of OPMD was based on the presence of intranuclear inclusions (INI) on muscle biopsy; currently muscle biopsy is only warranted in individuals who have two normal PABPN1 alleles.

  • INI, considered a specific histologic hallmark of OPMD, consist of tubular filaments [Tomé & Fardeau 1980] that are up to 250 nm in length and have an external diameter of 8.5 nm and an internal diameter of 3 nm. Of the nuclei seen in every ultra-thin section of deltoid muscle by electron microscopy, 4%-5% contain INI [Tomé & Fardeau 1980]. With use of a different technique (KCl-pretreatment followed by PABPN1 immunostaining), the percentage of INI was recently estimated at between 2% and 15% of myonuclei in OPMD muscles [Gidaro et al 2013].
  • To date, OPMD INI differ from other types of intranuclear inclusions described in other muscle disorders [Tomé & Fardeau 1980], such as the 15-18 nm filaments described in the nucleus and cytoplasm in individuals with sporadic inclusion body myositis (IBM) [Coquet et al 1990].

Besides the INI, all biopsies from clinically affected or unaffected OPMD muscles show dystrophic changes: variation in the diameter of muscle fibers, atrophic angulated muscle fibers, ragged red fibers, and rimmed vacuoles [Tomé & Fardeau 1994, Gidaro et al 2013]. Note that although the presence of rimmed vacuoles may be useful for diagnosis of OPMD, they are not present in all OPMD muscle biopsies [Fukuhara et al 1980]; nor are rimmed vacuoles specific for OPMD: they have been consistently found in several other muscular diseases; for example, in IBM [Askanas & Engel 1995], where they are much more numerous than in OPMD [Leclerc et al 1993].

Electromyography (EMG) of weak muscles usually reveals discrete signs of a myopathic process [Bouchard et al 1997]. Very mild neuropathic findings have been reported, but are thought to be related in most cases to old age or concomitant disease. EMG is not necessary for OPMD diagnosis because it is clinically nonspecific.

Serum CK concentrations elevated two to seven times above the normal value have been reported in individuals with OPMD with severe leg weakness [Barbeau 1996]. In most cases, however, serum CK concentration is normal or up to twice the upper normal value. CK level is not relevant for the diagnosis or follow up of persons with OPMD.

Clinical Characteristics

Clinical Description

Oculopharyngeal muscular dystrophy (OPMD) is characterized by late-onset involvement of small distinct muscles of the eyelid (levator palpebrae superioris muscle) causing ptosis and of the pharynx causing dysphagia. Ptosis and dysphagia usually become manifest around the fifth decade. Disease progression is slow.

Ptosis is always bilateral, but may be asymmetric, at least in the early stage of disease [Brais 2003]. Individuals with severe bilateral ptosis may compensate for visual field limitation with “astrologist’s posture,” retroflexion of the neck and downward gaze combined with contraction of the frontalis muscles [Rüegg et al 2005].

Dysphagia is detected first for solid foods, later also for liquids. The degenerative dystrophy and progressive onset of fibrosis in the pharyngeal muscles create difficulties in propulsing the food bolus in the pharynx. This together with a decreased relaxation of the cricopharyngeal muscle (the main muscle of the upper esophageal sphincter (UES) located between the pharynx and the esophagus) result in a delay in the transfer of the bolus through the UES.

Of note, while in the past dysphagia resulted in poor nutrition that usually caused death by starvation, recent progress (especially in the treatment of pharyngeal dysfunction) has improved the quality of life for persons with OPMD.

Extraocular muscles may become gradually affected but complete external ophthalmoplegia is rare [Tomé & Fardeau 1994].

Weakness and atrophy can occur in limb girdle muscles (shoulder girdle muscles more than pelvic girdle muscles). Limb muscle involvement is symmetric and nonselective.

Distal muscle weakness has been described in a Japanese family [Goto et al 1977, Satoyoshi & Kinoshita 1977] and in other ethnic groups [Jaspar et al 1977, Scrimgeour & Mastaglia 1984]; however, distal muscle involvement has not been associated with typical OPMD [Schotland & Rowland 1964, Vita et al 1983].

Although OPMD is considered a primary muscle disorder, in rare instances peripheral nervous system involvement has been described. The first of such reported cases presented a severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles pointing to neurogenic changes in these muscles and suggesting nerve involvement [Probst et al 1982, Schober et al 2001]. Other cases have also shown central nervous system involvement [Linoli et al 1991]. Dubbioso et al [2012] described an individual with central nervous system involvement with impaired executive functions.

Autosomal dominant OPMD. The age of onset of autosomal dominant OPMD varies and is often difficult to pinpoint. In a study of 72 symptomatic individuals of French-Canadian ancestry with a (GCN)13 pathogenic variant, the mean age of onset for ptosis was 48.1 years (range 26-65 years) and for dysphagia, 50.7 years (range 40-63 years).

Early symptoms suggestive of dysphagia caused by OPMD are increased time needed to consume a meal and an acquired avoidance of dry foods. Other signs observed as the disease progresses are tongue atrophy and weakness (82%), proximal lower-extremity weakness (71%), wet voice due to pooling of saliva (67%), limitation of upward gaze (61%), facial muscle weakness (43%), and proximal upper-extremity weakness (38%) [Bouchard et al 1997].

Disease severity varies. Severe disease, representing 5% to 10% of all OPMD, is characterized by onset of ptosis and dysphagia before age 45 years; incapacitating proximal leg weakness starts before age 60 years. Some eventually need a wheelchair.

Although OPMD does not appear to reduce life span, quality of life in later years is greatly diminished [Becher et al 2001]. Of note, the severity of dysphagia determines the prognosis, as it leads to potentially life-threatening aspiration pneumonia and poor nutrition.

Autosomal recessive OPMD. Ptosis and dysphagia occur after age 60 years. Some evidence suggests that heterozygous carriers of the recessive (GCG)7 allele may be at higher risk of developing dysphagia after age 70 years.

Genotype-Phenotype Correlations

The variability of age of onset and severity of weakness may depend on the number of (GCN) repeats; this important issue is as yet unresolved.

Severe autosomal dominant OPMD. Of the 5% to 10% of all individuals with autosomal dominant OPMD who have severe disease:

  • 20% are compound heterozygotes for an autosomal dominant pathogenic allele in the (GCN)12-17 range and an autosomal recessive allele of (GCN)11 [Brais et al 1998]. While (GCN)11 homozygosity is known to lead to autosomal recessive OMPD, in this scenario it acts as a severity modifier of a dominant OMPD phenotype, presumably because more mutated proteins are produced. The (GCN)11 carrier frequency is 1% to 2% of North American, European, and Japanese populations.
  • In 80% the reason for the increased disease severity is unknown. Of note, severely affected individuals cluster in families, a phenomenon suggesting that other genetic factors modulate severity.

Homozygous autosomal dominant OPMD. The most severe OPMD presentation is reported in individuals who are homozygous for an autosomal dominant OPMD pathogenic variant [Blumen et al 1996, Brais et al 1998, Blumen et al 1999]. A study of four French-Canadian and three Bukhara Jewish OPMD homozygotes documented that on average the onset was 18 years earlier than in (GCN)13 heterozygotes.

Autosomal recessive OPMD (i.e., caused by homozygosity for (GCN)11 alleles) has a later onset and milder disease than autosomal dominant OPMD.


Decade-specific cumulative penetrance for individuals with an autosomal dominant (GCN)13 pathogenic variant [Brais et al 1997]:

  • Age <40 years: 1%
  • Age 40-49 years: 6%
  • Age 50-59 years: 31%
  • Age 60-69 years: 63%
  • Age >69 years: 99%

Thus, autosomal dominant OPMD resulting from (GCN)13 heterozygosity is fully penetrant after age 70 years.


The GCN/alanine triplet repeat in PABPN1 is mitotically and meiotically stable. Therefore, expansion of the triplet repeat in meiosis is rare. Clinical anticipation is not observed with this disease. The estimated secondary mutation of an existent dominant pathogenic variant is on the order of 1:500 meioses [Brais et al 1998].


Autosomal dominant. The prevalence of OPMD has been estimated at 1:100,000 in France, 1:1000 in the French-Canadian population of the province of Quebec, and 1:600 among Bukhara Jews living in Israel [Brais et al 1995, Blumen et al 1997, Brunet et al 1997]. In the United States, the majority of affected individuals are of French-Canadian extraction, though a large number are also of other backgrounds, including Jewish Ashkenazi [Victor et al 1962] and Spanish American in Texas [Becher et al 2001] and California [Grewal et al 1999].

Autosomal dominant OPMD has been identified in individuals from more than 30 countries.

Autosomal recessive. The predicted prevalence of the autosomal recessive form should be in the order of 1:10,000 in France, Quebec, and Japan based on the carrier frequency of the (GCN)11 autosomal recessive pathogenic variant in these populations [Brais et al 1998].

Differential Diagnosis

The differential diagnosis should include all late-onset neuromuscular diseases characterized by swallowing difficulties and/or ptosis (see Figure 1):

Oculopharyngodistal myopathy (OMIM 164310) is still a poorly characterized condition in which dysphagia, ptosis, and distal weakness appear earlier in the twenties than in OPMD. The mode of transmission is still unclear; both dominant and recessive modes have been proposed. Pathologically, no intranuclear inclusions are observed and no PABPN1 (GCN) pathogenic variants are observed [van der Sluijs et al 2004].


Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with oculopharyngeal muscular dystrophy (OPMD), the following evaluations are recommended:

  • Evaluation for swallowing difficulties by history and in more severe cases with a videoendoscopic swallowing study (VESS) and/or videofluoroscopic swallowing study (VFSS) [Dodds et al 1990, Langmore et al 1991, St Guily et al 1995, Périé et al 1998].
    • VESS gives indirect signs of upper esophageal sphincter (UES) dysfunction
    • VFSS gives a direct evaluation of the UES using radiopaque barite in the tracheobronchial tree
    • The drink test, a global quantitative functional evaluation of swallowing, is abnormal when it takes longer than seven seconds to drink 80 mL of ice-cold water [Bouchard et al 1992, Brais et al 1995]. Questionnaires can also be used to evaluate the degree of dysphagia (i.e., the Mc Horney score [McHorney et al 2002] and the Salassa grade [Salassa 1999].
  • Neuromuscular examination performed by a neurologist to determine overall disease progression and the presence (and severity) of ptosis, dysphagia, proximal weakness, and the presence or absence of any other neurologic findings
  • Consideration of muscle biopsy in those cases with more severe or complicated presentations
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations


Surgery is recommended when ptosis interferes with vision or appears to cause cervical pain secondary to constant dorsiflexion of the neck. The two types of blepharoplasty used to correct the ptosis are resection of the levator palpebrae aponeurosis and frontal suspension of the eyelids [Codère 1993].

  • Resection of the aponeurosis is easily done, but usually needs to be repeated once or twice [Rodrigue & Molgat 1997].
  • Frontal suspension of the eyelids uses a thread of muscle fascia as a sling; the fascia is inserted through the tarsal plate of the upper eyelid and the ends are attached in the frontalis muscle, which is relatively preserved in OPMD [Codère 1993]. The major advantage of frontal suspension of the eyelids is that it is permanent; however, the procedure requires general anesthesia.


Prevention of Secondary Complications

The major complications of OPMD are aspiration pneumonia, weight loss, and social withdrawal because of frequent choking while eating. To reduce the risk for these complications:

  • Annual flu vaccination is recommended for elderly affected individuals
  • Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses.
  • Dietary supplements should be added if weight loss is significant.
  • In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow.

General anesthesia is not contraindicated even though individuals with OPMD may respond differently to certain anesthetics [Caron et al 2005].


The frequency of follow-up neurologic evaluations depends on the degree of ptosis, dysphagia, and muscle weakness.

Perform routine ophthalmologic evaluation o determine if ptosis interferes with driving or is associated with neck pain, and or if the eyelids cover more than 50% of the pupil, findings that might lead to consideration of surgical intervention.

Perform routine reevaluation for functional signs of dysphagia using videoscopy and fiberoscopy.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Repetitive dilatations of the upper-esophageal sphincter with bougies [Mathieu et al 1997, Manjaly et al 2012] and botulinum toxin injection of the cricopharyngeal muscle [Restivo et al 2000] have been suggested as treatment for dysphagia.

An autologous cell transplantation clinical Phase I/IIa study ( NCT00773227) has also been recently described [Périé et al 2014]. The trial was based on the observation that cells isolated from unaffected muscles of persons with OPMD are able to proliferate and differentiate normally, whereas cells isolated from affected muscles have reduced myogenicity (ability to proliferate and differentiate normally) [Périé et al 2006]. The therapeutic strategy is to isolate muscle progenitors (myoblasts) from clinically unaffected muscles of persons with OPMD and implant them into dystrophic pharyngeal muscles to reinforce their motor ability and restore contractility and, thus, reduce the dysphagia. The conclusions of this trial on 12 patients with OPMD support the hypothesis that an injection of autologous myoblasts into pharyngeal muscles is a safe and efficient procedure [Périé et al 2014].

In cellular models of OPMD, investigators have reduced cellular toxicity by inducing heat shock protein expression using ZnSO4, 8-hydroxyquinoline, ibuprofen, and indomethacin [Wang et al 2005] or exposing cells to an anti-PABPN1 single-domain antibody called intrabody that interferes with oligomerization [Verheesen et al 2006]. These intrabodies also reduced intranuclear inclusion (INI) formation and symptoms related to OPMD in a drosophila OPMD model [Chartier et al 2009].

More recently, investigators have tested molecules that interfere with the Wnt/beta-catenin pathway such as lithium chloride [Abu-Baker et al 2013].

In a transgenic mouse model of OPMD, investigators have reduced inclusion formation and cell death with agents that interfere with protein aggregation such as doxycycline [Davies et al 2005] and trehalose [Davies et al 2006].These studies suggest that therapeutic trials in OPMD are possible given that some of the tested molecules have already been given to humans.

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Oculopharyngeal muscular dystrophy is inherited in either an autosomal dominant or an autosomal recessive manner.

Autosomal Dominant OPMD – Risk to Family Members

Parents of a proband

Note: Although most individuals diagnosed with OPMD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the status of the parents.
  • If a parent of the proband has an expanded (GCN) allele, the risk to the sibs of inheriting the expanded allele is 50%.

Offspring of a proband

  • Heterozygotes. Each child of an individual heterozygous for one expanded allele (GCN)12-17 has a 50% chance of inheriting the expanded allele.
  • Homozygotes. A few individuals (French-Canadians and members of the inbred population of Bukhara Jews living in Israel [Blumen et al 1999]) who are homozygous for the expanded alleles (GCN)13 have been described. All offspring of such an individual are heterozygous for the expanded allele.

Other family members of the proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, the proband's family members are at risk.

Autosomal Recessive OPMD

Risk to Family Members

One individual homozygous for the (GCN)11 allele has been reported [Brais et al 1998]. This individual has been referred to as having autosomal recessive OPMD. Because the (GCN)11 allele has a 1% to 2% prevalence, other persons who are homozygous for this allele with a mild OPMD phenotype may be unrecognized because of a negative family history.

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one expanded allele.
  • Heterozygotes (carriers) are usually asymptomatic.
  • Parents of individuals with autosomal recessive OPMD are unlikely to be alive at the time of diagnosis of their child and should not have been affected.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are usually asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive OPMD are obligate heterozygotes (carriers) for an expanded allele causing autosomal recessive OPMD. The risk of the child being affected is less than 1%.

Other family members of a proband. Sibs of the proband's parents are at 50% risk of also being carriers.

Carrier (Heterozygote) Detection

Carrier testing is possible once the diagnosis has been established in the proband by molecular genetic testing. See Molecular Genetic Testing.

Related Genetic Counseling Issues

Specific risk issues. Individuals inheriting an autosomal dominant expanded allele from an affected parent and an autosomal recessive expanded allele [(GCN)11] from the other parent will develop a severe form of OPMD (see Genotype-Phenotype Correlations).

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Testing of at-risk asymptomatic adults for OPMD is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for OPMD, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Genetic testing is indicated in affected or symptomatic individuals in a family with established OPMD regardless of age.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for OPMD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
  • Muscular Dystrophy Association - Canada
    2345 Yonge Street
    Suite 900
    Toronto Ontario M4P 2E5
    Phone: 866-687-2538 (toll-free); 416-488-0030
    Fax: 416-488-7523
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
  • Oculopharyngeal Muscular Dystrophy (OPMD) National Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Oculopharyngeal Muscular Dystrophy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Oculopharyngeal Muscular Dystrophy (View All in OMIM)


Gene structure. PABPN1 has seven exons. The role of the two long introns preserved in many of its mRNAs is unknown. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Normal PABPN1 alleles have (GCN)10 encoding Ala10 residues.

Note on nomenclature: This GeneReview follows the nomenclature recommended by the European Neuromuscular Center (ENMC) workshop on OPMD [Raz et al 2013, Human Genome Variation Society].

Pathogenic variants. See Molecular Genetic Testing. The OPMD pathogenic alleles have an expanded (GCN) sequence that immediately follows the start codon ATG. As in other disorders caused by (CAG)/polyglutamine expansion, it is the absolute size of the domain that is the size of the pathogenic variant and not the size of the added expansions. It is not known for certain if the mutation mechanism is expansion of the GCN repeat through slippage or insertion of additional (GCN)s through unequal recombination or gene conversion events [Chen et al 2005].

Normal gene product. PABPN1 protein has at least the following six domains: polyalanine, coil-coiled, RNA binding, two oligomerization, and a nuclear localization signal (NLS) [Calado et al 2000, Fan et al 2001, Kühn et al 2003]. PABPN1 is an abundant nuclear protein of approsimately 49 kd that binds with high affinity to nascent poly(A) tails at the 3' end of mRNAs [Wahle et al 1993, Nemeth et al 1995]. The poly(A) tail is post-transcriptionally added to the mRNA by a number of trans-acting factors including PABPN1, the cleavage and polyadenylation specificity factor (CPSF), and the poly(A) polymerase (PAP) [Wahle & Rüegsegger 1999, Zhao et al 1999].

It was demonstrated that PABPN1 shuttles between nucleus and cytoplasm [Calado et al 2000] and plays a direct role in the export of poly(A) RNA from the nucleus [Apponi et al 2010]. PABPN1 is associated with RNA polymerase II during transcription and accompanies the released transcript though the nuclear pore [Bear et al 2003, Kerwitz et al 2003]. Nuclear export of PABPN1 is temperature sensitive, and depends on RNA binding and ongoing transcription. Nuclear import of PABPN1 is an active transportin-mediated process [Calado et al 2000].

Several PABPN1 binding partners have been identified to date, including the heterogeneous family members HNRPA/B, HNRPA1 [Fan et al 2003] and HNRPC [Calapez et al 2002]. By immunoprecipitation, PABPN1 was found to interact with proteins of the cap-binding complex (CBP80, CBP20, and EIF4G) and with proteins involved in mRNA decay (Upf2 and Upf3) [Ishigaki et al 2001]. PABPN1-interacting partners also include HSP40 (DNAJ) and BRG1 [Kim et al 2001]. Finally, PABPN1 has been shown to interact with SKIP and to stimulate muscle-specific gene expression when overexpressed [Kim et al 2001].

PABPN1 is also implicated in deadenylation via the CCR4-NOT complex that regulates translation of some transcripts [Chartier et al 2006].

Recently, using the A17.1 OPMD mouse model where mutated PABPN1 is overexpressed [de Klerk et al 2012] or RNAi to deplete PABPN1 in mammalian cells [Jenal et al 2012, Beaulieu et al 2012, Bresson & Conrad 2013], the following new functions of PABPN1 have been uncovered:

  • Involvement in the choice of alternative polyadenylation sites [de Klerk et al 2012, Jenal et al 2012]. It has been suggested that PABPN1 binds and masks proximal weak polyadenylation sites, competing with the recruitment of CPSF and enhancing the use of distal canonic polyadenylation sites. Such a shift in the cleavage/polyadenylation site is critical for regulation of gene expression (length of 3’UTR, miRNA target sites).
  • Control of lncRNA (long noncoding RNA) expression [Beaulieu et al 2012]. An RNAseq approach revealed stabilization of a proportion of lncRNA (16%) in cells depleted for PABPN1. This is a polyadenylation-dependent mechanism with PABPN1-sensitive lncRNAs targeted by the exosome and a RNA helicase.
  • mRNA decay [Bresson & Conrad 2013]. More precisely, the investigators revealed a new function for PABPN1 in a polyadenylation-dependent pathway of RNA decay that targets export-deficient mRNAs. Lastly, it has been suggested that PABPN1-dependent promotion of PAP activity can stimulate nuclear RNA decay.

Abnormal gene product. Various hypotheses of a polyalanine toxicity gain-of-function pathogenic mechanism have been proposed [Brais et al 1998, Brais et al 1999, Banerjee et al 2013]. Abnormal aggregation and inefficient protein degradation are some of the gain-of-function pathogenic mechanisms proposed [Brais 2003]. In these models, PABPN1 is thought to have a pathogenic expanded polyalanine domain with physical characteristics that cause it to accumulate and interfere with normal cellular processes. However, despite the growing number of studies exploring OPMD pathogenesis, the nature of the underlying pathologic mechanism has yet to be established. More generally, there are suggestions that in addition to having a gain-of-function toxic effect, OPMD aggregates could sequester RNA and proteins including PABPN1 essential for proper cellular function.

  • Accumulation/aggregation. It was proposed that when more than ten alanines (the normal number) are present in PABPN1, the polyalanine domains polymerize to form stable β-sheets that are resistant to nuclear proteosomal degradation. The polyalanine macromolecules grow over time to form the OPMD PABPN1-containing intranuclear filaments that are seen using electron microscopy [Tomé & Fardeau 1980, Tomé et al 1997, Calado et al 2000, Gidaro et al 2013].
    Various fusion proteins with long polyalanine domains accumulate as intranuclear inclusions (INI) [Gaspar et al 2000, Rankin et al 2000]. In one transfection experiment, a long 37-Ala-GFP fusion protein caused nuclear inclusion formation and cell death [Rankin et al 2000].
    Studies with agents that influence this aggregation have been explored and in most cases improve outcome in cellular and mice models of OPMD [Davies et al 2005, Wang et al 2005, Davies et al 2006, Verheesen et al 2006].
    These PABPN1 aggregates are a pathologic hallmark of the disease; however, their exact role in the pathology is still debated. The fact that nuclear aggregates are found in less than 20% of myofiber nuclei in affected and unaffected muscle sections of persons with OPMD [Tomé & Fardeau 1980, Tomé et al 1997, Calado et al 2000, Gidaro et al 2013] and that both wildtype and expanded PABPN1 proteins can form these aggregates suggest that the presence of PABPN1 aggregates per se may not be sufficient.
  • Inefficient protein degradation
    • Evidence suggesting that polyalanine oligomers form resistant macromolecules in vivo and in vitro includes the following:
      • Polyalanine oligomers are known to be resistant to protease digestion or chemical degradation [Forood et al 1995].
      • Polyalanine oligomers form a β-sheet structure in vitro [Forood et al 1995].
      • Polyalanine oligomers containing more than eight alanines in a row form fibrils spontaneously [Blondelle et al 1997].
        PABPN1 molecules in the intranuclear inclusions (INI) of OPMD muscle are more resistant to salt extraction than the protein dispersed in the nucleoplasm [Calado et al 2000].
    • In addition, a recent cross-species transcriptomic study using drosophila, mouse, and human samples identified deregulation of the ubiquitin-proteasome system (UPS) as the predominant molecular defect in OPMD [Anvar et al 2011].
  • Messenger RNA trapping is another proposed pathophysiologic hypothesis [Galvão et al 2001]. It has been shown that to aggregate and cause toxicity, PABPN1 has to enter the nuclei [Abu-Baker et al 2005]. Inclusion formation and PABPN1 inclusions have broad and significant impact on the expression of numerous genes, in particular ones that are involved in mRNA processing [Corbeil-Girard et al 2005].


Published Guidelines / Consensus Statements

  • Association française contre les myopathies. Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. 1995.
  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 8-29-19. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2018. Accessed 8-29-19.

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Chapter Notes

Author History

Bernard Brais, MD, MPhil, PhD; Hôpital Notre-Dame-CHUM, Montréal (2001-2014)
Gillian Butler-Browne, PhD (2014-present)
Teresa Gidaro, MD, PhD (2014-present)
Pierre Klein, MSc (2014-present)
Jean Lacau St Guily, MD (2014-present)
Sophie Périé, MD, PhD (2014-present)
Guy A Rouleau, MD, PhD; Hôpital Notre-Dame-CHUM, Montreal (2001-2014)
Capucine Trollet, PhD (2014-present)

Revision History

  • 20 February 2014 (me) Comprehensive update posted live
  • 22 June 2006 (ca) Comprehensive update posted live
  • 3 December 2003 (me) Comprehensive update posted live
  • 8 March 2001 (me) Review posted live
  • December 2000 (bb) Original submission
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