DiagnosisClinical DiagnosisAutosomal 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). TestingMuscle 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 TestingGene. 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 (rarely performed) Prenatal diagnosis (rarely performed) 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 DystrophyView in own windowGene SymbolTest MethodMutation DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityPABPN1Targeted mutation analysisHeterozygosity for (GCN)_12-17 >99%, autosomal dominantClinical Homozygosity for (GCN)₁₁ >99%, recessive 21. The ability of the test method used to detect a mutation that is present in the indicated gene2. One case reported [Brais et al 1998]Testing StrategyMolecular 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) DisordersNo other diseases are known to be caused by mutations in PABPN1.}

Natural HistoryAutosomal 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 CorrelationsThe 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.

Differential DiagnosisThe differential diagnosis includes:Myotonic dystrophy type 1 and myotonic muscular dystrophy type 2 Autosomal dominant distal myopathy Distal herditary motor neuropathy type VII (HMN7; Harper-Young myopathy) [OMIM 158580]. In these families spinal muscular atrophy is accompanied by vocal cord and pharyngeal weakness without ptosis [Young & Harper 1980]. McEntagart et al [2001] mapped this disorder to 2q14. Feit et al [1998] described a distal myopathy with a similar phenotype of vocal cord and pharyngeal dysfunction [OMIM 606070], which maps to chromosome 5q31. Mitochondrial myopathy with or without progressive external ophthalmoplegia (PEO) including mitochondrial neurogastrointestinal encephalomyopathy disease (MNGIE syndrome) Myasthenia gravis. The absence of family history and the fluctuation of symptoms in myasthenia gravis usually distinguish the two conditions. If in doubt, electromyography and neostigmine testing can confirm the diagnosis of myasthenia gravis, and molecular genetic testing can confirm the diagnosis of OPMD. Polymyositis and progressive bulbar palsy. These conditions do not have ptosis. Blepharophimosis, ptosis, and epicanthus inversus. In this condition, the ptosis is usually congenital, it is always associated with epicanthus inversus, and dysphagia is not a feature. Congenital fibrosis of the extraocular muscles. In this condition, the ptosis is congenital and dysphagia is not a feature. Other. At least one other dominant OPMD-like condition, which is more severe and is not caused by GCN expansion mutations in PABPN1, appears to exist [Hill et al 2004]. 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 (GCN) PABPN1 mutations are observed [van der Sluijs et al 2004].

ManagementEvaluations Following Initial DiagnosisTo 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 studiesNeurologic evaluation to establish the presence of ptosis, dysphagia, and proximal weakness and to exclude the presence of other neurologic findingsEMG and muscle biopsy (required only in cases with more severe complicated presentations) Treatment of ManifestationsPtosisSurgery 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. DysphagiaAlthough 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 ComplicationsThe 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].SurveillanceThe 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 InvestigationRepetitive 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPABPN114q11​.2Polyadenylate-binding protein 2PABPN1 homepage - Leiden Muscular Dystrophy pagesPABPN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Oculopharyngeal Muscular Dystrophy (View All in OMIM) View in own window 164300OCULOPHARYNGEAL MUSCULAR DYSTROPHY; OPMD 602279POLYADENYLATE-BINDING PROTEIN, NUCLEAR, 1; PABPN1Normal allelic variants. PABPN1 has seven exons. The role of the two long introns preserved in many of its mRNAs is unknown. Pathologic allelic variants. See Molecular Genetic Testing. The OPMD mutations expand a (GCN)_n sequence that immediately follows the start ATG. As in (CAG)/polyglutamine diseases, it is the absolute size of the domain that is the size of the mutation and not the size of the added expansions. It is not known for sure if the mutation mechanism is expansion of the GCN repeat through slippage or insertion of additional (GCN)_n 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, and two oligomerization and a nuclear localization signal (NLS) [Calado et al 2000, Fan et al 2001, Kuhn et al 2003]. PABPN1 is an abundant nuclear protein of ~49 kDa 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 & Ruegsegger 1999, Zhao et al 1999]. It was demonstrated that PABPN1 shuttles between nucleus and cytoplasm [Calado et al 2000]. 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. These include 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].Abnormal gene product. Various hypotheses of a polyalanine toxicity gain-of-function pathogenetic mechanism have been proposed [Brais et al 1998, Brais et al 1999]. Abnormal aggregation and inefficient protein degradation are some of the gain-of-function pathologic 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. 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 with time to form the OPMD PABPN1-containing intranuclear filaments that are seen on electron microscopy [Tomé & Fardeau 1980, Tomé et al 1997, Calado et al 2000].
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].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].Messenger RNA trapping is another proposed pathophysiologic hypothesis [Galvao 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].