Oculopharyngeal Muscular Dystrophy

Clinical characteristics.

Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. For the vast majority of individuals with typical OPMD, the mean age of onset of ptosis is usually 48 years and of dysphagia 50 years; in 5%-10% of individuals with severe OPMD, onset of ptosis and dysphagia occur before age 45 years and is associated with lower limb girdle weakness starting around age 60 years. Swallowing difficulties, which determine prognosis, increase the risk for potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations as the disease progresses can include limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, and proximal limb girdle weakness predominantly in lower limbs. Some individuals with severe involvement will eventually need a wheelchair. Neuropsychological tests have shown altered scores in executive functions in some.

Diagnosis/testing.

The diagnosis of OPMD is established in a proband with a suggestive phenotype in whom either of the following genetic findings are identified: a heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of PABPN1 (~90% of affected individuals) or biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], GCN[13]+[13], etc.) (~10% of affected individuals).

Management.

Treatment of manifestations: Treatment for ptosis may include blepharoplasty by either resection of the levator palpebrea aponeurosis or frontal suspension of the eyelids. The initial treatment for dysphagia is dietary modification; surgical intervention for dysphagia should be considered when symptomatic dysphagia has a significant impact on quality of life. Physical and occupational therapy are encouraged; assistive devices may be necessary to prevent falls and assist with walking and mobility. Neuropsychological support as needed.

Surveillance: Routine evaluation of: neuromuscular and oculomotor involvement; dysphagia including nutritional status and diet; respiratory function given the increased risk for both aspiration and nocturnal hypoventilation; and cognitive function including development of psychiatric symptoms.

Genetic counseling.

OPMD is inherited in an autosomal dominant manner. The risk to sibs of a proband depends on the genetic status of the parents of the proband:

• If one parent of a proband is heterozygous for a GCN repeat expansion in PABPN1 (GCN[11_18]+ [10]) and the other parent has two normal alleles (GCN[10]+[10]), the risk to the sibs of inheriting a GCN repeat expansion is 50%.
• If both parents of the proband are heterozygous for a GCN repeat expansion, sibs have a 25% risk of inheriting two GCN repeat expansions and a 50% risk of inheriting one GCN repeat expansion.
• If one parent of the proband has biallelic GCN repeat expansions and the other parent has two normal alleles, all sibs will inherit a GCN repeat expansion.
• If one parent of the proband has biallelic GCN repeat expansions and the other parent is heterozygous for a GCN repeat expansion, sibs of the proband have a 50% risk of inheriting biallelic GCN repeat expansions and 50% risk of inheriting one GCN repeat expansion.

Sibs who inherit either one or two GCN repeat expansions will be affected.

Suggestive Findings

Oculopharyngeal muscular dystrophy (OPMD) should be suspected in individuals with a mean age of 48 years with the following clinical and neuroimaging findings. Younger age at onset (<30 years) is often observed in longer GCN expansion or in individuals who are compound heterozygous or homozygous for the GCN expansion.

Clinical findings

• Ptosis, defined as EITHER a vertical separation of at least one palpebral fissure that measures less than 8 mm at rest OR previous corrective surgery for ptosis
• Dysphagia, defined as an increased swallowing time (i.e., >7 seconds when drinking 80 mL of ice-cold water) [Tabor et al 2018, Waito et al 2018].

Note: Proximal muscle weakness (particularly involving pelvic girdle and scapular girdle) may appear later, usually five to ten years after the onset of ptosis.

Whole-body muscle MRI. Fatty involvement of the tongue, soleus, and adductor muscles is very suggestive of OPMD [Alonso-Jimenez et al 2019].

Establishing the Diagnosis

The diagnosis of OPMD is established in a proband with suggestive findings and one of the following identified by molecular genetic testing (see Table 1) [Jouan et al 2014, Richard et al 2015, Richard et al 2017]:

• A heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of PABPN1 (~90% of affected individuals)
• Biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous (GCN[11]+[11], GCN[12]+[12], or GCN[13]+[13]) (~10% of affected individuals)
  Note: Penetrance of an expanded allele depends on both size and zygosity.

Allele sizes. The N in GCN represents any nucleotide (A/C/G/T). All four possible sequences have been observed in the PABPN1 complex repeat.

• Normal alleles have ten GCN repeats: GCN[10].
• Expanded alleles have 11 to 18 GCN repeats: GCN[11_18].

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, i.e., either sequence analysis of PABPN1 or targeted analysis for PABPN1 GCN trinucleotide repeats in exon 1, or a multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing).

Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of OPMD has not been considered are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Oculopharyngeal muscular dystrophy (OPMD) is characterized by ptosis and dysphagia due to selective involvement of the muscles of the eyelids and pharynx, respectively. Early manifestations of dysphagia include increased time needed to consume a meal and an acquired avoidance of dry foods. The severity of dysphagia is the major determinant of prognosis, as it leads to potentially life-threatening aspiration pneumonia and poor nutrition. Other manifestations, observed as the disease progresses, are limitation of upward gaze, tongue atrophy and weakness, chewing difficulties, wet voice, facial muscle weakness, axial muscle weakness, proximal limb girdle weakness predominantly in lower limbs, and proximal upper extremity weakness (Table 2). Moreover, neuropsychological tests have shown altered scores in executive function compared to controls, which appears to correlate with the larger expansions of PABPN1 [Dubbioso et al 2012] (see also Genotype-Phenotype Correlations).

In typical OPMD (i.e., 90%-95% of affected individuals), the mean age of onset of ptosis is usually 48 years and dysphagia 50 years. The mean age of onset of lower proximal weakness is 58 years [Brisson et al 2020]. In 333 individuals with a heterozygous (GCN)13 expansion, the median latency before the onset of proximal weakness was seven years (range 0-21 years) after the onset of ptosis and seven years (0-25 years) after the onset of dysphagia [Brisson et al 2020].

Severe OPMD (5%-10% of affected individuals) is characterized by onset of ptosis and dysphagia before age 45 years and incapacitating proximal leg weakness that starts before age 60 years. Some individuals with severe involvement eventually need a wheelchair. See also Table 3.

Although OPMD does not appear to reduce life span, in individuals with heterozygous GCN repeat expansions, quality of life in later years is greatly diminished [Becher et al 2001]. In a report of 333 individuals with the (GCN)13 expansion, the main cause of death was respiratory disease [Brisson et al 2020].

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

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

Dropped head beginning at age 67 years and associated with dysphagia, hypernasal speech, ptosis, and proximal limb weakness was reported in a woman who was homozygous for the (GCN)11 expansion [Garibaldi et al 2015].

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

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

Chewing and speaking are also frequently affected [Kroon et al 2020].

Limb muscle involvement is symmetric and mainly concerns the pelvic and scapular girdle. Fatty degeneration of the muscles involves the soleus muscles, the hip adductors, and the hamstrings, especially at the onset the semi-membranous and biceps femoralis muscles.

At later stages, the fatty degeneration spreads to the vastus medialis and intermediate muscles, the gastrocnemius, and the peroneus muscles. The sartorius, gracilis, and tibialis muscles are usually conserved for a longer time [Fischmann et al 2011, Gloor et al 2011]. In the upper limbs, the serratus anterior, latissimus dorsi, and subscapularis muscles are the most affected.

MRI studies also show fatty infiltration of the paraspinal muscles in 76% of affected individuals [Alonso-Jimenez et al 2019].

Distal muscle weakness has been described in a Japanese family [Goto et al 1977, Satoyoshi & Kinoshita 1977] and in other ethnic groups [Jaspar et al 1977, Scrimgeour & Mastaglia 1984]. However, distal muscle involvement at onset has not been associated with typical OPMD [Schotland & Rowland 1964, Vita et al 1983]. In some severe forms, whole-body muscle MRI has shown distal involvement of the lower limbs in the late stages of disease [Alonso-Jimenez et al 2019].

Pain and fatigue. A questionnaire-based study of fatigue, pain, and functional impairment in 35 individuals with genetically confirmed OPMD showed that 54% experienced severe fatigue and pain leading to difficulties with daily living activities and social participation [van der Sluijs et al 2016]. These findings were confirmed in 333 individuals with the (GCN)13 expansion [Brisson et al 2020].

Cognitive impairment. Some individuals have also shown central nervous system involvement [Linoli et al 1991]. Dubbioso et al [2012] described an individual with central nervous system involvement with impaired executive function. Ten persons, with homozygous PAPBN1 (GCN)13-(GCN)13 expansions had cognitive decline, depression, and psychotic manifestations [Blumen et al 2009].

Other clinical findings

• Reduction in FEV1 (forced expiratory volume in one second) ranging from 23% to 59% of the expected values was observed in 13 individuals with OPMD, none of whom required noninvasive ventilation [Witting et al 2014].
• Sleep apnea, reported rarely, is probably underestimated [Dedrick & Brown 2004].
• Cardiomyopathy or rhythm abnormalities have not been associated with OPMD.
• Although OPMD is considered a primary muscle disorder, there are rare reports of findings suggestive of peripheral nerve involvement including severe depletion of myelinated fibers in endomysial nerve twigs of extraocular, pharyngeal, and lingual muscles [Probst et al 1982, Schober et al 2001] and reports of axonal sensorimotor neuropathies in some affected individuals.

Other laboratory findings

• Electromyography (EMG) usually reveals a myopathic pattern especially in weak muscles [Bouchard et al 1997].
• Serum CK concentrations elevated two to seven times above the normal value have been reported in individuals with OPMD with severe leg weakness [Barbeau 1996]; however, serum CK concentration is usually normal or up to twice the upper limit of normal [Richard et al 2017].

Genotype-Phenotype Correlations

Variability of age of onset and severity of weakness correlates with GCN repeat size [Brais et al 1998, Richard et al 2017] (see Table 3). The following generalizations can be made:

• In persons with heterozygous repeats, longer repeat length is associated with earlier age of onset.
• In persons with two expanded alleles (either homozygous or compound heterozygous) age of onset is earlier than in individuals with a single (heterozygous) expanded allele.
• The most severe disease is associated two expanded alleles.

Penetrance

Decade-specific cumulative penetrance for individuals with a heterozygous GCN[13] pathogenic variant is [Brais et al 1997, Richard et al 2017]:

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

Thus, OPMD resulting from GCN[13] heterozygosity is fully penetrant after age 70 years.

Anticipation

Anticipation is not observed. The PABPN1 GCN repeat is mitotically and meiotically stable: expansion or contraction of the repeat in meiosis is rare. The estimated mutation (expansion/contraction) rate for a heterozygous ([GCN12_17]) allele is approximately 1:500 meiosis [Brais et al 1998].

Nomenclature

Historic numbering of the PABPN1 repeat GCN expansion is described in Molecular Genetics (see PABPN1-specific laboratory technical considerations).

Prevalence

The prevalence of OPMD has been estimated at 1:100,000 in France, 1:1000 in the French-Canadian population of the province of Quebec, and 1:600 among Bukhara Jews living in Israel [Brais et al 1995, Blumen et al 1997, Brunet et al 1997]. A few French-Canadians and members of the genetically isolated population of Bukhara Jews living in Israel [Blumen et al 1999] are homozygous for the expanded alleles GCN[13].

In the United States, the majority of affected individuals are of French-Canadian extraction, though a large number are also of other backgrounds, including Ashkenazi Jewish [Victor et al 1962], and Spanish American in Texas [Becher et al 2001] and California [Grewal et al 1999].

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

The frequency of GCN[11] alleles is 1% to 2% of North American, European, and Japanese populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with oculopharyngeal muscular dystrophy (OPMD), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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

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

Dysphagia

• Food should be cut into small pieces.
• Although no controlled trials have been performed [Hill et al 2004], surgical intervention for dysphagia should be considered when symptomatic dysphagia has a significant impact on quality of life [Duranceau et al 1983, Lacau St Guily et al 1995, Périé et al 1997, Coiffier et al 2006].
• Cricopharyngeal myotomy, consisting of extramucosal section of the cricopharyngeal muscle that improves swallowing through the upper esophageal sphincter [Montgomery & Lynch 1971, Duranceau et al 1980, Lacau St Guily et al 1994, Lacau St Guily et al 1995, Duranceau 1997, Gómez-Torres et al 2012], is easily performed through open approach and immediately improves symptoms in most cases [Duranceau et al 1983]; however, in a high proportion of patients progressive dysphagia may recur within a few years [Coiffier et al 2006]. An endoscopic approach may be an alternative approach to open surgery in cricopharyngeal myotomy, with better results than botox injection [Schneider et al 1994, Restivo et al 2000].
• Cricopharyngeal dilatation is an alternative to cricopharyngeal myotomy [Mathieu et al 1997]. Repeated cricopharyngeal dilatation is a safe, effective, well-tolerated, and long-lasting treatment for dysphagia in OPMD [Manjaly et al 2012].
• In social settings involving food consumption, affected individuals should either avoid eating or choose foods that are easy to swallow.

Limb muscle weakness. Physiotherapy and occupational therapy is encouraged in patients; Canes and walkers may be necessary in patients with walking difficulties to avoid falls. Severe forms of OPMD with advanced stages of lower limb weakness may require a wheelchair [Brisson et al 2020].

Cognitive impairment. A systematic neuropsychological evaluation may be proposed to patients with OPMD and is needed to obtain a better understanding of this issue. A multicentric neuropsychological and psychological evaluation may be considered.

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

• Annual flu vaccination is recommended for elderly affected individuals;
• Consultation should be sought promptly for a productive cough because of the increased risk for lung abscesses;
• Dietary supplements should be added if weight loss is significant.

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

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Several therapeutic strategies, developed and tested in OPMD models (mammalian cells, nematode, drosophila, mouse) are currently under investigation [Harish et al 2015]. The majority of them are pharmacologic approaches to reduce cell toxicity [Wang et al 2005, Abu-Baker et al 2013, Abu-Baker et al 2018] and/or reduce PABPN1 aggregation. Indeed, reducing PABPN1 aggregation (with drugs such as doxycycline or trehalose) with intrabodies or chaperone expression consistently enhanced cell survival in cell models of OPMD [Bao et al 2002, Bao et al 2004, Abu-Baker et al 2005, Verheesen et al 2006] and improved muscle weakness in both mouse and Drosophila OPMD models [Davies et al 2005, Davies et al 2006, Chartier et al 2009, Barbezier et al 2011, Malerba et al 2019b]. These studies suggest that therapeutic trials in persons with OPMD are possible given that some of the tested molecules have already been given to humans.

Gene replacement strategies (knockdown of mutated PABPN1 and replacement with a functional PABPN1) have also been developed and tested in OPMD models using AAV vectors [Malerba et al 2017, Malerba et al 2019a] or RNA (hammerhead ribozymes/miRNA) [Abu-Baker et al 2019]. Benitec BioPharma received the orphan drug designation for the AAV-based gene therapy product and is now conducting preclinical studies with the aim of a future clinical trial.

A few clinical trials on therapeutic strategies have already been performed on OPMD:

• An autologous cell transplantation clinical Phase I/IIa study (NCT00773227) has been conducted with safety and cell-dose efficacy results [Périé et al 2014]. Twelve individuals were initially included and published; 16 were subsequently added; their results have not yet been published.
• Trehalose has now been tested in a clinical setting in persons with OPMD (Bioblast Biopharma; HOPEMD; NCT02015481) with improvement in dysphagia and muscle function; the effect on the intranuclear inclusions observed in muscle biopsy have not yet been reported [Argov et al 2016].

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