Clinical Diagnosis

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 swallowing time greater than seven seconds when drinking 80 mL of ice-cold water [Brais et al 1995]

Autosomal recessive OPMD. The symptoms and signs are the same as for autosomal dominant OPMD, but appear during the sixties, whereas they generally appear earlier in the autosomal dominant form (see Natural History). The family history is consistent with autosomal recessive inheritance (i.e., affected sibs without affected parents and/or parental consanguinity).

Testing

Muscle biopsy. Previously the diagnosis of OPMD was based on the presence of intranuclear inclusions (INI) on muscle biopsy; now muscle biopsy is only warranted in those individuals with normal results on molecular genetic testing. The OPMD intranuclear inclusions consist of tubular filaments [Tomé & Fardeau 1980]. The filaments 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, 4% to 5% contain intranuclear inclusions [Tomé & Fardeau 1980]. The percentage of nuclei with inclusions is thought to correlate mostly with the limited volume that they occupy [Tomé et al 1997]. Other non-specific pathologic findings include rimmed vacuoles and small angulated muscle fibers [Tomé et al 1997].

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.

Serum CK concentration elevated two to seven times the normal value has 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.

Molecular Genetic Testing

Gene. PABPN1 (previously called PABP2), encoding the polyadenylate binding protein nuclear 1, is the only gene in which mutation is known to cause OPMD.

The molecular diagnosis of autosomal dominant and autosomal recessive OPMD depends on detection of larger than normal "GCN" trinucleotide repeat in the first exon of PABPN1 [Brais et al 1998].

Note: Since all four codon combinations — GCA, GCT, GCC, and GCG — encode the amino acid alanine, the term "GCN" is the generic designation for any one of these four possible codons. In the designation of mutations, it is appropriate to either give the sequence of the mutation or more practically refer to the normal allele (GCN)₁₀ and the abnormal alleles (GCN)_11-17, which is reminiscent of the classification of mutations in other triplet expansion diseases.

• Normal alleles. Ten GCN repeats (GCN)₁₀ (previously referred to as the (GCG)₆ normal allele).

Note: The PABPN1 mutations were first described as pure (GCG) expansions of a (GCG)₆ stretch coding for six alanines in the first exon of the gene [Brais et al 1998]. However, it has become clear that approximately 25% of these mutations consist of (GCN) insertions or cryptic synonymous expansions [Nakamoto et al 2002] that do not modify the impact on the PABPN1 protein because all four (GCN) triplets code for alanine.

• Autosomal dominant alleles. Twelve to 17 GCN repeats (GCG)_12-17]. The percentage of families sharing the different mutations is [Brais et al 1998]:
  • 5% (GCG)₁₂
  • 40% (GCG)₁₃
  • 26% (GCG)₁₄
  • 21% (GCG)₁₅
  • 7% (GCG)₁₆
  • 1% (GCG)₁₇
• Autosomal recessive alleles. Eleven GCN repeats (GCN)₁₁ (i.e., previously referred to as (GCN)₇). Autosomal recessive inheritance has only been observed in one instance in an individual homozygous for two (GCN)₁₁ alleles [Brais et al 1998].

Clinical uses

• Diagnostic testing for autosomal and recessive OPMB
• Diagnostic testing for compound heteroyzygotes for dominant and recessive OPMD
• Presymptomatic testing (technically available although rarely performed)
• Prenatal diagnosis (technically available although rarely performed)

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Clinical testing

• Targeted mutation analysis. 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 more than 99% of individuals with a severe dominant OPMD-like phenotype have a PABPN1 (GCN) expansion.

Table 1. Summary of Molecular Genetic Testing Used in Oculopharyngeal Muscular Dystrophy

View in own window

Gene Symbol	Test Method	Mutation Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PABPN1	Targeted mutation analysis	Heterozygosity for (GCN)12-17	>99%, autosomal dominant	Clinical
		Homozygosity for (GCN)11	>99%, recessive 2

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. One case reported [Brais et al 1998]

Testing Strategy

Molecular genetic testing is used to confirm the diagnosis individuals known or suspected to have OPMD. Muscle biopsy is warranted only in individuals with suspected OPMD who have two normal PABPN1 alleles.

Genetically Related (Allelic) Disorders

No other diseases are known to be caused by mutations in PABPN1.

Natural History

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

Early symptoms that are suggestive of dysphagia caused by OPMD are an increased time needed to complete 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%), dysphonia (67%), limitation of upward gaze (61%), facial muscle weakness (43%), and proximal upper extremity weakness (38%) [Bouchard et al 1997].

Severity of the autosomal dominant OPMD phenotype is variable. Severe cases represent 5% to 10% of all cases. These individuals have earlier onset of ptosis and dysphagia (before the age of 45 years) and an incapacitating proximal leg weakness that starts before age 60 years. Some of these individuals eventually need a wheelchair. OPMD does not appear to reduce life span but quality of life in later years is greatly diminished [Becher et al 2001].

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

Genotype-Phenotype Correlations

The variability of age of onset and severity of weakness may depend on the size of the (GCN)_n mutations, but this important issue is still unresolved.

• Severe autosomal dominant OPMD. Twenty percent of individuals with more severe autosomal dominant OPMD have inherited an allele in the (GCN)_12-17 range and a polymorphism in the other PABPN1 allele that causes the insertion of one extra GCN triplet, thus producing the (GCN)₁₁ recessive allele [Brais et al 1998]. This polymorphism has 1% to 2% prevalence in North America, Europe, and Japan.
• The cause of the increased severity in the other 80% of individuals with severe autosomal dominant OPMD is unknown. Severely affected individuals cluster in families, a phenomenon suggesting that other genetic factors modulate severity.
• The most severe OPMD presentation is reported for individuals who are homozygotes for an autosomal dominant OPMD mutation [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.
• Individuals with autosomal recessive OPMD (i.e., caused by homozygosity for (GCN)₁₁ alleles) have a later onset and milder disease.

Penetrance

The decade-specific cumulative penetrance for individuals with an autosomal dominant (GCN)₁₃ mutation is [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%

Therefore, autosomal dominant (GCN)₁₃ OPMD is fully penetrant past age 70 years.

Anticipation

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 mutation is in the order of 1:500 meioses [Brais et al 1998].

Prevalence

Autosomal dominant. The prevalence of OPMD has been estimated to be 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 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 allele frequency of the (GCN)₁₁ autosomal recessive mutation in these populations [Brais et al 1998].

Evaluations Following Initial Diagnosis

To establish the extent of disease in 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 swallowing studies
• Neurologic evaluation to establish the presence of ptosis, dysphagia, and proximal weakness and to exclude the presence of other neurologic findings
• EMG and muscle biopsy (required only in cases with more severe complicated presentations)

Treatment of Manifestations

Ptosis

• Surgery is recommended when the ptosis interferes with vision or appears to cause cervical pain secondary to constant dorsiflexion of the neck.
• Two types of blepharoplasty are used to correct the ptosis: resection of the levator palpebrae aponeurosis and frontal suspension of the eyelids [Codere 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 [Codere 1993]. The major advantage of frontal suspension of the eyelids is that it is permanent; however, the procedure requires general anesthesia.

Dysphagia

• Although there have been no controlled trials [Hill et al 2004], surgical intervention for dysphagia should be considered in the presence of very symptomatic dysphagia, marked weight loss, near-fatal choking (which is extremely rare), or recurrent pneumonia [Duranceau et al 1983].
• Cricopharyngeal myotomy alleviates symptoms in most cases [Duranceau et al 1983]. This surgery usually requires overnight hospitalization and a one-week convalescence. Dysphagia reappears slowly over years in many cases. Contraindications to surgery are severe dysphonia and lower esophageal sphincter incompetence [Duranceau 1997].

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 these risks, the following are recommended:

• 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.
• Food should be cut into small pieces.
• To diminish social withdrawal, when attending meals with family and friends, affected individuals should be encouraged to either not eat or choose a dish they can swallow easily.

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

Surveillance

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

Ophthalmologic evaluation should be performed when ptosis interferes with driving or is associated with neck pain or when the eyelids cover more than 50% of the pupils.

Swallowing evaluation and surgical consultations are requested when dysphagia becomes cumbersome.

Therapies Under Investigation

Repetitive dilatations of the upper-esophageal sphincter with bougies is still under investigation [Mathieu et al 1997].

Botulium toxin injection of the cricopharyngeal muscle may be an alternative treatment, although no large control study has been published [Restivo et al 2000].

A trial of myoblast injection into the cricopharyngeal muscle to alleviate dysphagia is underway in France.

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 anti-PABPN1 antibodies that interfere with oligomerization [Verheesen et al 2006].

In a transgenic 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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

Risk to Family Members — Autosomal Dominant OPMD

Parents of a proband

• Most individuals diagnosed with OPMD have at least one affected parent.
• A proband with OPMD may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is unknown but appears to be small.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include clinical evaluation and/or molecular genetic testing.

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 mutation 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 disease-causing mutation.
• 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 alleles (GCN)₁₃ have been described. All children of such a person will be heterozygous for the dominant mutation.

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.

Risk to Family Members — Autosomal Recessive OPMD

A single case of an individual homozygous for the (GCN)₁₁ allele has been reported [Brais et al 1998]. This single 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 mutant 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 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 a mutant allele causing 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 Detection

Carrier testing is technically available on a clinical basis 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 mutation from an affected parent and an autosomal recessive mutation [(GCN)₁₁] from the other parent will develop a severe form of OPMD.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

Testing of at-risk asymptomatic adults for OPMD is available using the techniques described in Molecular Genetic Testing. This 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 that the disorder in the family is actually OPMD.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations, including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of OPMD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long term follow-up and evaluations.

Testing of at-risk individuals during childhood. Consensus holds that individuals at risk for adult-onset disorders should not have testing during childhood in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990, Harper & Clarke 1990]. Individuals who are symptomatic during childhood usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is technically possible but uncommonly requested. DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation is analyzed. The disease-causing expansion must be identified in an affected family member before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions such as OPMD that do not affect intellect or life span, result in relatively mild physical limitations, and require that the asymptomatic at-risk parent be tested to confirm the at-risk status of the fetus are very uncommon. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 9-21-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. Association française contre les myopathies. Dystrophie Musculaire Oculopharyngée. Evry, France: Monographies Myoline. 1995.
3. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available online. 1995. Accessed 9-21-12.

Literature Cited

1. Abu-Baker A, Laganiere S, Fan X, Laganiere J, Brais B, Rouleau GA. Cytoplasmic targeting of mutant poly(A)-binding protein nuclear 1 suppresses protein aggregation and toxicity in oculopharyngeal muscular dystrophy. Traffic. 2005;6:766–79. [PubMed: 16101680]
2. Barbeau A. The syndrome of hereditary late-onset ptosis and dysphagia in French Canada. In: Kuhn E, ed. Symposium über Progressive Muskeldystrophie. Berlin, Germany: Springer-Verlag; 1996:102-9.
3. Bear DG, Fomproix N, Soop T, Bjorkroth B, Masich S, Daneholt B. Nuclear poly(A)-binding protein PABPN1 is associated with RNA polymerase II during transcription and accompanies the released transcript to the nuclear pore. Exp Cell Res. 2003;286:332–44. [PubMed: 12749861]
4. Becher MW, Morrison L, Davis LE, Maki WC, King MK, Bicknell JM, Reinert BL, Bartolo C, Bear DG. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA. 2001;286:2437–40. [PubMed: 11712939]
5. Bloch M, Hayden MR. Opinion: predictive testing for Huntington disease in childhood: challenges and implications. Am J Hum Genet. 1990;46:1–4. [PMC free article: PMC1683548] [PubMed: 2136787]
6. Blondelle SE, Forood B, Houghten RA, Perez-Paya E. Polyalanine-based peptides as models for self-associated beta-pleated-sheet complexes. Biochemistry. 1997;36:8393–400. [PubMed: 9204887]
7. Blumen SC, Brais B, Korczyn AD, Medinsky S, Chapman J, Asherov A, Nisipeanu P, Codere F, Bouchard JP, Fardeau M, Tome FM, Rouleau GA. Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. Ann Neurol. 1999;46:115–8. [PubMed: 10401788]
8. Blumen SC, Nisipeanu P, Sadeh M, Asherov A, Blumen N, Wirguin Y, Khilkevich O, Carasso RL, Korczyn AD. Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel. Neuromuscul Disord. 1997;7:S38–40. [PubMed: 9392014]
9. Blumen SC, Sadeh M, Korczyn AD, Rouche A, Nisipeanu P, Asherov A, Tome FM. Intranuclear inclusions in oculopharyngeal muscular dystrophy among Bukhara Jews. Neurology. 1996;46:1324–8. [PubMed: 8628475]
10. Bouchard JP, Brais B, Brunet D, Gould PV, Rouleau GA. Recent studies on oculopharyngeal muscular dystrophy in Quebec. Neuromuscul Disord. 1997;7:S22–9. [PubMed: 9392011]
11. Brais B. Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. Cytogenet Genome Res. 2003;100:252–60. [PubMed: 14526187]
12. Brais B, Bouchard JP, Xie YG, Rochefort DL, Chretien N, Tome FM, Lafreniere RG, Rommens JM, Uyama E, Nohira O, Blumen S, Korczyn AD, Heutink P, Mathieu J, Duranceau A, Codere F, Fardeau M, Rouleau GA, Korcyn AD. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998;18:164–7. [PubMed: 9462747]
13. Brais B, Bouchard JP, Gosselin F, Xie YG, Fardeau M, Tome FM, Rouleau GA. Using the full power of linkage analysis in 11 French Canadian families to fine map the oculopharyngeal muscular dystrophy gene. Neuromuscul Disord. 1997;7:S70–5. [PubMed: 9392020]
14. Brais B, Rouleau GA, Bouchard JP, Fardeau M, Tome FM. Oculopharyngeal muscular dystrophy. Semin Neurol. 1999;19:59–66. [PubMed: 10711989]
15. Brais B, Xie YG, Sanson M, Morgan K, Weissenbach J, Korczyn AD, Blumen SC, Fardeau M, Tome FM, Bouchard JP. et al. The oculopharyngeal muscular dystrophy locus maps to the region of the cardiac alpha and beta myosin heavy chain genes on chromosome 14q11.2-q13. Hum Mol Genet. 1995;4:429–34. [PubMed: 7795598]
16. Brunet G, Tome FM, Eymard B, Robert JM, Fardeau M. Genealogical study of oculopharyngeal muscular dystrophy in France. Neuromuscul Disord. 1997;7:S34–7. [PubMed: 9392013]
17. Calado A, Tome FM, Brais B, Rouleau GA, Kuhn U, Wahle E, Carmo-Fonseca M. Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet. 2000;9:2321–8. [PubMed: 11001936]
18. Calapez A, Pereira HM, Calado A, Braga J, Rino J, Carvalho C, Tavanez JP, Wahle E, Rosa AC, Carmo-Fonseca M. The intranuclear mobility of messenger RNA binding proteins is ATP dependent and temperature sensitive. J Cell Biol. 2002;159:795–805. [PMC free article: PMC2173399] [PubMed: 12473688]
19. Caron MJ, Girard F, Girard DC, Boudreault D, Brais B, Nassif E, Chouinard P, Ruel M, Duranceau A. Cisatracurium pharmacodynamics in patients with oculopharyngeal muscular dystrophy. Anesth Analg. 2005;100:393–7. [PubMed: 15673864]
20. Chen JM, Chuzhanova N, Stenson PD, Ferec C, Cooper DN. Complex gene rearrangements caused by serial replication slippage. Hum Mutat. 2005;26:125–34. [PubMed: 15977178]
21. Codere F. Oculopharyngeal muscular dystrophy. Can J Ophthalmol. 1993;28:1–2. [PubMed: 8439856]
22. Corbeil-Girard LP, Klein AF, Sasseville AM, Lavoie H, Dicaire MJ, Saint-Denis A, Page M, Duranceau A, Codere F, Bouchard JP, Karpati G, Rouleau GA, Massie B, Langelier Y, Brais B. PABPN1 overexpression leads to upregulation of genes encoding nuclear proteins that are sequestered in oculopharyngeal muscular dystrophy nuclear inclusions. Neurobiol Dis. 2005;18:551–67. [PubMed: 15755682]
23. Davies JE, Sarkar S, Rubinsztein DC. Trehalose reduces aggregate formation and delays pathology in a transgenic mouse model of oculopharyngeal muscular dystrophy. Hum Mol Genet. 2006;15:23–31. [PubMed: 16311254]
24. Davies JE, Wang L, Garcia-Oroz L, Cook LJ, Vacher C, O'Donovan DG, Rubinsztein DC. Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice. Nat Med. 2005;11:672–7. [PubMed: 15864313]
25. Duranceau A. Cricopharyngeal myotomy in the management of neurogenic and muscular dysphagia. Neuromuscul Disord. 1997;7:S85–89. [PubMed: 9392023]
26. Duranceau AC, Beauchamp G, Jamieson GG, Barbeau A. Oropharyngeal dysphagia and oculopharyngeal muscular dystrophy. Surg Clin North Am. 1983;63:825–32. [PubMed: 6351296]
27. Fan X, Dion P, Laganiere J, Brais B, Rouleau GA. Oligomerization of polyalanine expanded PABPN1 facilitates nuclear protein aggregation that is associated with cell death. Hum Mol Genet. 2001;10:2341–51. [PubMed: 11689481]
28. Fan X, Messaed C, Dion P, Laganiere J, Brais B, Karpati G, Rouleau GA. HnRNP A1 and A/B interaction with PABPN1 in oculopharyngeal muscular dystrophy. Can J Neurol Sci. 2003;30:244–51. [PubMed: 12945950]
29. Feit H, Silbergleit A, Schneider LB, Gutierrez JA, Fitoussi RP, Reyes C, Rouleau GA, Brais B, Jackson CE, Beckmann JS, Seboun E. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am J Hum Genet. 1998;63:1732–42. [PMC free article: PMC1377645] [PubMed: 9837826]
30. Forood B, Perez-Paya E, Houghten RA, Blondelle SE. Formation of an extremely stable polyalanine beta-sheet macromolecule. Biochem Biophys Res Commun. 1995;211:7–13. [PubMed: 7779112]
31. Galvao R, Mendes-Soares L, Camara J, Jaco I, Carmo-Fonseca M. Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis. Brain Res Bull. 2001;56:191–201. [PubMed: 11719250]
32. Gaspar C, Jannatipour M, Dion P, Laganiere J, Sequeiros J, Brais B, Rouleau GA. CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation. Hum Mol Genet. 2000;9:1957–66. [PubMed: 10942424]
33. Grewal RP, Karkera JD, Grewal RK, Detera-Wadleigh SD. Mutation analysis of oculopharyngeal muscular dystrophy in Hispanic American families. Arch Neurol. 1999;56:1378–81. [PubMed: 10555658]
34. Harper PS, Clarke A. Should we test children for "adult" genetic diseases? Lancet. 1990;335:1205–6. [PubMed: 1971046]
35. Hill M, Hughes T, Milford C. Treatment for swallowing difficulties (dysphagia) in chronic muscle disease. Cochrane Database Syst Rev. 2004;2:CD004303. [PubMed: 15106246]
36. Ishigaki Y, Li X, Serin G, Maquat LE. Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20. Cell. 2001;106:607–17. [PubMed: 11551508]
37. Kerwitz Y, Kuhn U, Lilie H, Knoth A, Scheuermann T, Friedrich H, Schwarz E, Wahle E. Stimulation of poly(A) polymerase through a direct interaction with the nuclear poly(A) binding protein allosterically regulated by RNA. EMBO J. 2003;22:3705–14. [PMC free article: PMC165617] [PubMed: 12853485]
38. Kim YJ, Noguchi S, Hayashi YK, Tsukahara T, Shimizu T, Arahata K. The product of an oculopharyngeal muscular dystrophy gene, poly(A)-binding protein 2, interacts with SKIP and stimulates muscle-specific gene expression. Hum Mol Genet. 2001;10:1129–39. [PubMed: 11371506]
39. Kuhn U, Nemeth A, Meyer S, Wahle E. The RNA binding domains of the nuclear poly(A)-binding protein. J Biol Chem. 2003;278:16916–25. [PubMed: 12637556]
40. Mathieu J, Lapointe G, Brassard A, Tremblay C, Brais B, Rouleau GA, Bouchard JP. A pilot study on upper oesophageal sphincter dilatation for the treatment of dysphagia in patients with oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7:S100–4. [PubMed: 9392026]
41. McEntagart M, Norton N, Williams H, Teare MD, Dunstan M, Baker P, Houlden H, Reilly M, Wood N, Harper PS, Futreal PA, Williams N, Rahman N. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am J Hum Genet. 2001;68:1270–6. [PMC free article: PMC1226107] [PubMed: 11294660]
42. Nakamoto M, Nakano S, Kawashima S, Ihara M, Nishimura Y, Shinde A, Kakizuka A. Unequal crossing-over in unique PABP2 mutations in Japanese patients: a possible cause of oculopharyngeal muscular dystrophy. Arch Neurol. 2002;59:474–7. [PubMed: 11890856]
43. Nemeth A, Krause S, Blank D, Jenny A, Jeno P, Lustig A, Wahle E. Isolation of genomic and cDNA clones encoding bovine poly(A) binding protein II. Nucleic Acids Res. 1995;23:4034–41. [PMC free article: PMC307339] [PubMed: 7479061]
44. Rankin J, Wyttenbach A, Rubinsztein DC. Intracellular green fluorescent protein-polyalanine aggregates are associated with cell death. Biochem J. 2000;348:15–9. [PMC free article: PMC1221030] [PubMed: 10794708]
45. Restivo DA, Marchese RR, Staffieri A, de Grandis D. Successful botulinum toxin treatment of dysphagia in oculopharyngeal muscular dystrophy. Gastroenterology. 2000;119:1416. [PubMed: 11185464]
46. Rodrigue D, Molgat YM. Surgical correction of blepharoptosis in oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7:S82–4. [PubMed: 9392022]
47. Tome FM, Chateau D, Helbling-Leclerc A, Fardeau M. Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7:S63–9. [PubMed: 9392019]
48. Tome FM, Fardeau M. Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol (Berl). 1980;49:85–7. [PubMed: 6243839]
49. van der Sluijs BM, ter Laak HJ, Scheffer H, van der Maarel SM, van Engelen BG. Autosomal recessive oculopharyngodistal myopathy: a distinct phenotypical, histological, and genetic entity. J Neurol Neurosurg Psychiatry. 2004;75:1499–501. [PMC free article: PMC1738751] [PubMed: 15377709]
50. Verheesen P, de Kluijver A, van Koningsbruggen S, de Brij M, de Haard HJ, van Ommen GJ, van der Maarel SM, Verrips CT. Prevention of oculopharyngeal muscular dystrophy-associated aggregation of nuclear polyA-binding protein with a single-domain intracellular antibody. Hum Mol Genet. 2006;15:105–11. [PubMed: 16319127]
51. Victor M, Hayes R, Adams RD. Oculopharyngeal muscular dystrophy. A familial disease of late life characterized by dysphagia and progressive ptosis of the evelids. N Engl J Med. 1962;267:1267–72. [PubMed: 13997067]
52. Wahle E, Lustig A, Jeno P, Maurer P. Mammalian poly(A)-binding protein II. Physical properties and binding to polynucleotides. J Biol Chem. 1993;268:2937–45. [PubMed: 8428968]
53. Wahle E, Ruegsegger U. 3'-End processing of pre-mRNA in eukaryotes. FEMS Microbiol Rev. 1999;23:277–95. [PubMed: 10371034]
54. Wang Q, Mosser DD, Bag J. Induction of HSP70 expression and recruitment of HSC70 and HSP70 in the nucleus reduce aggregation of a polyalanine expansion mutant of PABPN1 in HeLa cells. Hum Mol Genet. 2005;14:3673–84. [PubMed: 16239242]
55. Young ID, Harper PS. Hereditary distal spinal muscular atrophy with vocal cord paralysis. J Neurol Neurosurg Psychiatry. 1980;43:413–8. [PMC free article: PMC490568] [PubMed: 7420092]
56. Zhao J, Hyman L, Moore C. Formation of mRNA 3' ends in eukaryotes: mechanism, regulation, and interrelationships with other steps in mRNA synthesis. Microbiol Mol Biol Rev. 1999;63:405–45. [PMC free article: PMC98971] [PubMed: 10357856]

Revision History

• 22 June 2006 (ca) Comprehensive update posted to live Web site
• 3 December 2003 (me) Comprehensive update posted to live Web site
• 8 March 2001 (me) Review posted to live Web site
• December 2000 (bb) Original submission