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].
Table 2.
Select Features of Oculopharyngeal Muscular Dystrophy
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Feature | % of Persons w/Feature | Comment |
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Oculomotor involvement | Ptosis | 96%-100% 1 | Levator palpebrae muscle |
Limitation of upward gaze | 61% | Superior rectus muscle |
Dysphagia | 96%-100% 1 | |
Tongue weakness | 82% | |
Wet voice | 67% | Due to pooling of saliva |
Dysphonia | 50% 1 | |
Facial muscle weakness | 43% | Facial muscles: orbicularis oris, orbicularis oculi, nasalis, levator anguli muscle, masseter muscles |
Proximal lower-extremity weakness | 71%-86% 1 | Predominantly hamstrings & glutei |
Proximal upper-extremity weakness | 38% | |
Fatigue | 88% 1 | |
Cognitive impairment | Rare, but probably underestimated due to a lack of systematic studies in these patients |
|
Dropped head | Rare | 1 report 4 |
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
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].
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.