Oculopharyngeal Muscular Dystrophy (PABPN1)

A progressive adult-onset myopathy, usually beginning after age 40, with bilateral eyelid ptosis, oropharyngeal dysphagia, and late proximal weakness, caused by short, stable expansions of the polyalanine tract encoded by exon 1 of PABPN1, in the heterozygous (about 90%) or biallelic (about 10%) state.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Clinical description and naming

The name "oculopharyngeal muscular dystrophy" was proposed in 1962 by Maurice Victor, Richard Hayes, and Raymond Adams, who described, in an American family of Ashkenazi Jewish descent, a late-onset familial disease characterised by dysphagia and progressive eyelid ptosis [4, 18]. The association of late-onset ptosis and dysphagia with vertical transmission had already been observed in French-Canadian families, and the Quebec pedigrees went on to form the largest patient population described. In France, the census of affected families and the genealogical study by Brunet and colleagues (1990, 1997) documented the distribution of the disease and its origin in common ancestors [19, 20]. In Israel, Blumen and colleagues identified in 1997 a cluster of patients among Jews originating from Bukhara (Uzbekistan), with a minimum prevalence of 1:600, and in 1999 showed that homozygotes have an earlier-onset, more severe form [21, 22].

1.2. From histological to molecular diagnosis

Until the end of the 20th century, diagnosis rested on the clinical picture, the family history, and the demonstration by electron microscopy of muscle biopsy of filamentous intranuclear inclusions 8.5 nm in outer diameter, described by Tomé and Fardeau in 1980 [4]. The locus was mapped in 1995 to 14q11.2-q13, near the cardiac α- and β-myosin heavy chain genes, by linkage analysis in French-Canadian families, and refined in 1997 in 11 Quebec families [23, 24]. In 1998, Brais and colleagues isolated the PABP2 gene (now PABPN1) within a 217-kb candidate interval and demonstrated short expansions of the exon 1 GCG repeat in all 144 families screened; the same study described homozygosity for the allele then designated "(GCG)7", present in about 2% of the population, as the cause of an autosomal recessive form, and its action as a modifier in compound heterozygotes [25]. In 2000, a Lisbon group with French and Canadian collaborators showed that the nuclear inclusions are aggregates of the protein itself that sequester polyadenylated RNA [26].

1.3. Nomenclature and reclassification

Variant nomenclature has changed twice. The original description counted only the pure GCG codons at the start of the tract, so that the normal allele was "(GCG)6" and the pathogenic alleles "(GCG)8–13"; the finding that the normal tract also contains GCA codons, (GCG)6(GCA)3(GCG)1, and that all GCN codons encode alanine led the 191st ENMC (European Neuromuscular Centre) workshop, in 2012, to recommend counting the total number of codons, with the normal allele as (GCN)10 or Ala10 and the pathogenic alleles as (GCN)11 to (GCN)18 [4, 7, 27]. The 2017 Oxford Desk Reference still uses the symbol PABP2 and the notation "(GCG)6" for the normal allele, which correspond to (GCN)10 in current nomenclature [2]. In 2022, the description of frameshift variants in HNRNPA2B1 in families with a similar picture but onset in childhood or adolescence led OMIM to create the OPMD2 entry (#620460) and to rename the classic disease OPMD1 (#164300) [10, 28]. The oculopharyngodistal myopathies (OPDM1 to OPDM5), caused by noncoding CGG/GGC or CCG expansions in other genes, are distinct entities with distal weakness and different histopathology, and remain in the differential diagnosis [8, 10].

1.4. Scope of this article

This article covers OPMD1 due to PABPN1 alterations in all its forms: the typical dominant heterozygous form, the severe form due to long expansions, the biallelic forms (homozygous and compound heterozygous, including the recessive form due to (GCN)11 homozygosity), the heterozygous (GCN)11 allele with reduced penetrance, and the point variants that lengthen the tract without an expansion. OPMD2 and the oculopharyngodistal myopathies are discussed as differential diagnoses in section 6.

2. Molecular Genetics and Pathophysiology

2.1. The PABPN1 gene and protein

PABPN1 maps to 14q11.2 and encodes polyadenylate-binding nuclear protein 1, an abundant, ubiquitously expressed protein, present at very low levels in skeletal muscle, that shuttles between the nucleus and the cytoplasm and is concentrated in nuclear speckles [4]. PABPN1 binds nascent poly(A) tails, confers processivity on poly(A) polymerase, and sets the tail length at about 200–250 nucleotides; it associates with RNA polymerase II during transcription and accompanies transcripts through the nuclear pore; it participates in nonsense-mediated mRNA decay (NMD) and, as a component of the PAXT complex, in exosomal degradation of nuclear RNA [4, 5]. Other described functions include regulation of splicing, polyadenylation site selection, nuclear surveillance by hyperadenylation, regulation of long noncoding RNAs, processing of small nucleolar RNAs, and control of nuclear transcripts encoding mitochondrial proteins [4]. The N-terminal region contains the polyalanine tract encoded by exon 1; in the reference sequence NM_004643.4, codons 2 to 7 are GCG, codons 8 to 10 are GCA, and codon 11 is GCG, making 10 alanines followed by glycine 12 (GGG) [7, 8].

2.2. Nature of the pathogenic variants

Pathogenic alleles lengthen the tract to 11 to 18 alanines. Pathogenicity depends on the total number of contiguous alanines, not on codon composition: expansions may be pure GCG or mixtures of GCG and GCA, and the same length can result from different sequences [4, 8]. In the United Kingdom, analysis of 86 patients identified 13 different expansion types, six of them containing GCA and GCG codons, nearly all consistent with unequal crossing over between chromatids as the mutational mechanism rather than the polymerase slippage typical of large repeat expansions [29]. The expansions are mitotically and meiotically stable; there is no anticipation, and the rate of meiotic expansion or contraction of a heterozygous allele of 12 to 17 codons has been estimated at about 1 in 500 meioses [4, 25]. The observation by Blumen and colleagues (1997) of "some evidence" of anticipation in Israel predates molecular diagnosis and has not been confirmed [8, 21]. Polyalanine tract expansions cause other monogenic disorders (synpolydactyly type II, cleidocranial dysplasia in one family, holoprosencephaly 5), usually in transcription factor genes; PABPN1 is the exception, because it is not a transcription factor and because of the late-onset phenotype [30].

Rare point variants produce the same effect without changing the repeat number. The substitution NM_004643.4:c.35G>C p.(Gly12Ala) converts the glycine 12 codon (GGG) to GCG; because codons 13 and 14 are GCT and GCG, the tract becomes 13 contiguous alanines, with the structure (GCG)6(GCA)3(GCG)2(GCT)1(GCG)1 [9, 31]. It was first described in the United Kingdom, where exon 1 sequencing in 202 patients with clinically suspected OPMD and no expansion found one case [32], and later in a Japanese case [31]. The variant c.34G>T p.(Gly12Trp), described in a patient with suspected OPMD, is the only known exception to the polyalanine-lengthening mechanism and rests on a single case [8, 9].

2.3. HGVS nomenclature and correspondence with historical notation

How the same expansion is described under HGVS (Human Genome Variation Society) nomenclature varies among laboratories. GeneReviews uses a codon-centred repeat notation, c.4_6GCN[10] p.2Ala[10] for the normal allele and c.4_6GCN[11_18] p.2Ala[11_18] for expanded alleles, on the previous transcript version (NM_004643.3), as provided by the GeneReviews authors [4]. ClinVar describes the expansions on NM_004643.4 as GGC trinucleotide repeats starting at c.3, with the reference allele being c.3_23(GGC)7; other laboratories describe them as duplications or insertions. The following table compiles the correspondences given by ClinVar itself through the protein consequence, without manual conversions [33]. The number of alanines is the clinically useful information, and the report should state the length of each allele [3, 8].

The correspondence with the historical notation is as follows: "(GCG)6" = normal (GCN)10; "(GCG)7" = (GCN)11; "(GCG)8" = (GCN)12; "(GCG)9" = (GCN)13; and so on up to "(GCG)14" = (GCN)18 [4, 8, 25]. An example given by GeneReviews is the Ala13 allele with the sequence GCG[10]GCA[1]GCG[2], formerly written "(GCG)10(GCA)1(GCG)2" [4]. The genomic coordinates of the most frequent point variant are NC_000014.9:g.23321504G>C (GRCh38) and NC_000014.8:g.23790713G>C (GRCh37), validated in VariantValidator [9]. The notation "c.30_32dup, p.Ala11dup" used in a 2026 report corresponds to an 11-alanine allele (NC_000014.9:g.23321499_23321501dup) [9, 34]. The conflicting ClinVar classifications for (GCN)11 reflect the dual nature of this allele: a common polymorphism in the heterozygous state, a cause of disease in the homozygous state, and a modifier in compound heterozygosity. The synonymous variant c.24A>G, within the tract, is classified as of uncertain significance [33].

2.4. Molecular and tissue mechanisms

The pathological hallmark is tubulofilamentous intranuclear inclusions of PABPN1, with unbranched filaments 8.5 nm in outer diameter and 3 nm in inner diameter and about 0.25 µm long, present in 2–15% of myonuclei in both affected and unaffected muscles [4]. The aggregates sequester poly(A) RNA, ubiquitin, p62, the chaperone HSP70, and other components, such as GRP78/BiP and the ribosomal protein RPL24 [8, 26, 35]. In a large collection of human biopsies, the percentage of myonuclei with aggregates increased with age, aggregates were larger and more often associated with HSP70 with longer tracts, and pharyngeal muscle, with low PABPN1 levels and regenerating fibres, had fewer aggregates; in a biopsy xenograft model in immunodeficient mice, aggregates reappeared shortly after regeneration of the human muscle, which limits the expected durability of cell therapies [35]. The in vivo aggregation properties of PABPN1 were characterised by the same Lisbon group that described the composition of the inclusions [36].

Three mechanisms coexist. Toxic gain of function results from abnormal aggregation and inefficient degradation of the elongated protein, which oligomerises into insoluble filaments and alters the expression of RNA-processing genes and splicing [4, 5]. Loss of function stems from a reduced functional pool of PABPN1, either directly or through sequestration in aggregates, and manifests as shorter poly(A) tails, a shift towards proximal polyadenylation sites, and disorganisation of nuclear speckles [4, 8]. Proximity-labelling data (TurboID) from 2026 suggest a dominant-negative effect, with reduced interaction of the elongated protein with the TREX export complex, nuclear retention of poly(A) RNA, and impaired mRNA export [37]. Mitochondrial dysfunction, with cytochrome c oxidase (COX)-negative fibres and paracrystalline inclusions, is considered a downstream contributor and should not lead to a diagnosis of primary mitochondrial disease [8]. The sources consulted do not explain the selectivity for the eyelid and pharyngeal muscles; GeneReviews notes that the expression level of PABPN1 in skeletal muscle is much lower than in other tissues [4].

2.5. Inheritance, dosage, and penetrance

About 90% of patients have one (GCN)10 allele and one expanded allele of 11 to 18 codons; about 10% are biallelic, through compound heterozygosity with (GCN)11 or through homozygosity for (GCN)11, (GCN)12, or (GCN)13 [4, 8]. The relationship between length and phenotype, the greater severity with two expanded alleles, and the similarity between biallelic individuals with (GCN)12 or longer and (GCN)18 heterozygotes, the maximum length described, point to a dosage effect with incomplete dominance [8, 38]. Biallelic individuals with (GCN)12 or longer become symptomatic before age 35, progress faster, may have extramuscular manifestations (mild cognitive impairment, psychiatric symptoms), and have reduced life expectancy, with death in the sixth decade [8, 39].

The (GCN)11 allele has a frequency of 1–2% in populations of European, North American, and Japanese ancestry and acts in three ways: in the homozygous state it causes autosomal recessive OPMD; in compound heterozygosity with a larger expansion it accelerates progression; and in a minority of simple heterozygotes it is associated with a mild, late-onset form consistent with dominant transmission with very reduced penetrance [4, 8, 40]. In the United Kingdom, (GCN)11 was not detected in more than 200 British controls in a 2001 series, and in Spain the frequency described in other countries was not confirmed in controls; these discrepancies indicate that the allele frequency varies across populations and methods [41, 42]. In the UK Biobank, 1896 (GCN)11 heterozygotes were identified, most without diagnostic codes consistent with OPMD [11]. The cumulative penetrance in (GCN)13 heterozygotes by decade is 1% before age 40, 6% between 40 and 49, 31% between 50 and 59, 63% between 60 and 69, and 99% after age 69 [4]. Men and women are affected in equal proportions, and no difference according to the sex of the transmitting parent has been demonstrated, although a Greek series of 23 patients associated maternally transmitted expansions with earlier onset [8, 43].

2.6. Allelic disorders and modifiers

No other phenotypes are known to be associated with heterozygous or biallelic PABPN1 variants [4]. Variability among patients with the same genotype suggests modifiers: in the Canary Islands, a cohort with (GCN)15 had a milder course than European cohorts with shorter expansions [44]; in the Netherlands, repeat length did not correlate with clinical phenotype [45]; and in Israel, women with the 10/13 genotype became symptomatic 3.7 years earlier than men, a finding that has not been replicated [46]. The mitochondrial contribution proposed to explain the maternal effect in Greece is an observational hypothesis [43].

3. Clinical Spectrum and Manifestations by System

3.1. Typical and severe forms

Typical OPMD, which accounts for 90–95% of affected individuals, begins in the fifth or sixth decade: the mean age at onset is 48 years for ptosis and 50 years for dysphagia, and proximal lower limb weakness appears at a mean age of 58 years [4]. The severe form, in 5–10% of patients, is defined by ptosis and dysphagia before age 45 and disabling proximal lower limb weakness before age 60; some of these patients eventually become wheelchair dependent [4]. The French PNDS places the first symptoms between ages 40 and 70, with marked interfamilial and little intrafamilial variability, and complete penetrance after age 70 [3]. The abstract of the study by Brisson and colleagues (2020) gives medians of 54 years for the onset of ptosis and dysphagia and 58 years for proximal lower limb weakness, whereas GeneReviews, citing the same study, gives means of 48 and 50 years; the sources do not explain the discrepancy, which may reflect the measure used (mean or median) and the sample [4, 47]. Onset before age 30 is seen with longer expansions or in compound heterozygotes and homozygotes [4].

The frequency of manifestations in symptomatic disease, according to the GeneReviews table, which incorporates data from 333 Quebec patients (Brisson 2020), is as follows [4]. The PNDS gives similar figures, from Trollet and colleagues (2001): ptosis and dysphagia in 100%, tongue atrophy or weakness in 82%, pelvic girdle weakness in 71%, dysphonia in 67%, limited upgaze in 61%, facial weakness in 43%, and shoulder girdle weakness in 38% [3].

3.2. Eyelids and ocular motility

Ptosis is usually the first sign and is always bilateral, although it may be asymmetric at onset [3, 4]. Compensation occurs through contraction of the frontalis muscle, which raises the eyebrows and deepens the forehead wrinkles (Hutchinson facies), and, in severe ptosis, through the "astrologer's posture", with neck extension and downward gaze [3, 4]. In the late stage, the eyelids become very thin, almost transparent, and the lid crease is shallow or absent [3]. Ptosis interferes with vision, driving, and neck posture, and compensatory neck extension worsens swallowing [3, 4]. The extraocular muscles become gradually involved: limited upgaze due to superior rectus weakness is common but nonspecific; strabismus and permanent diplopia appear in the advanced stage; complete external ophthalmoplegia is rare; the intrinsic muscles are spared and pupillary reactivity is normal [3, 4]. Ophthalmoplegia was described in half of the patients in a British series of 31 patients and in 9 of 13 in a Danish series, and diplopia in 10.5% of the Israeli registry [41, 46, 48].

3.3. Swallowing, chewing, and speech

Dysphagia begins insidiously: the time needed to finish a meal increases and the patient starts to avoid dry foods; liquids are affected later [3, 4]. Dystrophic degeneration and progressive fibrosis of the pharyngeal muscles impair bolus propulsion, and reduced relaxation of the cricopharyngeus muscle, the main component of the upper oesophageal sphincter (UES), delays passage through the sphincter [4]. With progression come longer meals, dietary restriction and food selection, weight loss, nasal regurgitation with hypernasal speech due to reduced velar mobility, nocturnal pooling of unswallowed saliva and nasal secretions, and aspiration pneumonia [3]. The severity of dysphagia is the main determinant of prognosis, through aspiration pneumonia and malnutrition [4]. The PNDS notes that dysphagia may precede ptosis, particularly in men [3]; in the Israeli registry, dysphagia was the first symptom in 42.1% of the 95 patients with the 10/13 genotype, ptosis in 27.4%, and limb weakness in 6.3% [46], whereas in a Danish series of 13 patients dysphagia was never the presenting symptom [48].

Instrumental assessment shows early abnormalities. In a series of 22 patients studied by videofluoroscopy (134 swallows), 96% had pharyngeal dysphagia, 10 had a cricopharyngeal bar, 77.3% of swallows left vallecular residue and 90.1% pyriform sinus residue, and 33% of swallows were unsafe, with 45 penetrations and 9 aspirations, all during the swallow [49]. In 11 adults aged 48 to 62 years assessed at baseline in a phase 2 trial, maximum pharyngeal constriction, hyoid displacement and velocity, and airway closure were reduced; swallowing was unsafe in 3 of 11 and residue was clinically significant in 7 [50]. In a Dutch cohort of 48 patients, 82% reported swallowing difficulties, 27% chewing difficulties, and 67% speech difficulties; asymptomatic carriers already had worse chewing times, swallowing speed, and articulation rate than controls; on videofluoroscopy, all but one asymptomatic carrier had abnormal residue and 19% aspirated; residue is an early sign and aspiration a late one, and disease duration (odds ratio, OR, 1.11 per year) and residue with 20 mL (OR 4.03) predicted aspiration of thin liquids [51]. In Israel, 68 of 70 patients assessed by otolaryngology had dysphagia, and 64.3% had dietary restrictions on the FOIS (Functional Oral Intake Scale) [46]. Salivary viscosity is higher in patients than in household controls and is associated with aspiration risk, as described in section 5 [52].

3.4. Limb, trunk, and facial muscles

Limb weakness is symmetric, begins in the pelvic girdle, and later involves the shoulder girdle; the iliopsoas is the first clinically weak muscle, followed by the thigh adductors, glutei, and deltoids, and the distal muscles are classically spared [3, 4]. Reflexes are preserved except in severe weakness, and fasciculations are never present [3]. On magnetic resonance imaging (MRI), fatty degeneration first affects the soleus, hip adductors, and hamstrings (semimembranosus and biceps femoris); in later stages, the vastus medialis and intermedius, gastrocnemius, and peroneal muscles; the sartorius, gracilis, and tibialis muscles are preserved the longest [4]. In the largest imaging series (168 patients), fatty replacement was present in 96.7% of symptomatic patients, with the tongue, adductor magnus, and soleus as the most affected muscles, and correlated with disease duration and disability [53]; the paraspinal muscles were infiltrated in 76% [4]. The face becomes emaciated, with a horizontal smile due to weakness of the orbicularis oris and masseters, and the neck flexors weaken [3].

In Quebec, among 333 (GCN)13 patients, the median latency to proximal weakness was 7 years after ptosis (range 0–21) and 7 years after dysphagia (0–25); before age 75, 27% had limited walking, 14% could not climb stairs unaided, and 14% used a wheelchair for long distances or in daily life [4, 47]. In Israel, limb weakness appeared 4.4 years after ptosis, the iliopsoas was weak in 47.9% of the 188 muscles tested, the gluteus medius in 39.1%, the deltoid in 19.7%, and the tibialis anterior in 11.3%, and 8.4% used a walking aid [46]. The PNDS estimates the need for a wheelchair at 5–10% and describes initial pelvic girdle weakness in 7% of a Canadian series [3]. In a cross-sectional study of 113 patients from four Canadian clinics, muscle strength ranged from 41.4% to 81.4% of age- and sex-specific reference values, with the hip flexors as the weakest muscles, and balance, balance confidence, and lower limb strength explained 57.4–79.9% of the variance in mobility measures [54]. Distal weakness was described in a Japanese family and in other groups in the 1970s, but distal involvement at onset is not part of typical OPMD; one of the Japanese studies, by Satoyoshi and Kinoshita (1977), described the entity now called oculopharyngodistal myopathy [4]. In some severe forms, whole-body MRI shows distal lower limb involvement in the late stage [4].

Progression is measurable in less than two years. In a Dutch national cohort of 43 patients assessed 20 months apart, 8 of 18 measures detected decline, with the largest reductions in strength of the deltoid (−27%), quadriceps (−14%), iliopsoas (−12.2%), and tongue (−9.9%), in the 10-step test (−12.5%), and in dimension 1 of the MFM (Motor Function Measure, −7.1%), unrelated to genotype or disease duration [55]. In the same cohort, the fat fraction on quantitative MRI was highest in the tongue (37.0%), adductor magnus (31.9%), and soleus (27.9%) and increased by 1.7% in the thigh, 1.7% in the lower leg, and 1.9% in the orofacial muscles over 20 months, with the largest increase in the soleus [56].

3.5. Respiratory system

Respiratory involvement is usually mild. In 13 Danish patients, forced expiratory volume in the first second (FEV1) was reduced to 23% to 59% of predicted, without need for noninvasive ventilation [4, 48]. In Israel, the mean forced vital capacity (FVC) of 28 patients was 80.4% of predicted, with 39.3% below 80% [46]. Sleep apnoea is rare and probably underestimated [4]. The leading cause of death among the 333 Quebec patients was respiratory disease, and the median age at death was 77 years [4, 47]. The PNDS states that OPMD has no intrinsic cardiorespiratory involvement and considers its presence a red flag for another diagnosis; severe axial weakness warrants pulmonary function testing [3].

3.6. Heart and other systems

Cardiomyopathy and dysrhythmias are not associated with OPMD [4]; the Danish series found no cardiac involvement on electrocardiogram, Holter monitoring, or echocardiogram [48]. The PNDS describes the disease as "purely motor", without cardiac or systemic involvement [3]. Rare cases of depletion of myelinated fibres in the endomysial nerve branches of the extraocular, pharyngeal, and lingual muscles, and of axonal sensorimotor neuropathies, have been reported; whether they are attributable to OPMD or to age is unclear [3, 4]. In a single-centre series of 46 patients, 32.6% had at least one cancer, at a median age of 71.5 years; without a population control group, this figure does not demonstrate increased risk [57].

3.7. Cognition, behaviour, and mental health

Neuropsychological testing shows executive function abnormalities in heterozygotes compared with controls, correlated with larger expansions [4, 58]. In a Dutch study of 24 patients and their informants using the ALS-FTD-Q questionnaire, 29% had behavioural change and 17% a severity consistent with behavioural-variant frontotemporal dementia [59]. In a 69-year-old man with language-predominant cognitive decline and left anterior temporal atrophy, carrying a (GCN)11 allele without neuromuscular manifestations, the authors interpreted the picture as frontotemporal lobar degeneration in a carrier and not as a consequence of OPMD [34]. Severe fatigue and pain affected 54% of 35 Dutch patients, and 94% reported limitations in daily activities and social participation, without more psychological distress than healthy adults [60]. The PNDS considers that the cognitive disorders described cannot be confidently attributed to OPMD rather than to age [3].

3.8. Biallelic forms and the (GCN)11 allele

(GCN)13 homozygotes from Quebec and Israel became symptomatic before age 36, on average 18 years earlier than heterozygotes, and had more myonuclei with inclusions (9.4% vs. 4.9%) [22]. Over 15–20 years of follow-up of 4 French-Canadian and 6 Uzbek Jewish (GCN)13 homozygotes, ptosis and dysphagia began before age 35, followed within a few years by external ophthalmoparesis, dysphonia, and proximal weakness; all had recurrent aspiration and weight loss, 4 underwent surgery for dysphagia and 5 received a gastrostomy, most had cognitive decline, recurrent depression, or psychotic episodes, and 6 died between ages 50 and 57 [39]. In the Israeli registry, the 3 13/13 homozygotes developed dysphagia at 39.7 years, about 11 years earlier than heterozygotes, whereas 3 11/11 homozygotes from a Karaite family had dysphagia as the first symptom at 64.3 years [46]. In Italy, a woman homozygous for (GCN)11 presented at age 67 with dropped head due to severe neck extensor weakness, followed by mild dysphagia, hypernasal speech, ptosis, and proximal weakness [61]. In France, a patient with a single (GCN)11 allele had an atypical form with mild, late-onset dysphagia and oculomotor symptoms and intranuclear inclusions on biopsy [40].

3.9. Treated disease and natural history

Historically, dysphagia led to malnutrition and death from starvation; treatment of pharyngeal dysfunction has improved quality of life [4]. Cohort data combine operated and nonoperated patients, and the proportion of interventions varies among series: surgery for severe dysphagia was performed in 4.6% of patients in the Canary Islands and in 22.8% of a European comparison cohort, and cricopharyngeal myotomy in 3.2% of the Israeli registry (section 7). This proportion shapes the frequency of malnutrition and pneumonia reported in each series, and the cohorts do not allow natural history to be separated from treated disease [44, 46].

4. Clinical Recognition and Red Flags

4.1. When to suspect

Clinical suspicion rests on the combination of ptosis and swallowing impairment with onset after age 40 and a suggestive family history [3]. GeneReviews defines the suggestive findings, in an individual with a mean age of 48 years, as ptosis, that is, vertical separation of at least one palpebral fissure of less than 8 mm at rest or previous corrective ptosis surgery, and dysphagia, that is, increased swallowing time, more than 7 seconds to drink 80 mL of ice-cold water [4]. Proximal weakness of the pelvic and shoulder girdles may appear later, usually 5 to 10 years after ptosis [4]. The history should ask about meal duration, avoidance of dry or hard foods, coughing during meals, pooling of saliva, nasal regurgitation, weight loss, recurrent respiratory infections, and eyelid surgery in relatives [3, 4]. Old photographs and identity documents help date the onset of ptosis [3].

4.2. Presentation settings

Presentation may be ophthalmological (ptosis operated on once or more before the systemic disease is recognised), otolaryngological (isolated oropharyngeal dysphagia), pulmonary (recurrent aspiration pneumonia), neurological (proximal weakness with ptosis), or genetic (relative of an identified patient). At two institutions in Southern California, 25 patients with genetically confirmed OPMD between 2000 and 2015 had been referred without a diagnosis, with ptosis, diplopia, dysphagia, weakness, nonspecific "dystrophy", or suspected myasthenia [62]. In Israel, the interval between the first symptom and genetic diagnosis averaged 8.8 years [46], and in Greece the diagnostic delay was also considerable [43]. A 68-year-old man was investigated for weeks for recurrent pneumonia, with interstitial pneumonia and opportunistic infection considered, before ptosis and girdle weakness pointed to OPMD (section 10) [63]. Myasthenia gravis is the most common misdiagnosis, and some patients receive immunosuppressants before the correct diagnosis is made [8].

4.3. Red flags for another diagnosis

The PNDS recommends looking for an alternative diagnosis when one of the four elements of the picture (ptosis, dysphagia, age over 40, dominant transmission) is missing, when molecular testing is negative, or when one of the following red flags is present: onset before age 40, marked fluctuation of symptoms, complete or early external ophthalmoplegia, involvement of the intrinsic eye muscles, distal limb involvement, or cardiorespiratory involvement [3]. Isolated ptosis in an older person should prompt exclusion of aponeurotic ptosis, which may coexist with OPMD [3]. Onset before age 40 does not rule out OPMD when both parents are affected or the family belongs to a high-prevalence population, because it suggests a biallelic form [4, 21].

4.4. Emergency signs

Situations requiring immediate assessment are productive cough or fever in a patient with dysphagia, because of the risk of aspiration pneumonia and lung abscess; choking with airway obstruction; rapid weight loss or inability to maintain hydration; and respiratory compromise after general anaesthesia or sedation [3, 4, 64]. Death may result from massive aspiration, cachexia, or pneumonia [3].

4.5. Newborn and population screening

There is no newborn screening, because this is an adult-onset disease with no presymptomatic intervention of proven benefit [4]. Pathogenic PABPN1 alleles may emerge as findings in exomes performed for another reason: in the UK Biobank, the genetic prevalence of pathogenic alleles was 1:10,200, about 10 times the estimated clinical prevalence, which means that many carriers have mild, late-onset, or undiagnosed disease [11].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Diagnostic criteria

The diagnosis is confirmed in a proband with suggestive findings and one of the following PABPN1 alterations: a heterozygous expansion of 11 to 18 GCN codons in exon 1 (about 90% of patients); or biallelic expansions, either through compound heterozygosity, (GCN)11 with a second expanded allele, or through homozygosity, (GCN)11/(GCN)11, (GCN)12/(GCN)12, or (GCN)13/(GCN)13 (about 10%) [4]. The PNDS adds that, as of 2022, no patients with OPMD without one or two altered PABPN1 alleles had been described, that all known variants were expansions of 11 to 18 GCN, and that the normal allele invariably has 10 GCN [3]; the PNDS does not mention the codon 12 point variants, described both before and after [31, 32]. The GCN expansion is the only reported cause of OPMD in the genotyped series from the United Kingdom, Spain, China, and California [4].

5.2. Molecular testing

The usual technique is fragment size analysis by capillary electrophoresis with a fluorescent primer after PCR (polymerase chain reaction) amplification of exon 1, for index cases and relatives; the result should precisely quantify the GCN count of each allele [3]. Sanger sequencing is used to determine length and zygosity and characterises GCG/GCA combinations; it establishes zygosity in heterozygotes with one expanded allele, but when two expanded alleles are present it should be complemented by fragment sizing or next-generation sequencing (NGS) [4, 8]. Repeat-primed PCR is another option, and complex motifs can make measurement difficult [8]. Knowing the exact repeat sequence is not necessary for diagnosis, but it should be reported when available [4]. The proportion of probands with a variant detectable by sizing exceeds 99%; this is the analytic yield of the method among patients with an expansion, not the clinical sensitivity when OPMD is suspected [4]. In Uruguay, reanalysis of 90 samples by capillary fragment electrophoresis without fluorescent primers showed complete agreement with Sanger sequencing in detecting expanded alleles, at lower cost and in less time; agreement between methods is not the same as clinical sensitivity, and this method does not detect point variants [65].

Alternatives to single-gene testing are multigene panels that include PABPN1 and the genes in the differential diagnosis and, for atypical phenotypes, exome or genome sequencing, which can detect the expanded alleles because they are short [4]. The high GC content of exon 1 means that the repeat and its flanking region may have low coverage on NGS; when OPMD is suspected, it should be confirmed that the laboratory actually determined the number of GCN repeats [4, 8]. In the Netherlands, massively parallel sequencing with the FDSTools package, which distinguishes true sequences from short tandem repeat artefacts, identified expansions from (GCN)11 to (GCN)16, with (GCN)16 the most frequent [45]. The 2026 ACMG (American College of Medical Genetics and Genomics) "points to consider" statement on detection of expansions by NGS lists PABPN1 with the GCN motif in exon 1, reference (GCG)6 at NC_000014.9:23321473-23321490, normal alleles up to 10, and pathogenic alleles from 11 to 18 [66]. The statement recommends that expansions detected by short-read NGS be confirmed by an orthogonal method, that the exact repeat number be reported only when confirmed or supported by reads that traverse the entire repeat (spanning reads), that, without such reads, the number be given with the software confidence interval, and that the report state the limits of detection and the loci not tested [66].

5.3. Test limitations

A negative sizing result does not rule out OPMD. The point variants p.(Gly12Ala) and p.(Gly12Trp) do not change fragment size and escape fragment analysis; they require sequencing of exon 1 [8, 32]. In the British series, sequencing of 202 expansion-negative patients found one case, a yield of about 1 in 202 [32]. A panel or exome that calls only point variants in PABPN1 without sizing the repeat also does not rule out the disease [5]. In a study of 31 patients from the United Kingdom, one family with an oculopharyngeal syndrome had no expansion, showing that similar pictures with another cause exist [41]. The sources consulted do not describe somatic mosaicism with clinical expression, which is consistent with the mitotic stability of the repeat, but leukocyte DNA does not rule out germline mosaicism in a parent (section 8) [4].

5.4. Report content

The report should state the gene, the versioned transcript (NM_004643.4), the number of GCN codons in each allele (for example, (GCN)10/(GCN)13), the zygosity, the repeat sequence when determined, the HGVS description adopted by the laboratory and its correspondence with the (GCN)n nomenclature, the method and its limitations (in particular, whether exon 1 point variants were sought), and the classification according to ACMG/AMP (Association for Molecular Pathology) criteria [3, 33, 66]. The heterozygous (GCN)11 allele deserves a specific comment: it is common in the population, has very reduced penetrance and conflicting classifications in ClinVar, and its significance depends on the clinical context and on the other allele [8, 33, 40].

5.5. Ancillary investigations

Creatine kinase (CK) is usually normal or elevated up to 2 times the upper limit of normal; values 2 to 7 times normal have been described in patients with severe lower limb weakness, and the PNDS mentions cases above 5 times, with no diagnostic value [3, 4]. In Israel, the mean CK of 21 patients was 274 U/L (range 26–800), with 3 above 500 U/L [46]. Electromyography (EMG) is usually myopathic, especially in weak muscles, sometimes with spontaneous activity at rest in the tongue, face, and proximal muscles; nerve conduction studies are normal, and repetitive nerve stimulation and single-fibre EMG serve to exclude neuromuscular junction disease [3, 4]. In a typical presentation with a family history, the PNDS considers EMG unnecessary [3]. In the Israeli registry, EMG was myopathic in 16 of 30 patients, anti–acetylcholine receptor antibodies were negative in the 8 tested, and single-fibre EMG was negative in 4 [46].

Muscle MRI is not essential in the typical presentation, but it is useful in atypical forms and during follow-up, preferably as whole-body imaging (CT, computed tomography, if contraindicated) [3]. The suggestive pattern is early fatty infiltration of the tongue, adductor magnus, and soleus, followed by the vastus lateralis, rectus femoris, and lateral gastrocnemius; the iliopsoas, clinically affected early, is not among the first muscles involved on MRI [3, 53]. The tongue is also involved in mitochondrial diseases, Pompe disease, amyotrophic lateral sclerosis (ALS), and anti-MuSK antibody myasthenia, and the soleus in myofibrillar myopathies and limb-girdle dystrophies [3].

5.6. Muscle biopsy

Biopsy is not a first-line investigation. GeneReviews reserves it for patients with suggestive findings, two normal PABPN1 alleles, and negative molecular testing for similar disorders, and the PNDS for cases referred by a reference centre [3, 4]. Findings include variation in fibre size with hypertrophic type 2 fibres and small angular atrophic fibres, rimmed vacuoles, fatty infiltration, increased connective tissue, type 1 fibre predominance, ragged red fibres and COX-negative fibres (to be interpreted according to age), and core-like areas [3, 4]. Rimmed vacuoles are not present in every biopsy and are not specific [4]. The 8.5-nm intranuclear inclusions in palisades appear in 2–5% of nuclei (up to about 10% in homozygotes) and before symptoms; the filaments of inclusion body myositis, myofibrillar myopathies, and oculopharyngodistal myopathy measure 15–18 nm and appear in both the nucleus and the cytoplasm [3, 4]. Intranuclear immunohistochemistry for PABPN1 and ubiquitin after potassium chloride (KCl) pretreatment identifies aggregates that the PNDS considers pathognomonic [3]. In an Italian series of 423 biopsies, this immunofluorescence had a sensitivity of 100% (30 genetically confirmed OPMD cases) and a specificity of 96% (143 other neuromuscular diseases and 30 controls), and identified 23 new cases among 220 undiagnosed patients with ptosis, dysphagia, proximal weakness, or rimmed vacuoles (10.4%) [67]. Immunohistochemistry for p62 shows frequent intranuclear inclusions and helps distinguish OPMD from OPDM [8]. If a biopsy performed as a first-line test shows mitochondrial abnormalities with rimmed vacuoles, OPMD should be sought first [3].

5.7. Swallowing assessment

The water-swallow test consists of drinking 80 mL of water in one go; the normal duration averages 3 to 4 seconds and is abnormal above 7 seconds, and coughing or signs of aspiration are also indicative [3, 4]. The PNDS uses still water in the main text and cold water in the appendix, and GeneReviews ice-cold water [3, 4]. The TOMASS (Test of Masticating and Swallowing Solids) is the solid-food alternative [3]. The instrumental studies are videoendoscopic evaluation of swallowing by nasofibrescopy (VESS, videoendoscopic swallowing study, also called FEES, fibreoptic endoscopic evaluation of swallowing), which is accessible, requires no local anaesthesia, shows hypopharyngeal stasis and overflow aspiration, and provides indirect signs of UES dysfunction; and videofluoroscopy (VFSS, videofluoroscopic swallowing study), which directly assesses the UES (cricopharyngeal bar, "struggling" pharynx, vallecular and hypopharyngeal residue) and which many regard as the reference functional study [3, 4, 68]. High-resolution manometry is not a routine investigation in OPMD [3]. Scales include the FOIS and the NdSSS (Neuromuscular Disease Swallowing Status Scale), and quality-of-life questionnaires include the DHI (Dysphagia Handicap Index), the McHorney scale, the Salassa grade, and the SWAL-QOL [3, 4]. The Dysphagiameter-OPMD, a patient-reported outcome questionnaire in French and English, was validated in 162 patients, with a part A of 21 items on textures and 3 on liquids (Cronbach's alpha 0.90) and a part B on the impact on meals and thick saliva [69].

5.8. Biomarkers under investigation

In an Israeli series of 30 patients and 27 household controls, the kinematic viscosity of saliva was higher in patients (difference of 0.85 cSt; 95% confidence interval, 95% CI, 0.27–1.44) and was associated with aspiration risk (adjusted OR of 2.5 per cSt; 95% CI 1.1–6.1), with an area under the curve of 0.76 and preserved salivary flow; it is a candidate biomarker awaiting prospective validation [52]. In 25 (GCN)13 patients, plasma proteomics identified 18 proteins that distinguished severity, with six muscle proteins (ACTN2, MYOM2, CA3, APOBEC2, MYL3, PDLIM3) more than 200% higher in patients with limb weakness and correlated with soleus fat fraction; the data are exploratory [70].

5.9. Practical algorithm

5.10. Prenatal and preimplantation diagnosis

Once the familial expansion has been identified, prenatal diagnosis and preimplantation genetic testing are technically possible but rarely requested, given the late onset and the absence of early intellectual impact and of reduced life expectancy in the heterozygous forms (section 8) [3, 4].

6. Differential Diagnosis

6.1. Comparison table

The table combines the GeneReviews list, the PNDS differential diagnosis table, and the OMIM numbering confirmed in MedGen [3, 4, 10]. GeneReviews groups GIPC1 and LRP12 under "oculopharyngodistal myopathy 2 (OMIM PS164310)"; PS164310 is the phenotypic series, and the current gene-based numbering is OPDM1 #164310 (LRP12), OPDM2 #618940 (GIPC1), OPDM3 #619473 (NOTCH2NLC), OPDM4 #619790 (RILPL1), and OPDM5 #621446 (ABCD3), with OPMD2 #620460 (HNRNPA2B1) [4, 10, 72].

6.2. Myasthenia gravis

Myasthenia gravis is the main differential, especially in sporadic cases, and the most frequent cause of misdiagnosis [3, 8]. It is distinguished by fluctuation and fatigability of symptoms, asymmetric ptosis and activity-induced diplopia, response to anticholinesterases, electrophysiology (decrement on 3-Hz repetitive nerve stimulation, jitter on single-fibre EMG), anti–acetylcholine receptor and anti-MuSK antibodies, and the absence of a family history [3, 4, 46]. The Oxford Desk Reference includes the edrophonium (Tensilon®) test in the workup of ptosis [2]. Lambert-Eaton syndrome and the congenital myasthenic syndromes complete this group [3]. Coexistence is rare but possible: in a woman in her sixth decade with fluctuating bilateral ptosis, proximal weakness, increased jitter and a brother with confirmed OPMD, genetic testing was positive for OPMD and anti–acetylcholine receptor antibodies were also positive, in the setting of systemic lupus erythematosus treated with hydroxychloroquine for more than 30 years [73]. In Israel, 9 patients had been tested for myasthenia before diagnosis, all with negative results [46].

6.3. Mitochondrial diseases with ophthalmoplegia

Late-onset chronic progressive external ophthalmoplegia (CPEO) can be difficult to distinguish from OPMD [3]. In mitochondrial disease, ptosis begins earlier, ophthalmoparesis is more marked and there are multisystem signs, such as deafness, cardiac conduction abnormalities and diabetes, or the Kearns-Sayre picture [3, 8]. If PABPN1 testing is negative, biopsy looking for ragged red and COX-negative fibres (nonspecific in older people) and analysis of mtDNA and the nuclear maintenance genes (POLG, TWNK, RRM2B, SLC25A4, TK2) are indicated [3, 4]. Because OPMD also produces secondary mitochondrial changes, a biopsy with mitochondrial abnormalities and rimmed vacuoles should prompt a search for OPMD first [3, 8]. MNGIE (mitochondrial neurogastrointestinal encephalomyopathy, TYMP) combines bilateral ptosis and dysphagia with demyelinating neuropathy, leukodystrophy and intestinal pseudo-obstruction [4].

6.4. Oculopharyngodistal myopathies and OPMD2

The oculopharyngodistal myopathies share ptosis, ophthalmoplegia, dysphagia, dysarthria, and facial and pharyngeal weakness, but they affect the distal limb muscles, begin earlier (estimated mean age of 28 years, with the full phenotype in about 10 years), have moderately elevated CK and, according to the PNDS, variable early respiratory failure and long-term cardiovascular risk [3]. About 300 patients have been described since 1977, mainly in China, Japan, and South Korea [3]. OPDM1 to OPDM4 result from noncoding CGG/GGC expansions in LRP12, GIPC1, NOTCH2NLC, and RILPL1, and OPDM5 from a CCG expansion in the 5'UTR of ABCD3 in individuals of European ancestry [8, 74, 75]. Biopsy shows eosinophilic intranuclear inclusions of 1–2 µm that are positive for p62 and ubiquitin, with 15–18-nm filaments [3]. On MRI, in a comparison of 54 patients with OPDM and 57 with OPMD, early involvement of the soleus and medial gastrocnemius was characteristic of OPDM, severe involvement of the adductor magnus and the gluteus medius and minimus indicated OPMD, and a tibialis anterior score equal to or greater than that of the adductor magnus identified OPDM with a sensitivity of 86.4% and a specificity of 100% [8]. The pathogenic thresholds listed by the ACMG for these genes are more than 100 repeats in NOTCH2NLC (OPDM3), 93 or more in LRP12, 73 to 164 in GIPC1, and 135 or more in RILPL1 [66]. A Brazilian case from 2017, with ptosis since age 36, dysphagia since 52, and a claw hand with distal weakness at 57, illustrates the difficulty of separating the two entities without molecular testing [76].

OPMD2, described in 2022 in 10 unrelated families, results from heterozygous frameshift variants in the last coding exon of HNRNPA2B1 that abolish the native stop codon, escape NMD, and produce a common C-terminal extension; the altered protein has reduced affinity for karyopherin β2 and accumulates in the cytoplasm. The picture is a progressive OPMD-like dystrophy, but with much earlier onset, in childhood or adolescence [8, 28].

6.5. Other differentials

Myotonic dystrophy type 1 should be tested for when there is late-onset ptosis and dysphagia and PABPN1 testing is negative, given the facies, distal weakness, myotonia, early cataract, cognitive and multisystem involvement, and the need for cardiac screening [3, 77]. The Oxford Desk Reference includes OPMD in the differential of DM1, in which early dysphagia and ptosis are disproportionate to the general weakness [77]. DM2 is not a useful differential for the PNDS, because ptosis is rare [3]. Sporadic inclusion body myositis affects the anterior forearm compartment and the thigh, and the face without ptosis [3]; the MRI and ultrasound pattern, with involvement of the tongue, hamstrings, and gastrocnemius and sparing of the quadriceps, points to OPMD rather than to the quadriceps pattern of inclusion body myositis [31]. Polymyositis and progressive bulbar palsy lack ptosis, but late forms of OPMD may present with dysphagia and mild ptosis [4]. Late-onset Pompe disease can mimic OPMD: in a woman in her late seventies with slowly progressive ptosis, oropharyngeal dysphagia, and dysarthria over several years, the diagnosis was made by dried blood spot screening, which matters in practice because enzyme replacement therapy exists [3, 71]. ALS and Kennedy disease cause bulbar dysphagia without ptosis; OPMD never produces fasciculations [3, 4]. In children, simple congenital ptosis is the most common cause of ptosis, usually unilateral and nonprogressive, and congenital fibrosis of the extraocular muscles and blepharophimosis are congenital; the history of any ptosis should include questions about muscle weakness and dysphagia [2]. Aponeurotic ptosis in older people has a high lid crease, more than 10 mm from the lid margin, preserved levator function, and greater excursion on downgaze, and its association with OPMD is not rare [3].

7. Treatment and Risk Management Strategies

7.1. General principles and sources of recommendations

No disease-modifying treatment is approved; management is surgical, rehabilitative, nutritional, and preventive [4, 12, 78]. The GeneReviews recommendations are based on expert consensus, not on trials [5]. The 2022 French PNDS, prepared by a neuromuscular reference centre following the methodology of the Haute Autorité de Santé (HAS) and published by the HAS, FILNEMUS, and the Société Française de Myologie, without formal HAS validation, is the only specific national consensus identified; its recommendations on surgery are largely expert opinion [3]. The 2004 Cochrane review on the treatment of dysphagia in chronic muscle diseases found no randomised trials, only 7 surgical series, and could not determine the benefit of myotomy or dilation; it was withdrawn in 2014 and has not been replaced by a new version [79, 80]. Practical Neurology published a 2026 review on multisystem management, prompted by avoidable complications in general hospitals during ocular, pharyngeal, and gastrointestinal procedures; only the abstract was accessible [78]. In France, OPMD is recognised as a long-term condition (affection de longue durée, ALD), and follow-up is coordinated by the FILNEMUS reference and competence centres [3].

7.2. Ptosis

Initial nonsurgical measures are eyelid tape and the Mercier anti-ptosis clip (or an equivalent device) mounted on spectacles, with an adjustable spring; both expose the cornea to the risk of dryness and exposure keratitis [3, 81]. Surgery is indicated when ptosis interferes with vision, driving, or posture (neck pain from constant neck dorsiflexion), or when the eyelids cover more than 50% of the pupil [4]. Early correction indirectly reduces dysphagia, because it eliminates compensatory neck extension [3]. The PNDS recommends outpatient surgery under local anaesthesia, so that eyelid height can be adjusted with the patient awake; the choice of technique depends on the function of the levator palpebrae superioris and the frontalis muscle, on orbicularis weakness with lagophthalmos, and on whether the Bell phenomenon is absent or weak [3].

Two main techniques are used. Resection (shortening) of the levator palpebrae superioris or its aponeurosis is technically simple but usually has to be repeated once or twice because of recurrence as the disease progresses; the PNDS reserves it for moderate ptosis with good levator function (excursion greater than 8 mm) and a preserved Bell phenomenon, with limited resection to avoid corneal exposure [3, 4]. Frontalis suspension uses a sling passed through the tarsal plate of the upper eyelid and attached to the frontalis muscle, which is relatively spared in OPMD, using synthetic (silicone or polytetrafluoroethylene, PTFE) or autologous (fascia lata, temporalis fascia) material; it is permanent but, according to GeneReviews, requires general anaesthesia (the PNDS describes eyelid surgery under local anaesthesia), and it is the most common technique when levator function is poor or ocular elevation is limited [3, 4, 82]. Complications of suspension are rare: recurrence, extrusion of the material, lagophthalmos, keratitis or corneal abscess, usually transient and treated with artificial tears and ointment [3].

Published results come from single-centre or single-surgeon series. In Quebec, 20 years of applying Beard's surgical guidelines yielded satisfactory results, with 13% recurrence among patients followed for 9 years or more [83]. In 31 patients with levator function of 10 mm or more who underwent primary bilateral silicone suspension, the margin-reflex distance went from about −0.1 mm to 2.1–2.2 mm and the palpebral fissure from 5.2 mm to 7.7–7.9 mm; early sling adjustments and late retightening, after 39 months, for recurrence were sometimes needed [84]. In a 34-year single-surgeon series of 40 patients operated on via an anterior approach, unilateral biopsy of Müller muscle showed dystrophic changes and fatty infiltration in 29 (72.5%), and combined Müller-aponeurotic advancement was more effective than isolated aponeurotic advancement when Müller muscle was infiltrated; the decision factors were age at onset, levator function, previous surgery, systemic frailty, and other eye conditions (dry eye, glaucoma filtering surgery, corneal or refractive surgery) [85–87]. In the Israeli registry, 57.9% of patients with the 10/13 genotype had undergone ptosis surgery, with recurrence in 41.8%, in a procedure of about 1 hour usually under local anaesthesia [46].

There is no universally accepted algorithm, and thresholds differ among sources. A 2026 review proposes aponeurotic advancement with good levator function (greater than 12 mm), combined levator-Müller advancement with intermediate function (8–12 mm), and frontalis suspension with poor function (less than 8 mm), favouring undercorrection to avoid corneal exposure and allowing primary suspension in early-onset disease with moderate to severe ptosis [8]. The PNDS sets the threshold for levator resection at an excursion greater than 8 mm [3], and the series by Allen and colleagues used frontalis suspension even with levator function of 10 mm or more [84]. The table summarises the options.

7.3. Dysphagia: dietary measures and speech therapy

Initial management of dysphagia is dietary and behavioural. GeneReviews recommends cutting food into small pieces, avoiding eating in social settings or choosing easy-to-swallow foods, and using supplements if there is significant weight loss [4]. The PNDS details calm, divided meals without dual tasking; a seated position with the feet on the floor, hips and knees flexed, and the head slightly flexed (with a role for ptosis correction); homogeneous semisolid or puréed textures and thickening sauces (starch, fats, egg, gelling agents), according to the IDDSI (International Dysphagia Diet Standardisation Initiative) framework; treatment of aggravating factors (dental status, oral candidiasis, dental occlusion, salivation, gastro-oesophageal reflux); and food fortification and supplements if there is weight loss [3]. Speech therapy, usually weekly, addresses understanding of the problem, behaviour, textures, and posture; muscle strengthening is possible but of unproven efficacy; coughing and throat clearing are effective in clearing stasis, and there are exercises for velopharyngeal insufficiency and breathing-voice coordination [3]. Muscular Dystrophy UK adds, in its patient information, taking time over meals, avoiding talking while eating, and using thickeners in liquids and high-calorie drinks when there is unplanned weight loss [81].

7.4. Dysphagia: interventions on the upper oesophageal sphincter

Cricopharyngeal myotomy is extramucosal division of the cricopharyngeus muscle, which improves bolus passage through the UES [4]. GeneReviews recommends considering surgery when symptomatic dysphagia significantly affects quality of life, despite the absence of controlled trials [4]. The PNDS recommends it, as expert opinion, because it is the only applicable surgical technique, and notes that its value and efficacy decrease in advanced forms [3]. Preserved pharyngeal propulsion has been proposed as an indicator for myotomy [88]. The external extramucosal approach is through a left cervicotomy, without dividing the mucosa, with an increased risk of recurrent laryngeal nerve injury; the endoscopic transmucosal CO2 laser approach is faster, rarely causes fistulas if the mucosa is sutured, and is impossible with limited mouth opening, a narrow palate, or neck stiffness; it is now preferred for UES hypertonia, but there are no OPMD-specific publications [3]. Myotomy rapidly improves swallowing in most patients, but a significant proportion relapse after a few years, and gastropharyngeal reflux may occur [3, 4]. At a university hospital, of 39 patients who underwent extramucosal myotomy, 25 had complete remission, 10 marked improvement, and 4 no improvement (90% success); with a mean follow-up of 4 years, 12 of the 35 responders relapsed, on average at 39 months, about one third within 3 years; 2 of 3 relapses improved with endoscopic transmucosal myotomy, as did 1 of the 4 nonresponders [89]. In a retrospective review covering 1997–2002, 33 myotomies had more respiratory complications than eyelid surgery (section 7.7) [90].

UES dilation is the alternative to myotomy and the option for postsurgical relapse, using bougies or balloons, under general anaesthesia as an outpatient procedure (PNDS expert opinion) [3]. In a pilot study, dilation with a Maloney bougie (14 patients) or an achalasia dilator (3) produced improvement in 64.3% (95% CI 39.2–89.4) at 3 and 6 months and 55.7% (95% CI 28.9–82.5) at 12 and 18 months, with the dysphagia score falling from 9.6 to 7.2 at 3 months (p=0.05); manometry and radionuclide transit did not predict response [91]. At a regional swallowing clinic, 9 patients treated over a median of 13 years (3–15) with wire-guided 18-mm (54 Fr) Savary-Gilliard bougie dilation, as outpatients under sedation and repeated when symptoms recurred, received a median of 7.2 dilations (1–16), with a median interval of 15 months (4.5–45); the SSQ (Sydney Swallow Questionnaire) score fell from 1108 to 298 (73% reduction; 95% CI 52–94; p=0.0001), with no adverse events, and all maintained oral feeding [92].

Botulinum toxin injected into the UES is the point of greatest disagreement. GeneReviews cites it as an option and notes that endoscopic myotomy may be an alternative to open surgery with better results than toxin; the supporting evidence is a 2000 letter on therapeutic success and a 2014 letter on safety, by the same authors [4, 93, 94]. The PNDS does not recommend it in OPMD (expert opinion), because of the lack of controlled trials and the small size of the series [3]. Muscular Dystrophy UK patient information presents it as an alternative with a more temporary effect than myotomy [81]. The disagreement stems from scarce evidence, not from comparative data.

Intervention rates vary widely. In Israel, cricopharyngotomy was performed in 3.2% of patients, with relief lasting less than a year reported by one of them, and percutaneous endoscopic gastrostomy (PEG) in 2.1%; one patient with a distal jejunostomy after complications developed ileus and fatal aspiration pneumonia, and the authors attribute the low myotomy rate to awareness of relapse [46]. In the Canary Islands, 4.6% of patients underwent surgery for severe dysphagia, compared with 22.8% in a European comparison cohort of 139 patients [44].

7.5. Enteral nutrition and other surgery

Gastrostomy, endoscopic or radiologic, is indicated when oral intake is insufficient or there is severe aspiration; weight loss and pulmonary status determine the indication, which should be discussed in advance because acceptance is difficult [3]. Pharyngoplasty is possible for velar insufficiency with hypernasal speech impairing intelligibility, with no published series and a complex technique (expert opinion) [3]. Weight and body mass index (BMI) should be measured at the initial evaluation and at every visit, with monthly self-weighing, dietary surveys, nutrition consultation, and, if needed, laboratory tests for malnutrition (total protein, albumin, prealbumin, C-reactive protein, vitamins) [3]. The pharmaceutical form of medications should be adapted to the dysphagia [3].

7.6. Limb weakness, rehabilitation, and support

Physiotherapy and occupational therapy are encouraged, with walking sticks and walking frames to prevent falls and a wheelchair in severe forms [4]. The PNDS proposes physiotherapy twice a week, in 30- to 45-minute sessions adapted to fatigue, with self-directed rehabilitation in mildly affected patients; intensity should be stepped down if myalgia or weakness appears in the following days; eccentric strengthening should be avoided (in muscles graded below 4 on the MRC, Medical Research Council, scale) in favour of concentric work, balance, and functional tasks; aerobic reconditioning is considered essential, and adapted physical activity should be gentle, regular, and slowly progressive [3]. Occupational therapy provides assistive devices for bathing, transfers, and toileting and for walking (walking frame, forearm crutches, rollator), a manual wheelchair when fatigue or falls warrant it (a powered one is rarely needed), speech synthesis, and adaptation of the home, vehicle, and workplace [3]. Fitness to drive should be reassessed by the competent medical authority when ptosis or weakness compromises it [3]. Early screening for anxiety and depression, psychological support, attention to caregivers, and palliative care in advanced forms are part of the plan [3]. Systematic neuropsychological evaluation may be offered [4]. Some patients receive immunosuppressants for a misdiagnosis of myasthenia before the correct diagnosis is reached, an exposure avoidable with early genetic testing [8].

7.7. Anaesthesia and the perioperative period

General anaesthesia is not contraindicated, but the response to some drugs may differ and the risk of aspiration should always be assessed [3, 4]. No specific recommendations have been published. The PNDS advises favouring local and regional anaesthesia, measuring vital capacity before general anaesthesia, and anticipating respiratory complications (aspiration, atelectasis, bronchial infection, decompensation), especially in thoracic or abdominal surgery [3]. Regarding neuromuscular blocking agents, it recommends avoiding long-acting agents (pancuronium) in favour of shorter-acting ones (atracurium, vecuronium), states that rocuronium "seems to increase" the risk of postoperative respiratory decompensation, and recommends avoiding suxamethonium because of the potential risk of hyperkalaemia and rhabdomyolysis; there is no risk of malignant hyperthermia as such [3]. The available clinical sources are small and not always consistent, as summarised in the table.

A normal train-of-four (TOF) at the adductor pollicis did not guarantee safe extubation in the Japanese case, and the authors recommend considering routine pharmacological reversal and assessing tongue protrusion and head lift before extubation, even in the absence of pharyngeal symptoms, because subclinical upper airway dysfunction may be present [64]. The assertion of increased sensitivity to neuromuscular blockers in the shoulder arthroplasty case contrasts with the normal recovery described in the cisatracurium study [95, 97]. The discrepancy between the PNDS, which advises against rocuronium, and the two 2025 cases, which used it with sugammadex reversal, has not been resolved by comparative studies [3, 64, 97]. The doses shown in the table are those administered in the studies and cases and do not constitute recommended dosing; the dose of each drug follows its summary of product characteristics, adjusted by the anaesthetist.

7.8. Drugs, vaccines, and prevention of complications

No drug has a specific effect in OPMD, and none is formally contraindicated, including statins [3]. Aspiration pneumonia should be treated, protein and vitamin deficiencies corrected, and osteoporosis prevented and treated [3]. Fracture risk warrants bone densitometry and, if there is risk, annual assessment of calcium-phosphate metabolism and vitamin D, with referral to rheumatology [3]. Vaccines have no contraindications; they should be injected into a minimally affected muscle or subcutaneously, and influenza and COVID-19 vaccines are recommended [3]; GeneReviews recommends annual influenza vaccination in older patients [4]. Productive cough requires immediate medical attention because of the increased risk of lung abscess [4]. Therapeutic education and support from patient organisations are part of preventing the social isolation caused by frequent choking [3, 4].

7.9. Pregnancy, lactation, and transition

The sources consulted contain no specific recommendations for pregnancy or lactation in OPMD; in the typical heterozygous forms, symptoms usually begin after reproductive age, and the practical issue is reproductive counselling (section 8) [3, 4]. The biallelic forms with onset before age 35 and OPMD2 with onset in childhood or adolescence may require transition from paediatric to adult care, for which the sources also describe no protocol [8, 28].

7.10. Source recommendations and divergences

7.11. Regulatory status

As of 17 October 2026, no drug, gene therapy, or cell therapy is approved for OPMD in the USA or the EU [12, 15, 98]. Orphan drug designations and Fast Track designation are development tools that give the sponsor incentives, not marketing authorisations.

Table sources: FDA OOPD database [15]; EMA pages [14, 99, 100]; sponsor press release and annual report [16, 98]. The OOPD designation does not use the code "BB-301"; the match with the product is based on the product description (AAV9 vector with shRNA and optimised PABPN1) and the sponsor (Benitec), not on the name in the record [15]. The date of the Fast Track designation comes only from the sponsor, without confirmation in an official FDA source [16]. At the time of the 2015 and 2017 designations, the COMP (Committee for Orphan Medicinal Products) estimated the EU prevalence at about 0.1 per 10,000 population, about 5000 people [14, 99].

7.12. Clinical trials

The completed human trials are open-label, small, and uncontrolled, and none has been followed by a published confirmatory trial. The results do not allow indirect comparison between interventions, because the outcomes (quality of life, drinking test, videofluoroscopic measures, composite response analysis) and the populations differ. The trehalose trial defined laboratory safety as its primary outcome, and the functional improvements are uncontrolled secondary outcomes; the completed extension trial has no published results, and development was discontinued [103, 105, 106]. The efficacy data for BB-301 come exclusively from sponsor press releases, without numerical values by outcome, confidence intervals, or a control group, and have not been peer reviewed; an independent 2026 review confirms this limitation [8, 16]. Trehalose (SLS-005) has also been studied in other diseases: in ALS, regimen E of the HEALEY platform did not meet its primary endpoints, according to a review; in spinocerebellar ataxia, the trial was terminated for financial reasons; in Alzheimer disease, it was withdrawn; no SLS-005 trial in OPMD is registered on ClinicalTrials.gov [8, 110].

7.13. BB-301 and developments in the past 12 months

BB-301 is a modified AAV9 vector (AAV9PL) with a single bifunctional construct that expresses, under the muscle-specific Spc5-12 promoter, two microRNA-backbone shRNAs against endogenous PABPN1 (mutant and normal) and a codon-optimised copy of PABPN1 resistant to this silencing [13, 111]. In the A17 mouse, a single intramuscular injection inhibited mutant PABPN1, replaced it, and restored muscle strength and weight to wild-type levels [111]. The strategy derives from silence-and-replace work with two vectors, which reduced aggregates and fibrosis and normalised strength and the transcriptome in the mouse, including reversal of established inclusions [112, 113].

The recent timeline, according to the sponsor, is as follows, with the level of evidence for each step. On 3 November 2025, Benitec announced that the 6 cohort 1 patients were "responders" in an analysis requiring improvement in at least 2 of 5 components (SSQ without worsening, PhAMPC, 30% reduction in pathological sequential swallows, pharyngeal residue, cold water drinking test), with no deaths or related serious adverse events, and that the FDA had granted Fast Track designation (sponsor press release) [16, 114]. By that date, 23 patients had been enrolled in the BNTC-OPMD-NH-001 natural history study, with swallowing assessments every 3 months for 26 weeks before treatment [114]. In February 2026, the 4 patients with 12 months of follow-up were responders and the first patient maintained improvement at 24 months; in May 2026, the 6 cohort 1 patients had completed 12 months (press releases) [108, 115]. According to a 2026 review citing the press releases, in one patient pathological sequential swallows of thin liquid fell from 80% to 17% [8]. In September 2026, cohort 2 was complete, with 3 patients treated, and a type C meeting with the FDA on the pivotal trial design had taken place in the third quarter [109]. On 5 October 2026, the sponsor announced that the FDA had requested additional data, including those from the natural history study, before agreeing to an open-label single-arm pivotal trial, that the final design is expected to be confirmed in the first quarter of 2027, and that enrolment in the pivotal trial is planned for mid-2027 (press release; formal FDA opinion not public) [116]. The 12-month cohort 1 data and interim cohort 2 data will be presented as a poster at the ESGCT (European Society of Gene and Cell Therapy) congress in Hamburg, 27–30 October 2026, after the reference date of this article [116]. Additional sites are planned in Canada and France [8]. The sponsor estimates about 15,000 patients in North America, Europe, and Israel, an unvalidated commercial figure [116].

Other 2025–2026 developments are observational: the Israeli national registry IsrO-PMD (NCT07146256, 300 patients planned through 2030) and the saliva and oral health study (NCT07118280, 100 patients), both recruiting at Sheba Medical Center [110, 117]; the estimate of genetic prevalence in the UK Biobank [11]; and the 2026 reviews identifying as prerequisites for trials the availability of natural history data, validated outcome measures and biomarkers, patient registries, epidemiological and economic data, and the involvement of patient organisations [12, 78]. Other ClinicalTrials.gov registrations without results are a study of expiratory muscle training in neuromuscular diseases (NCT04009408, status unknown), a study of aerobic training (NCT02158156, status unknown), a natural history study at the University of New Mexico (NCT03161847, withdrawn with no enrolment), and a screening study in Florida (NCT02877784, 8 participants, completed) [110].

7.14. Preclinical strategies

The strategies under investigation have been tested in mammalian cells, nematodes, Drosophila, and mice; most are pharmacological and aim to reduce cellular toxicity or PABPN1 aggregation, and none has yet reached human studies, except those already described [4, 8, 118].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

The risk to relatives depends on whether the disease in the family results from a heterozygous expansion of 11 to 18 GCN or from biallelic expansions, and on whether the partner is a carrier [4]. The probability that the partner also has an expansion is higher among French Canadians and Bukharan Jews in Israel, and in any population the (GCN)11 allele has a frequency of 1–2% [4, 8]. Siblings with one or two expansions will be affected, and age at onset and severity correlate with length and zygosity [4].

8.2. Parents and family history

Most heterozygous probands have an affected parent, and molecular testing of the parents is recommended regardless of the family history [4]. A heterozygous (GCN)11 parent may have a mild, unrecognised form [4, 40]. The family history may appear negative because of failure to recognise the disease, early death of a parent, or late onset; only molecular testing of the parents can confirm it as negative [4]. If the expansion is not found in either parent, the explanations are a de novo variant (if parentage is confirmed; otherwise only presumed) or parental germline or somatic-germline mosaicism, which leukocyte DNA may not detect [4]. If the parents have not been tested but are clinically unaffected, siblings remain at increased risk because of the late onset and the possibility of mosaicism [4]. In biallelic probands, the parents are typically both heterozygous and, more rarely, one heterozygous and the other biallelic; they may or may not have manifestations depending on the size of the expansions [4]. All children of a biallelic patient inherit an expansion, unless the partner is a carrier [4]. Other relatives are at risk if a parent of the proband has the expansion [4]. In the Israeli registry, 96.8% of patients had a family history and 67.4% an affected parent [46].

8.3. Interpretation of the (GCN)11 allele and of population findings

The (GCN)11 allele has low penetrance in the heterozygous state and manifests late, after age 70, and is frequently detected in homozygotes or compound heterozygotes, which is why it was considered recessive [3, 40]. In the UK Biobank, most of the 1896 (GCN)11 heterozygotes had no compatible diagnostic codes, whereas 11.4% of (GCN)12 carriers and 70% of (GCN)13 carriers did [11]. A genetic prevalence about 10 times the clinical prevalence implies many minimally symptomatic or asymptomatic carriers, which matters for the interpretation of secondary PABPN1 findings in exomes and for estimating the number of candidates for therapies [11]. Attributing neurological manifestations to a heterozygous carrier requires caution, as in the patient with frontotemporal lobar degeneration without myopathy [34]. The Greek suggestion that maternally transmitted expansions are associated with earlier onset contradicts the absence of a parent-of-origin difference described in other series and is exploratory [8, 43].

8.4. Predictive testing and minors

Predictive testing is possible once the expansion has been identified in an affected relative and should be preceded by formal counselling that discusses the socioeconomic consequences, long-term follow-up, and limitations [4]. In France, asymptomatic relatives of a patient with a variant of 12 to 18 GCN may request presymptomatic diagnosis, which can be ordered only by a multidisciplinary team with expertise in medical genetics, under a protocol declared to the Agence de la Biomédecine [3]. Predictive testing in asymptomatic minors is considered inappropriate, because this is an adult-onset disease without benefit from early treatment and because of issues of autonomy, family dynamics, discrimination, and anxiety, according to the positions of the NSGC (National Society of Genetic Counselors, 2018) and the AAP/ACMG (American Academy of Pediatrics, 2013) cited by GeneReviews [4]. In families with an established diagnosis, symptomatic individuals should be tested regardless of age [4]. Presymptomatic testing in young adults should be handled with particular tact [3].

8.5. Prenatal and preimplantation diagnosis

Family planning should include risk assessment and discussion of prenatal or preimplantation testing before pregnancy, and counselling should be offered to young adults who are affected or at risk [4]. There are differing perspectives on prenatal testing for adult-onset diseases: the NSGC does not recommend it if it will not change the management of the pregnancy or of childhood and recommends prior counselling on the natural history, treatments, the child's future autonomy, and discrimination [4]. In France, requests are directed to a Centre Pluridisciplinaire de Diagnostic Prénatal and reviewed case by case; they are rare, given the late onset and the absence of early intellectual impact and of reduced life expectancy [3]. When both members of a couple are heterozygous, the 25% risk of a biallelic child, with early onset, central nervous system involvement, and reduced life expectancy, is the key information in preconception counselling [4, 39].

8.6. Counselling content

The diagnosis should be disclosed in a dedicated consultation by a specialist from a reference or competence centre, preferably in the presence of a trusted person, with information on the autosomal dominant nature and the risk to ascendants, descendants, and collateral relatives, and on patient organisations and reliable information sources, with an offer of psychological support, a post-disclosure visit within the following month, a written report, and immediate liaison with the attending physician [3]. Counselling should be provided by a specialist physician, a clinical geneticist, or a genetic counselor, ideally at a neuromuscular centre, and should explain the relationship between repeat number and severity, the earlier onset and potential cognitive decline of homozygotes and compound heterozygotes, and the low penetrance of (GCN)11 [3]. Family support resources and social services complete the plan [4].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

OPMD has been identified in individuals from more than 30 countries [4]. Prevalence estimates are of different kinds and are not interchangeable.

The UK Biobank figure comes from a volunteer cohort that is not a random sample of the British population, and clinical expression was inferred from diagnostic codes rather than examination; only the abstract of the study was read [11]. The 2025 review of the prevalence of 17 neuromuscular diseases (literature from 1990 to 2023) does not report, in its abstract, a separate figure for OPMD [125]. Point prevalences in founder populations do not generalise to unselected populations [5].

9.2. Founder populations and North America

In Quebec, OPMD has its highest prevalence among patients of French-Canadian origin, and the families share the (GCN)13 expansion [2, 4]. The Saguenay cohort of 333 (GCN)13 patients is the largest natural history series, with a median age at onset of 54 years for ptosis and dysphagia and 58 years for proximal lower limb weakness, and a median age at death of 77 years [47]. In the USA, most affected individuals descend from French Canadians, but there are patients of Ashkenazi Jewish origin, the family of the original description, and Hispanic Americans [4, 18]. In New Mexico, records from 1965 to 2001 identified 216 cases in 39 Hispanic kindreds, spanning up to four generations, mainly from the northern part of the state, with 10 individuals from different kindreds carrying the same (GCN)13 expansion and no reduction in life expectancy compared with unaffected relatives (P=0.81) [126]. GeneReviews attributes this study to Hispanic Americans in Texas, but the original article refers to New Mexico [4, 126]. In California, Hispanic American families have been described [127] and, in the southern part of the state, 25 initially misdiagnosed patients [62]. The University of New Mexico maintains a patient registry structured according to the NIH (National Institutes of Health) standard [128].

In Israel, the IsrO-PMD national registry at Sheba Medical Center enrolled, between 2022 and September 2025, 102 symptomatic Jewish patients with a molecular diagnosis, from 75 nuclear families: 90.2% of Bukharan ancestry, 5 Bulgarian, 1 from Georgia, 1 from Tunisia, and 3 Karaites from Egypt; only 39.2% had been born in Israel [46]. The 10/13 genotype was present in 93.1% (89 Bukharan, 5 Bulgarian, 1 Georgian), 13/13 in 3 Bukharan patients, 11/11 in 3 Karaites from one family, and 10/15 in a Tunisian patient with no family history [46]. Based on the 1997 estimate of 1:600 and assuming the population had doubled, the authors would expect about 233 patients, and they acknowledge that the registry is underrepresentative [21, 46]. The (GCN)13 homozygotes described in Quebec and among Bukharan Jews result from the high frequency of the allele in these populations [4, 22, 39].

9.3. Europe

In France, the series of 354 unrelated index cases diagnosed between 1999 and 2014 is the basis for the genotype–phenotype correlation (section 11), with 10/13 as the most frequent genotype (176 patients) [4, 38]. In Spain, 34 patients showed no correlation between expansion size, age at onset, and phenotype, and the frequency of the (GCN)11 polymorphism described in other countries was not confirmed in controls [42]. In the Canary Islands, a retrospective study of 123 patients found the (GCN)15 allele in 113 (94.2%), a probable founder effect, with onset at 45.1 years, ptosis as the first symptom in 85.2%, and dysphagia in 12%; compared with a European cohort of 139 patients, limb weakness (35.1% vs. 50.4%), need for a walking aid or wheelchair (9.3% vs. 27.4%), and surgery for severe dysphagia (4.6% vs. 22.8%) were less frequent, despite the larger expansion [44]. In the United Kingdom, 31 patients had expansions from (GCN)12 to (GCN)17, with (GCN)14 almost as frequent as (GCN)13, which argues against a strong founder effect [41]; a series of 86 patients identified 13 expansion types [29]. In the Netherlands, the most frequent expansion was (GCN)16 [45]. In Greece, 23 patients from 19 families had 8 distinct expansion genotypes, with no founder effect and considerable diagnostic delay [43]. In Denmark, 13 patients from 8 families were characterised for ocular, bulbar, limb, and cardiopulmonary involvement [48]. In Italy, the first Italian case of (GCN)11 homozygosity, the eighth worldwide, was described [61].

9.4. Asia and South America

In China, 21 patients from 9 families had onset at 50.6 years (45–60), ptosis as the first symptom in 42.9%, dysphagia a median of 5.5 years later, external ophthalmoplegia in 38.1%, and muscle weakness in 33.3%, always involving the neck flexors; there were 5 genotypes, with classic GCG expansions in 7 families and lengthenings with additional GCA codons in 2 [129]; another Chinese series was published in 2014 [130]. In Japan, the frequency of the (GCN)11 allele is 1–2%, and the first Asian case of the p.(Gly12Ala) variant was described in 2021 [4, 31]. The oculopharyngodistal myopathies, the main differential, are more frequent in East Asia [3]. In Uruguay, a laboratory validated a low-cost fragment method in 90 samples [65].

9.5. Portugal and Brazil

In the sources consulted, the Portuguese contributions are in basic research: Maria Carmo-Fonseca's group in Lisbon, with French and Canadian collaborators, showed that the inclusions are PABPN1 aggregates that sequester polyadenylated RNA and characterised the aggregation properties of the protein in vivo [26, 36]. From Brazil, the sources include a case published in 2017 of a 62-year-old man with ptosis since age 36, dysphagia since age 52, distal weakness, and a family history, without genetic confirmation, in whom OPMD could not be distinguished from OPDM [76]. The sources consulted contain no clinical series, prevalence estimates, or data on access to care for Portugal or Brazil; absence from the sources consulted does not demonstrate an absence of published data.

9.6. Special populations

Older people with dysphagia are the group at highest risk of aspiration pneumonia and malnutrition, and GeneReviews recommends annual influenza vaccination for them [4]. Institutionalised patients or those with other respiratory diseases may have pulmonary presentations that delay diagnosis [63]. Biallelic forms are concentrated in populations with a high carrier frequency, such as French Canadians and Bukharan Jews [4, 21].

9.7. Reference networks and patient organisations

The relevant European Reference Network is EURO-NMD (European Reference Network for rare neuromuscular diseases) [17]. In France, the FILNEMUS network, AFM-Téléthon (with care pathway coordinators), and the Société Française de Myologie took part in the PNDS [3]; AFM-Téléthon also published a monograph on OPMD in 2018 [4]. In the USA, there are the Muscular Dystrophy Association and the University of New Mexico national OPMD registry; in Canada, Muscular Dystrophy Canada; in the United Kingdom, Muscular Dystrophy UK, which maintains an information page reviewed in February 2025 and a helpline [4, 81]. The OPMD-specific page of Muscular Dystrophy Canada was not accessible in October 2026. The PABPN1 variant database is part of the Leiden Muscular Dystrophy pages (LOVD, Leiden Open Variation Database) [4]. In Israel, the IsrO-PMD registry is affiliated with Sheba Medical Center [46, 117].

10. Illustrative Clinical Case

10.1. OPMD due to the p.(Gly12Ala) point variant, without expansion (Nishii et al., 2021)

A 78-year-old Japanese woman was admitted for recurrent aspiration pneumonia [31]. She had had slowly progressive bilateral ptosis and dysphagia since age 62; at age 66 she had undergone bilateral levator palpebrae resection, with recurrence of ptosis 5 years later. During the admission, swallowing was so impaired that a gastrostomy was performed. Her son had the same symptoms (ptosis and dysphagia), and her parents' medical history was unknown; the pedigree is shown in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8256512/figure/Fig1/) [31].

Examination showed symmetric weakness predominantly affecting proximal and neck muscles: neck extensors MRC grade 4, neck flexors 2, deltoid 4, pectoralis major 3, latissimus dorsi 4, iliopsoas 3, quadriceps 4, gluteus maximus 2, and biceps femoris 2, with normal tibialis anterior and gastrocnemius. She walked unaided but needed support on stairs and could not run; she had a hypernasal voice, dysphagia, and dysarthria, without tongue atrophy [31]. The electrocardiogram was normal, CK was 45 U/L, anti–acetylcholine receptor and anti-MuSK antibodies were negative, and arterial partial pressure of CO2 was 45.9 mmHg. Repetitive nerve stimulation was normal, and needle EMG of the tongue and orbicularis oculi showed small polyphasic potentials without denervation, a chronic myopathic pattern [31]. On T2-weighted thigh MRI, the long head of the biceps femoris and the adductor magnus were hyperintense and the anterior compartment was spared; ultrasound showed a diffuse hyperechoic pattern in the tongue, biceps femoris, and gastrocnemius, with relative sparing of the vastus lateralis and tibialis anterior, a posterior-predominant pattern (Figure 2, https://pmc.ncbi.nlm.nih.gov/articles/PMC8256512/figure/Fig2/) [31].

The slowly progressive ptosis and dysphagia, the symmetric proximal-predominant muscle involvement without myocardial disease, the family history consistent with dominant transmission, and the myopathic pattern pointed to OPMD. Testing for the expansion was negative, and direct sequencing of PABPN1 identified the heterozygous variant NM_004643.4:c.35G>C, p.(Gly12Ala) (written by the authors as "c.35G > C, p.Gly12Ala"), which converts the GGG codon of glycine 12 to GCG and produces 13 contiguous alanines without an expansion, (GCG)6(GCA)3(GCG)2(GCT)1(GCG)1, with the same effect as a (GCN)13 expansion [9, 31]. The son was not tested [31]. The authors described the case as the first in Asia and the fourth worldwide, after three cases from the United Kingdom; in all four, symptoms began in the seventh decade, and the authors compare the mean age of 71 years of the four cases with the mean age at diagnosis of 64 years in French (GCN)13 heterozygotes to suggest slower progression with the point variant, a hypothesis based on four patients [31, 38].

10.2. Lessons from the case

The case shows that a normal sizing test does not rule out OPMD when the phenotype is typical, and that sequencing of exon 1 is the next step [8, 31, 32]. It also shows the natural course of dysphagia not treated surgically through to the stage of aspiration pneumonia and gastrostomy, and recurrence of ptosis after levator resection, which GeneReviews and the PNDS describe as expected [3, 4]. The report does not mention videofluoroscopic assessment or discussion of myotomy or UES dilation before gastrostomy, which the guidelines propose when dysphagia significantly affects quality of life and the disease is not yet far advanced [3]. The imaging pattern, with involvement of the tongue and the posterior thigh compartment and sparing of the quadriceps, helped rule out inclusion body myositis [31].

10.3. Pulmonary presentation (Mañana Valdés et al., 2026)

A second case illustrates presentation via the respiratory route [63]. A 68-year-old man, a former miner and ex-smoker of 40 pack-years, living in a care facility but independent, was admitted with dyspnoea, fever, productive cough, peripheral oxygen saturation of 89%, and bibasal crackles, with lymphopenia of 0.61 × 10⁹/L, C-reactive protein of 13.3 mg/dL, and partial pressure of oxygen of 66 mmHg. Febrile relapses with radiological worsening, ground-glass opacities and peribronchiolar consolidations on CT (Figure 1, https://pmc.ncbi.nlm.nih.gov/articles/PMC12887766/figure/fig0005/), T-cell lymphopenia, an isolated anti-SSA/Ro52 antibody, and detection of Pneumocystis jirovecii in the first bronchoalveolar lavage, considered colonisation after a second negative lavage, led to an extensive workup [63]. At 6 weeks, at the fourth relapse, bilateral ptosis without ophthalmoparesis and weakness of both girdles were noted; CK was 80 U/L, pulmonary function tests showed no diaphragmatic weakness, MRI showed atrophy of the posterior thigh compartment, oropharyngeal dysphagia was confirmed, quadriceps biopsy showed rimmed vacuoles, and genetic testing identified a PABPN1 GCN expansion, the size of which is not reported [63]. Oral methylprednisolone 1.5 mg/kg/day and enteral nutrition were started; corticosteroid therapy was the authors' decision, has no specific rationale in OPMD, and is not included in the guidelines [3, 63]. The patient died 7 years after diagnosis from recurrent aspiration-related respiratory infections [63].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In heterozygotes, OPMD does not appear to shorten life expectancy, but quality of life in the final years is greatly diminished [4]. In New Mexico, life-table analysis showed no difference from unaffected relatives (P=0.81) [126]; in Quebec, among 333 (GCN)13 patients, the median age at death was 77 years and the leading cause of death was respiratory disease [47]. The designs of these studies differ and the figures are not directly comparable. Before age 75, 27% of the Quebec patients had limited walking and 14% used a wheelchair for long distances or in daily life [47]. The severity of dysphagia is the main determinant of prognosis, and life-threatening risks are assessed through the weight curve and sarcopenia, pulmonary status, and choking episodes [3, 4]. In (GCN)13 homozygotes, the disease begins before age 35, involves the central nervous system, and shortens life, with deaths between ages 50 and 57 in a series of 10 patients [39].

Repeat length and zygosity modulate age at diagnosis, as shown by the French series of 354 index cases, adapted by GeneReviews [4, 38]. The table shows mean age at diagnosis, not age at onset, and the gradings (±, +, ++, +++) are those of the source.

The correlation is not universal: in Spain and the Netherlands no relationship was found between length and phenotype, in the United Kingdom the association was weak, in the Canary Islands the (GCN)15 expansion had a milder course than the European cohorts, and in the Dutch cohort progression over 20 months did not depend on genotype or disease duration [41, 42, 44, 45, 55]. In the UK Biobank, the proportion of carriers with compatible diagnostic codes rose from 11.4% for (GCN)12 to 70% for (GCN)13 [11].

11.2. Initial evaluation after diagnosis

Cardiac evaluation is not needed for OPMD, because cardiomyopathy and dysrhythmias are not associated with the disease; an electrocardiogram may be useful when the differential diagnosis with DM1 or mitochondrial disease has not yet been settled [3, 4].

11.3. Surveillance

Asymptomatic at-risk relatives have no specific presymptomatic surveillance; predictive testing and follow-up are guided by counselling (section 8) [4]. Productive cough requires immediate medical attention [4].

11.4. Outcome measures for follow-up and trials

In the Dutch cohort, deltoid, quadriceps, iliopsoas, and tongue strength, the 10-step test, MFM dimension 1, and repetition of the syllable /pa/ detected decline over 20 months [55]. Muscle fat fraction on quantitative MRI increased by 1.7–1.9% over 20 months, with the soleus as the most responsive muscle, making it an imaging biomarker of progression [56]. The Dysphagiameter-OPMD, salivary viscosity, and plasma muscle proteins are being validated [52, 69, 70]. The 2026 reviews regard validation of these measures as a prerequisite for trials of the therapies in development [12].

12. Summary and Concluding Remarks

Oculopharyngeal muscular dystrophy is an adult-onset myopathy caused by lengthening of the N-terminal polyalanine tract of PABPN1 from 10 to 11 to 18 alanines, through short, stable expansions of the exon 1 GCN repeat or, rarely, through substitutions of the glycine 12 codon that produce the same effect [4, 8, 31]. The disease is dominant in most families, but the dosage effect is evident: biallelic individuals have earlier onset and more severe disease, with central nervous system involvement and reduced life expectancy when both alleles have 12 or more codons, and the (GCN)11 allele, present in 1–2% of European, North American, and Japanese populations, is recessive in the homozygous state, a modifier in compound heterozygosity, and rarely causes mild, late-onset disease in the heterozygous state [8, 39, 40]. The historical "(GCG)n" nomenclature differs from the current one by four units, and HGVS descriptions vary among laboratories; the report should give the GCN count of each allele on transcript NM_004643.4 [3, 4, 33].

The typical clinical picture, with bilateral ptosis and dysphagia from age 48–50 and proximal weakness 5 to 10 years later, without cardiac involvement, allows a clinical diagnosis of suspicion, which repeat sizing confirms in more than 99% of patients with an expansion [3, 4]. A normal result does not rule out the disease when the phenotype is typical, because codon 12 variants require sequencing of exon 1, and panels or exomes that do not size the repeat do not rule it out [8, 32, 66]. Myasthenia gravis is the most common misdiagnosis; the oculopharyngodistal myopathies, with distal weakness and noncoding expansions in other genes, and HNRNPA2B1-related OPMD2, with onset in childhood or adolescence, are distinct entities [8, 10, 28].

Clinical prevalence is about 1:100,000 in France and much higher in the founder populations of Quebec (1:1000) and of Bukharan Jews in Israel (1:600), and the Canary Islands have a probable founder effect for the (GCN)15 allele; the genetic prevalence of 1:10,200 in the UK Biobank indicates that many carriers go undiagnosed [4, 11, 44]. Clinical data from Portugal and Brazil are lacking in the sources consulted.

Treatment remains surgical and supportive: correction of ptosis by levator resection or frontalis suspension, with frequent recurrence; dietary modification and speech therapy; cricopharyngeal myotomy or repeated upper oesophageal sphincter dilation when dysphagia compromises quality of life, bearing in mind that about one third of patients relapse within 3 years after myotomy; gastrostomy when oral intake is insufficient; and rehabilitation, prevention of aspiration pneumonia, vaccination, and specific anaesthetic precautions [3, 4, 89]. Sources diverge on botulinum toxin in the sphincter, on the thresholds for choosing the eyelid surgery technique, and on the use of rocuronium, divergences that reflect the scarcity of comparative studies [3, 8, 64]. No disease-modifying therapy is approved; the gene therapy BB-301, which silences endogenous PABPN1 and replaces it with a functional copy, is in a phase 1b/2a trial with orphan designations in the EU and the USA, with efficacy data released only by the sponsor and a pivotal trial planned for mid-2027, whereas trehalose and autologous myoblasts have not progressed [13, 100, 106, 116]. Annual neurological, ophthalmological, swallowing, and respiratory surveillance, monthly weight monitoring, and genetic counselling tailored to each family's genotype are the foundation of follow-up [3, 4].

13. References

1. Orphanet. Oculopharyngeal muscular dystrophy (ORPHA:270). Available from: https://www.orpha.net/en/disease/detail/270
2. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 292–5.
3. Centre de référence des maladies neuromusculaires Atlantique Occitanie Caraïbes (AOC). Protocole National de Diagnostic et de Soins (PNDS):Dystrophie musculaire oculopharyngée. Saint-Denis La Plaine: Haute Autorité de Santé; 2022 [final version 2022-09-16; cited 2026 Oct 17]. Available from: https://www.has-sante.fr/jcms/p_3374041/fr/dystrophie-musculaire-oculopharyngee
4. Trollet C, Boulinguiez A, Roth F, Stojkovic T, Butler-Browne G, Evangelista T, et al. Oculopharyngeal Muscular Dystrophy. 2001 Mar 8 [updated 2020 Oct 22]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA):University of Washington, Seattle; 1993–. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1126/
5. GeneGuidance. PABPN1 — clinical curation of the gene and the OPMD condition (OMIM 164300, ORPHA 270). Version of 2026-09-26.
6. VariantValidator. Transcripts of the PABPN1 gene (MANE, GRCh38) [cited 2026 Oct 17]. Available from: https://variantvalidator.org
7. National Center for Biotechnology Information. Homo sapiens poly(A) binding protein nuclear 1 (PABPN1), transcript variant 1, mRNA. NCBI Reference Sequence NM_004643.4 [cited 2026 Oct 17]. Available from: https://www.ncbi.nlm.nih.gov/nuccore/NM_004643.4
8. Alberti C, Gagliardi D, Ronchi D, Ripolone M, Napoli L, Moggio M, et al. Oculopharyngeal muscular dystrophy: from molecular pathogenesis to gene therapy. Mol Neurobiol. 2026;63(1). doi:10.1007/s12035-026-06251-7. PMID: 42867740. PMC13661686.
9. VariantValidator. Validation of NM_004643.4:c.35G>C, c.34G>T, c.30_32dup, and c.33_35dup (GRCh38, mane_select) [cited 2026 Oct 17]. Available from: https://variantvalidator.org
10. National Center for Biotechnology Information. MedGen: oculopharyngeal muscular dystrophy 1–2 and oculopharyngodistal myopathy 1–5 [cited 2026 Oct 17]. Available from: https://www.ncbi.nlm.nih.gov/medgen/?term=oculopharyngodistal+myopathy
11. Villella C, Gagliardi D, Sebastiani E, Corti S, Comi G, Houlden H, et al. PABPN1 pathogenic expansion in the UK Biobank: reframing genetic prevalence of oculopharyngeal muscular dystrophy. J Neurol Neurosurg Psychiatry. 2026. doi:10.1136/jnnp-2026-339153. PMID: 42816172.
12. Oelbrandt F, Voermans N, Warman-Chardon J. Recent progress in emerging therapeutics and evaluation of oculopharyngeal muscular dystrophy. Curr Opin Neurol. 2026;39(5):483-490. doi:10.1097/WCO.0000000000001508. PMID: 42630085.
13. ClinicalTrials.gov. NCT06185673: A Phase 1b/2a, open-label, dose escalation study to evaluate the safety and clinical activity of intramuscular doses of BB-301 administered to subjects with oculopharyngeal muscular dystrophy with dysphagia. Bethesda (MD):National Library of Medicine; [last updated 2025-12-31; cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT06185673
14. European Medicines Agency. EU/3/16/1816 – orphan designation for treatment of oculopharyngeal muscular dystrophy (genetically modified adeno-associated viral vector serotype 9 expressing shRNA as well as a codon-optimised shRNA-insensitive wildtype PABPN1; BB-301). Amsterdam: EMA; 2017 [cited 2026 Oct 17]. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-16-1816
15. U.S. Food and Drug Administration, Office of Orphan Products Development. Search Orphan Drug Designations and Approvals: genetically modified, non-self replicating adeno-associated virus serotype 9 expressing shRNA to knock down mutant PABP1 as well as a codon optimized, shRNA-insensitive, wildtype PABN1 – treatment of oculopharyngeal muscular dystrophy (designated 2018-01-08; Benitec Biopharma) [cited 2026 Oct 17]. Available from: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=617717
16. Benitec Biopharma Inc. Benitec Biopharma provides positive interim clinical study results for BB-301 phase 1b/2a clinical trial and receives FDA Fast Track designation for BB-301 [press release, 2025-11-03]. Form 8-K, Exhibit 99.2. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312525261665/bntc-ex99_2.htm
17. European Reference Network for rare neuromuscular diseases (EURO-NMD) [cited 2026 Oct 17]. Available from: https://ern-euro-nmd.eu/
18. Victor M, Hayes R, Adams RD. Oculopharyngeal muscular dystrophy. A familial disease of late life characterized by dysphagia and progressive ptosis of the eyelids. N Engl J Med. 1962;267:1267-72. doi:10.1056/NEJM196212202672501. PMID: 13997067.
19. Brunet G, Tomé FM, Samson F, Robert JM, Fardeau M. [Oculopharyngeal muscular dystrophy. A census of French families and genealogic study]. Rev Neurol (Paris). 1990;146(6-7):425-9. PMID: 2204987.
20. Brunet G, Tomé FM, Eymard B, Robert JM, Fardeau M. Genealogical study of oculopharyngeal muscular dystrophy in France. Neuromuscul Disord. 1997;7 Suppl 1:S34-7. doi:10.1016/s0960-8966(97)00079-5. PMID: 9392013.
21. Blumen SC, Nisipeanu P, Sadeh M, Asherov A, Blumen N, Wirguin Y, et al. Epidemiology and inheritance of oculopharyngeal muscular dystrophy in Israel. Neuromuscul Disord. 1997;7 Suppl 1:S38-40. doi:10.1016/s0960-8966(97)00080-1. PMID: 9392014.
22. Blumen SC, Brais B, Korczyn AD, Medinsky S, Chapman J, Asherov A, et al. Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. Ann Neurol. 1999;46(1):115-8. PMID: 10401788.
23. Brais B, Xie YG, Sanson M, Morgan K, Weissenbach J, Korczyn AD, 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(3):429-34. doi:10.1093/hmg/4.3.429. PMID: 7795598.
24. Brais B, Bouchard JP, Gosselin F, Xie YG, Fardeau M, Tomé FM, et al. Using the full power of linkage analysis in 11 French Canadian families to fine map the oculopharyngeal muscular dystrophy gene. Neuromuscul Disord. 1997;7 Suppl 1:S70-4. doi:10.1016/s0960-8966(97)00086-2. PMID: 9392020.
25. Brais B, Bouchard JP, Xie YG, Rochefort DL, Chrétien N, Tomé FM, et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat Genet. 1998;18(2):164-7. doi:10.1038/ng0298-164. PMID: 9462747.
26. Calado A, Tomé FM, Brais B, Rouleau GA, Kühn U, Wahle E, et al. Nuclear inclusions in oculopharyngeal muscular dystrophy consist of poly(A) binding protein 2 aggregates which sequester poly(A) RNA. Hum Mol Genet. 2000;9(15):2321-8. doi:10.1093/oxfordjournals.hmg.a018924. PMID: 11001936.
27. Raz V, Butler-Browne G, van Engelen B, Brais B. 191st ENMC international workshop: recent advances in oculopharyngeal muscular dystrophy research: from bench to bedside 8-10 June 2012, Naarden, The Netherlands. Neuromuscul Disord. 2013;23(6):516-23. doi:10.1016/j.nmd.2013.03.001. PMID: 23578714.
28. Kim HJ, Mohassel P, Donkervoort S, Guo L, O'Donovan K, Coughlin M, et al. Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy. Nat Commun. 2022;13(1):2306. doi:10.1038/s41467-022-30015-1. PMID: 35484142. PMC9050844.
29. Robinson DO, Hammans SR, Read SP, Sillibourne J. Oculopharyngeal muscular dystrophy (OPMD):analysis of the PABPN1 gene expansion sequence in 86 patients reveals 13 different expansion types and further evidence for unequal recombination as the mutational mechanism. Hum Genet. 2005;116(4):267-71. doi:10.1007/s00439-004-1235-2. PMID: 15645184.
30. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 939–44.
31. Nishii YS, Noto YI, Yasuda R, Kitaoji T, Ashida S, Tanaka E, et al. A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation. BMC Neurol. 2021;21(1):265. doi:10.1186/s12883-021-02300-x. PMID: 34225694. PMC8256512.
32. Robinson DO, Wills AJ, Hammans SR, Read SP, Sillibourne J. Oculopharyngeal muscular dystrophy: a point mutation which mimics the effect of the PABPN1 gene triplet repeat expansion mutation. J Med Genet. 2006;43(5):e23. doi:10.1136/jmg.2005.037598. PMID: 16648376. PMC2564528.
33. National Center for Biotechnology Information. ClinVar: PABPN1[gene], pathogenic/likely pathogenic variants [cited 2026 Oct 17]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/?term=PABPN1%5Bgene%5D
34. Harahsheh EY, Olarewaju BA, Asif MB, Woodruff BK, Osundiji MA. Frontotemporal lobar degeneration in a patient carrying a pathogenic PABPN1 expansion. Neuroradiology. 2026. doi:10.1007/s00234-026-04100-x. PMID: 42387033.
35. Roth F, Dhiab J, Boulinguiez A, Mouigni HR, Lassche S, Negroni E, et al. Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy. Acta Neuropathol. 2022;144(6):1157-1170. doi:10.1007/s00401-022-02503-7. PMID: 36197469. PMC9637588.
36. Tavanez JP, Calado P, Braga J, Lafarga M, Carmo-Fonseca M. In vivo aggregation properties of the nuclear poly(A)-binding protein PABPN1. RNA. 2005;11(5):752-62. doi:10.1261/rna.7217105. PMID: 15811916. PMC1370760.
37. Mezzell AT, Zhang Y, Perez AM, Vest KE. Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics. PLoS Genet. 2026;22(1):e1011743. doi:10.1371/journal.pgen.1011743. PMID: 41587185. PMC12858073.
38. Richard P, Trollet C, Stojkovic T, de Becdelievre A, Perie S, Pouget J, et al. Correlation between PABPN1 genotype and disease severity in oculopharyngeal muscular dystrophy. Neurology. 2017;88(4):359-365. doi:10.1212/WNL.0000000000003554. PMID: 28011929.
39. Blumen SC, Bouchard JP, Brais B, Carasso RL, Paleacu D, Drory VE, et al. Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes. Neurology. 2009;73(8):596-601. doi:10.1212/WNL.0b013e3181b388a3. PMID: 19704078.
40. Richard P, Trollet C, Gidaro T, Demay L, Brochier G, Malfatti E, et al. PABPN1 (GCN)11 as a Dominant Allele in Oculopharyngeal Muscular Dystrophy -Consequences in Clinical Diagnosis and Genetic Counselling. J Neuromuscul Dis. 2015;2(2):175-180. doi:10.3233/JND-140060. PMID: 27858728. PMC5271460.
41. Hill ME, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain. 2001;124(Pt 3):522-6. doi:10.1093/brain/124.3.522. PMID: 11222452.
42. Tondo M, Gámez J, Gutiérrez-Rivas E, Medel-Jiménez R, Martorell L. Genotype and phenotype study of 34 Spanish patients diagnosed with oculopharyngeal muscular dystrophy. J Neurol. 2012;259(8):1546-52. doi:10.1007/s00415-011-6374-5. PMID: 22231868.
43. Kekou K, Papadopoulos C, Svingou M, Chrysanthou-Piterou M, Nitsa E, Veltra D, et al. Insights into the heterogeneity of oculopharyngeal muscular dystrophy. Neurogenetics. 2025;26(1):68. doi:10.1007/s10048-025-00849-0. PMID: 40991068. PMC12460444.
44. Alonso-Pérez J, de León Hernández JC, Pérez-Pérez H, Mendoza-Grimón MD, Gutierrez-Martinez AJ, Hadjigeorgiou I, et al. Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands. Eur J Neurol. 2022;29(5):1488-1495. doi:10.1111/ene.15252. PMID: 35112761.
45. de Leeuw RH, Garnier D, Kroon RMJM, Horlings CGC, de Meijer E, Buermans H, et al. Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools. Eur J Hum Genet. 2019;27(3):400-407. doi:10.1038/s41431-018-0302-4. PMID: 30455479. PMC6460572.
46. Ben-David M, Greenbaum L, Nikitn V, Zvulunov A, Charas H, Divon N, et al. The genetic and clinical characteristics of oculopharyngeal muscular dystrophy patients in Israel. Orphanet J Rare Dis. 2026;21(1). doi:10.1186/s13023-026-04313-6. PMID: 42157275. PMC13188457.
47. Brisson JD, Gagnon C, Brais B, Côté I, Mathieu J. A study of impairments in oculopharyngeal muscular dystrophy. Muscle Nerve. 2020;62(2):201-207. doi:10.1002/mus.26888. PMID: 32270505.
48. Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M, et al. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy. Acta Neurol Scand. 2014;130(2):125-30. doi:10.1111/ane.12244. PMID: 24611576.
49. Tabor LC, Plowman EK, Romero-Clark C, Youssof S. Oropharyngeal dysphagia profiles in individuals with oculopharyngeal muscular dystrophy. Neurogastroenterol Motil. 2018;30(4):e13251. doi:10.1111/nmo.13251. PMID: 29144056.
50. Waito AA, Steele CM, Peladeau-Pigeon M, Genge A, Argov Z. A Preliminary Videofluoroscopic Investigation of Swallowing Physiology and Function in Individuals with Oculopharyngeal Muscular Dystrophy (OPMD). Dysphagia. 2018;33(6):789-802. doi:10.1007/s00455-018-9904-9. PMID: 29725764.
51. Kroon RHMJM, Horlings CGC, de Swart BJM, van Engelen BGM, Kalf JG. Swallowing, Chewing and Speaking: Frequently Impaired in Oculopharyngeal Muscular Dystrophy. J Neuromuscul Dis. 2020;7(4):483-494. doi:10.3233/JND-200511. PMID: 32804098. PMC7592669.
52. Zvulunov A, Saif R, Olmer L, Ben-David M, Benyamini L, Dori A, et al. Salivary Viscosity as a Non-Invasive Candidate Biomarker Associated With Aspiration Risk in Oculopharyngeal Muscular Dystrophy. J Oral Rehabil. 2026. doi:10.1111/joor.70285. PMID: 42557017.
53. Alonso-Jimenez A, Kroon RHMJM, Alejaldre-Monforte A, Nuñez-Peralta C, Horlings CGC, van Engelen BGM, et al. Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy. J Neurol Neurosurg Psychiatry. 2019;90(5):576-585. doi:10.1136/jnnp-2018-319578. PMID: 30530568.
54. Bélair N, Brisson JD, Brais B, Rodrigue X, Lochmüller H, Hébert LJ, et al. Muscle Strength, Balance, and Indoor Mobility in Oculopharyngeal Muscular Dystrophy: An Exploratory Canadian Multicenter Study. Muscle Nerve. 2026;74(3):656-668. doi:10.1002/mus.70343. PMID: 42439050. PMC13472016.
55. Kroon RHMJM, Kalf JG, de Swart BJM, van der Sluijs BM, Glennon JC, Raz V, et al. Longitudinal Assessment of Strength, Functional Capacity, Oropharyngeal Function, and Quality of Life in Oculopharyngeal Muscular Dystrophy. Neurology. 2021;97(15):e1475-e1483. doi:10.1212/WNL.0000000000012640. PMID: 34380753. PMC8575133.
56. Kroon RHMJM, Kalf JG, de Swart BJM, Heskamp L, de Rooy JWJ, van Engelen BGM, et al. Muscle MRI in Patients With Oculopharyngeal Muscular Dystrophy: A Longitudinal Study. Neurology. 2024;102(1):e207833. doi:10.1212/WNL.0000000000207833. PMID: 38165364. PMC10834117.
57. Bareja N, Desai B, Vytopil M, Srinivasan J, Ghasemi M. Cancer and benign tumors in myotonic dystrophy, facioscapulohumeral muscular dystrophy, and oculopharyngeal muscular dystrophy: a 23-year, single-center, retrospective study. Acta Myol. 2025;44(2):49-56. doi:10.36185/2532-1900-997. PMID: 40626678. PMC12250585.
58. Dubbioso R, Moretta P, Manganelli F, Fiorillo C, Iodice R, Trojano L, et al. Executive functions are impaired in heterozygote patients with oculopharyngeal muscular dystrophy. J Neurol. 2012;259(5):833-7. doi:10.1007/s00415-011-6255-y. PMID: 21956377.
59. Tankink M, Horlings CGC, Voermans N, van der Sluijs B, Kessels RPC, van Engelen B, et al. Behavioural Impairment and Frontotemporal Dementia in Oculopharyngeal Muscular Dystrophy. J Neuromuscul Dis. 2022;9(1):129-135. doi:10.3233/JND-200592. PMID: 34334411. PMC8842748.
60. van der Sluijs BM, Knoop H, Bleijenberg G, van Engelen BG, Voermans NC. The Dutch patients' perspective on oculopharyngeal muscular dystrophy: A questionnaire study on fatigue, pain and impairments. Neuromuscul Disord. 2016;26(3):221-6. doi:10.1016/j.nmd.2015.12.009. PMID: 26948710.
61. Garibaldi M, Pennisi EM, Bruttini M, Bizzarri V, Bucci E, Morino S, et al. Dropped-head in recessive oculopharyngeal muscular dystrophy. Neuromuscul Disord. 2015;25(11):869-72. doi:10.1016/j.nmd.2015.08.011. PMID: 26494409.
62. Goyal NA, Mozaffar T, Chui LA. Oculopharyngeal Muscular Dystrophy, an Often Misdiagnosed Neuromuscular Disorder: A Southern California Experience. J Clin Neuromuscul Dis. 2019;21(2):61-68. doi:10.1097/CND.0000000000000271. PMID: 31743248.
63. Mañana Valdés C, Arias Guillén M, Moris de la Tassa G. Recurrent Pneumonia in a Patient With Oculopharyngeal Muscular Dystrophy (OPMD) due to GCN Expansion in the PABPN1 Gene: A Diagnostic Challenge. Open Respir Arch. 2026;8(2):100580. doi:10.1016/j.opresp.2026.100580. PMID: 41676387. PMC12887766.
64. Akizawa C, Tokumine J, Motoyama H, Takeuchi N, Okuni M, Yorozu T, et al. Glossoptosis After Tracheal Extubation in a Patient With Oculopharyngeal Muscular Dystrophy: A Case Report. Cureus. 2025;17(10):e93696. doi:10.7759/cureus.93696. PMID: 41181735. PMC12579378.
65. Vital M, Salazar E, Acordagoitia C, Vázquez C, Esperón P. Rapid and reliable molecular diagnosis of oculopharyngeal muscular dystrophy: a cost-effective alternative for PABPN1 gene (GCN)n repeat analysis. J Appl Genet. 2026. doi:10.1007/s13353-026-01115-1. PMID: 42809144.
66. Guha S, Rajan-Babu IS, Kesari A, Garg S, Rose NC, Seifert BA, et al.; ACMG Laboratory Quality Assurance Committee. Detection of repeat expansion variants using next generation sequencing: a points to consider statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2026;28(7):102520. doi:10.1016/j.gim.2026.102520. PMID: 42287278. PMC13271160.
67. Galimberti V, Tironi R, Lerario A, Scali M, Del Bo R, Rodolico C, et al. Value of insoluble PABPN1 accumulation in the diagnosis of oculopharyngeal muscular dystrophy. Eur J Neurol. 2020;27(4):709-715. doi:10.1111/ene.14131. PMID: 31769567.
68. Périé S, Laccourreye L, Flahault A, Hazebroucq V, Chaussade S, St Guily JL. Role of videoendoscopy in assessment of pharyngeal function in oropharyngeal dysphagia: comparison with videofluoroscopy and manometry. Laryngoscope. 1998;108(11 Pt 1):1712-6. doi:10.1097/00005537-199811000-00022. PMID: 9818831.
69. Côté C, Brais B, Batcho CS, Brisson JD, Youssof S, Sogbossi ES, et al. Measurement Properties of the Dysphagiameter for the Assessment of Dysphagia in Oculopharyngeal Muscular Dystrophy. Dysphagia. 2025;40(4):931-942. doi:10.1007/s00455-024-10791-2. PMID: 39708080.
70. Smith IC, Sampaio ML, Melkus G, Meier-Ross K, Chakraborty S, Stotts C, et al. Plasma-derived protein and imaging biomarkers distinguish disease severity in oculopharyngeal muscular dystrophy. J Neuromuscul Dis. 2025;12(2):244-259. doi:10.1177/22143602241304990. PMID: 39973404. PMC13142862.
71. Mikail M, Gladman M. Late-onset Pompe disease mimicking oculopharyngeal muscular dystrophy. Pract Neurol. 2025;25(5):466-469. doi:10.1136/pn-2024-004506. PMID: 40032504.
72. Orphanet. Oculopharyngodistal myopathy (ORPHA:98897). Available from: https://www.orpha.net/en/disease/detail/98897
73. M Barbosa J, A Pereira P. Oculopharyngeal muscular dystrophy, myasthenia gravis, systemic lupus erythematosus: overlap and interactions. BMJ Case Rep. 2024;17(11). doi:10.1136/bcr-2024-262742. PMID: 39532331.
74. Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet. 2019;51(8):1222-1232. doi:10.1038/s41588-019-0458-z. PMID: 31332380.
75. Deng J, Yu J, Li P, Luan X, Cao L, Zhao J, et al. Expansion of GGC Repeat in GIPC1 Is Associated with Oculopharyngodistal Myopathy. Am J Hum Genet. 2020;106(6):793-804. doi:10.1016/j.ajhg.2020.04.011. PMID: 32413282.
76. Maeda MY, Hashimoto TY, Oliveira Neto IC, Neves LR. Oculopharyngeal muscular dystrophy or oculopharyngeal distal myopathy: case report. Braz J Otorhinolaryngol. 2017;83(2):235-238. doi:10.1016/j.bjorl.2015.07.019. PMID: 26616227. PMC9442695.
77. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 496–9.
78. Reintjes W, Knuijt S, Oelbrandt F, Hastings RN, Evangelista T, Tasca G, et al. Oculopharyngeal muscular dystrophy: diagnosis, management and multisystem care. Pract Neurol. 2026. doi:10.1136/pn-2026-005241. PMID: 42386213.
79. Hill M, Hughes T, Milford C. Treatment for swallowing difficulties (dysphagia) in chronic muscle disease. Cochrane Database Syst Rev. 2004(2):CD004303. doi:10.1002/14651858.CD004303.pub2. PMID: 15106246.
80. Hill M, Hughes T, Milford C. WITHDRAWN: Treatment for swallowing difficulties (dysphagia) in chronic muscle disease. Cochrane Database Syst Rev. 2014(8):CD004303. doi:10.1002/14651858.CD004303.pub3. PMID: 25105911.
81. Muscular Dystrophy UK. Oculopharyngeal muscular dystrophy (OPMD) [page reviewed February 2025; cited 2026 Oct 17]. Available from: https://www.musculardystrophyuk.org/conditions/a-z/oculopharyngeal-muscular-dystrophy-opmd/
82. Codère F. Oculopharyngeal muscular dystrophy. Can J Ophthalmol. 1993;28(1):1-2. PMID: 8439856.
83. Rodrigue D, Molgat YM. Surgical correction of blepharoptosis in oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7 Suppl 1:S82-4. doi:10.1016/s0960-8966(97)00088-6. PMID: 9392022.
84. Allen RC, Zimmerman MB, Watterberg EA, Morrison LA, Carter KD. Primary bilateral silicone frontalis suspension for good levator function ptosis in oculopharyngeal muscular dystrophy. Br J Ophthalmol. 2012;96(6):841-5. doi:10.1136/bjophthalmol-2011-300667. PMID: 22493036.
85. Jordan DR, Klapper SR, Farmer J. Oculopharyngeal Muscular Dystrophy Ptosis, Mueller's Muscle Involvement, and a Review of Management Over 34 Years. Ophthalmic Plast Reconstr Surg. 2022;38(6):535-542. doi:10.1097/IOP.0000000000002118. PMID: 35030153.
86. Burnstine MA. Re: "Oculopharyngeal Muscular Dystrophy Ptosis, Mueller's Muscle Involvement, and a Review of Management Over 34 Years". Ophthalmic Plast Reconstr Surg. 2023;39(4):395. doi:10.1097/IOP.0000000000002451. PMID: 37413679.
87. Jordan DR, Klapper SR, Farmer J. Reply Re: "Oculopharyngeal Muscular Dystrophy Ptosis, Mueller's Muscle Involvement, and a Review of Management Over 34 Years". Ophthalmic Plast Reconstr Surg. 2023;39(4):395-396. doi:10.1097/IOP.0000000000002452. PMID: 37413680.
88. St Guily JL, Moine A, Périé S, Bokowy C, Angelard B, Chaussade S. Role of pharyngeal propulsion as an indicator for upper esophageal sphincter myotomy. Laryngoscope. 1995;105(7 Pt 1):723-7. doi:10.1288/00005537-199507000-00010. PMID: 7603277.
89. Coiffier L, Périé S, Laforêt P, Eymard B, St Guily JL. Long-term results of cricopharyngeal myotomy in oculopharyngeal muscular dystrophy. Otolaryngol Head Neck Surg. 2006;135(2):218-22. doi:10.1016/j.otohns.2006.03.015. PMID: 16890071.
90. Pellerin HG, Nicole PC, Trépanier CA, Lessard MR. Postoperative complications in patients with oculopharyngeal muscular dystrophy: a retrospective study. Can J Anaesth. 2007;54(5):361-5. doi:10.1007/BF03022658. PMID: 17470887.
91. Mathieu J, Lapointe G, Brassard A, Tremblay C, Brais B, Rouleau GA, et al. A pilot study on upper esophageal sphincter dilatation for the treatment of dysphagia in patients with oculopharyngeal muscular dystrophy. Neuromuscul Disord. 1997;7 Suppl 1:S100-4. doi:10.1016/s0960-8966(97)00092-8. PMID: 9392026.
92. Manjaly JG, Vaughan-Shaw PG, Dale OT, Tyler S, Corlett JC, Frost RA. Cricopharyngeal dilatation for the long-term treatment of dysphagia in oculopharyngeal muscular dystrophy. Dysphagia. 2012;27(2):216-20. doi:10.1007/s00455-011-9356-y. PMID: 21805106.
93. Restivo DA, Marchese Ragona R, Staffieri A, de Grandis D. Successful botulinum toxin treatment of dysphagia in oculopharyngeal muscular dystrophy. Gastroenterology. 2000;119(5):1416. doi:10.1053/gast.2000.20113. PMID: 11185464.
94. Restivo DA, Marchese-Ragona R. Safety of botulinum toxin for dysphagia in oculopharyngeal muscular dystrophy. Muscle Nerve. 2014;50(5):869-70. doi:10.1002/mus.24433. PMID: 25155080.
95. Caron MJ, Girard F, Girard DC, Boudreault D, Brais B, Nassif E, et al. Cisatracurium pharmacodynamics in patients with oculopharyngeal muscular dystrophy. Anesth Analg. 2005;100(2):393-397. doi:10.1213/01.ANE.0000140783.39597.FD. PMID: 15673864.
96. Chun R, Ananthanarayan C. Safe use of mivacurium in oculopharyngeal muscular dystrophy. Can J Anaesth. 1998;45(11):1134. doi:10.1007/BF03012412. PMID: 10021972.
97. Bajaj P, Overholt D, Chura M. Perioperative Considerations in a Patient With Oculopharyngeal Muscular Dystrophy: A Case Report. Cureus. 2025;17(8):e90496. doi:10.7759/cureus.90496. PMID: 40978992. PMC12445392.
98. Benitec Biopharma Inc. Annual report (Form 10-K) for the fiscal year ended June 30, 2026 [2026-09-14]. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312526390570/bntc-20260630.htm
99. European Medicines Agency. EU/3/15/1496 – orphan designation for treatment of oculopharyngeal muscular dystrophy (trehalose). Amsterdam: EMA; 2015 [cited 2026 Oct 17]. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-15-1496
100. European Medicines Agency. Refusal of orphan designation for treatment of oculopharyngeal muscular dystrophy (autologous skeletal myoblasts expanded ex vivo). EMA/689216/2018. Amsterdam: EMA; 2019 [cited 2026 Oct 17]. Available from: https://www.ema.europa.eu/hu/node/88197
101. Périé S, Trollet C, Mouly V, Vanneaux V, Mamchaoui K, Bouazza B, et al. Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study. Mol Ther. 2014;22(1):219-25. doi:10.1038/mt.2013.155. PMID: 23831596.
102. ClinicalTrials.gov. NCT00773227: Treatment of dysphagia in oculopharyngeal muscular dystrophy by autologous transplantation of myoblasts. [Cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT00773227
103. ClinicalTrials.gov. NCT02015481: Multi-center, dose-escalation study to assess safety, tolerability and efficacy of intravenous Cabaletta® in OPMD patients (Bioblast Pharma). [Results posted in the registry; last updated 2017-10-17; cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT02015481
104. Argov Z, Gliko-Kabir I, Brais B, Caraco Y, Megiddo D. Intravenous trehalose improves dysphagia and muscle function in oculopharyngeal muscular dystrophy (OPMD):preliminary results of 24 weeks open label phase 2 trial (S28.004). Neurology. 2016;86(16 Suppl):S28.004.
105. ClinicalTrials.gov. NCT02328482: Continuation protocol to protocol BBCO-001 (Cabaletta® in OPMD). [Last updated 2019-07-17; cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT02328482
106. ClinicalTrials.gov. NCT04226924: Treatment of oculopharyngeal muscular dystrophy with trehalose (withdrawn). [Cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT04226924
107. ClinicalTrials.gov. NCT02878694: Treatment of ptosis to muscular dystrophy oculopharyngeal by myoblast autologous graft (terminated). [Cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT02878694
108. Benitec Biopharma Inc. Benitec Biopharma releases third quarter 2026 financial results and provides operational update [press release, 2026-05-14]. Form 8-K, Exhibit 99.1. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312526222879/bntc-ex99_1.htm
109. Benitec Biopharma Inc. Benitec Biopharma releases full year 2026 financial results and provides operational update [press release, 2026-09-14]. Form 8-K, Exhibit 99.1. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312526390539/bntc-ex99_1.htm
110. ClinicalTrials.gov. Search for "oculopharyngeal" (condition), "OPMD," "BB-301," "SLS-005," and sponsor "Benitec," API v2 [cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/api/v2/studies?query.cond=oculopharyngeal
111. Strings-Ufombah V, Malerba A, Kao SC, Harbaran S, Roth F, Cappellari O, et al. BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy. Mol Ther Nucleic Acids. 2021;24:67-78. doi:10.1016/j.omtn.2021.02.017. PMID: 33738139. PMC7940701.
112. Malerba A, Klein P, Bachtarzi H, Jarmin SA, Cordova G, Ferry A, et al. PABPN1 gene therapy for oculopharyngeal muscular dystrophy. Nat Commun. 2017;8:14848. doi:10.1038/ncomms14848. PMID: 28361972.
113. Malerba A, Klein P, Lu-Nguyen N, Cappellari O, Strings-Ufombah V, Harbaran S, et al. Established PABPN1 intranuclear inclusions in OPMD muscle can be efficiently reversed by AAV-mediated knockdown and replacement of mutant expanded PABPN1. Hum Mol Genet. 2019;28(19):3301-3308. doi:10.1093/hmg/ddz167. PMID: 31294444.
114. Benitec Biopharma Inc. BB-301 clinical data presentation [presentation, 2025-11-03]. Form 8-K, Exhibit 99.3. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312525261665/bntc-ex99_3.htm
115. Benitec Biopharma Inc. Benitec Biopharma releases second quarter 2026 financial results and provides operational update [press release, 2026-02-12]. Form 8-K, Exhibit 99.1. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312526047742/bntc-ex99_1.htm
116. Benitec Biopharma Inc. Benitec Biopharma announces regulatory update following Type C meeting with FDA for BB-301 pivotal study [press release, 2026-10-05]. Form 8-K, Exhibit 99.1. Available from: https://www.sec.gov/Archives/edgar/data/1808898/000119312526413177/bntc-ex99_1.htm
117. ClinicalTrials.gov. NCT07146256: Natural history of oculo-pharyngeal muscular dystrophy (OPMD) – Israel National OPMD Registry. [Cited 2026 Oct 17]. Available from: https://clinicaltrials.gov/study/NCT07146256
118. Harish P, Malerba A, Dickson G, Bachtarzi H. Progress on gene therapy, cell therapy, and pharmacological strategies toward the treatment of oculopharyngeal muscular dystrophy. Hum Gene Ther. 2015;26(5):286-92. doi:10.1089/hum.2015.014. PMID: 25860803.
119. Abu-Baker A, Laganiere J, Gaudet R, Rochefort D, Brais B, Neri C, et al. Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/β-catenin pathway. Cell Death Dis. 2013;4(10):e821. doi:10.1038/cddis.2013.342. PMID: 24091664.
120. Abu-Baker A, Parker A, Ramalingam S, Laganiere J, Brais B, Neri C, et al. Valproic acid is protective in cellular and worm models of oculopharyngeal muscular dystrophy. Neurology. 2018;91(6):e551-e561. doi:10.1212/WNL.0000000000005942. PMID: 30006409. PMC6105050.
121. Chartier A, Raz V, Sterrenburg E, Verrips CT, van der Maarel SM, Simonelig M. Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo. Hum Mol Genet. 2009;18(10):1849-59. doi:10.1093/hmg/ddp101. PMID: 19258344.
122. Malerba A, Roth F, Harish P, Dhiab J, Lu-Nguyen N, Cappellari O, et al. Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy. Hum Mol Genet. 2019;28(10):1694-1708. doi:10.1093/hmg/ddz007. PMID: 30649389.
123. Abu-Baker A, Kharma N, Perreault J, Grant A, Shekarabi M, Maios C, et al. RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement. Mol Ther Nucleic Acids. 2019;15:12-25. doi:10.1016/j.omtn.2019.02.003. PMID: 30831428.
124. Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126-133. doi:10.1038/ng.3469. PMID: 26656846.
125. Deenen JC, Verbeek AL, Verschuuren JJ, van Engelen BG, Voermans NC. Prevalence and incidence rates of 17 neuromuscular disorders: An updated review of the literature. J Neuromuscul Dis. 2025;12(6):713-722. doi:10.1177/22143602241313118. PMID: 40034005. PMC13142861.
126. Becher MW, Morrison L, Davis LE, Maki WC, King MK, Bicknell JM, et al. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans. JAMA. 2001;286(19):2437-40. doi:10.1001/jama.286.19.2437. PMID: 11712939.
127. Grewal RP, Karkera JD, Grewal RK, Detera-Wadleigh SD. Mutation analysis of oculopharyngeal muscular dystrophy in Hispanic American families. Arch Neurol. 1999;56(11):1378-81. doi:10.1001/archneur.56.11.1378. PMID: 10555658.
128. Daneshvari S, Youssof S, Kroth PJ. The NIH Office of Rare Diseases Research patient registry Standard: a report from the University of New Mexico's Oculopharyngeal Muscular Dystrophy Patient Registry. AMIA Annu Symp Proc. 2013;2013:269-77. PMID: 24551336. PMC3900177.
129. Lin F, Yang K, Lin MT, Zheng FZ, Chen L, Ding YL, et al. The phenotypic and genotypic features of Chinese patients with oculopharyngeal muscular dystrophy. Ann Clin Transl Neurol. 2023;10(3):426-439. doi:10.1002/acn3.51733. PMID: 36691350. PMC10014010.
130. Shan J, Chen B, Lin P, Li D, Luo Y, Ji K, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a Chinese population. Neuromolecular Med. 2014;16(4):782-6. doi:10.1007/s12017-014-8327-5. PMID: 25283883.