Clinical Guidance

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. Moreover, neuropsychological tests have shown altered scores in executive function compared to controls, which appears to correlate with the larger expansions of PABPN1 (see also ). 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 . 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 . 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 . 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 . In a report of 333 individuals with the (GCN)13 expansion, the main cause of death was respiratory disease . Table 2. Select Features of Oculopharyngeal Muscular Dystrophy

Source: GeneReviews — "Oculopharyngeal Muscular Dystrophy"

Penetrance

Decade-specific cumulative penetrance for individuals with a heterozygous GCN[13] pathogenic variant is :

• 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.

Source: GeneReviews — "Oculopharyngeal Muscular Dystrophy"

Differential Diagnosis

The differential diagnosis of oculopharyngeal muscular dystrophy (OPMD) should include myasthenia gravis and other late-onset neuromuscular diseases characterized by swallowing difficulties and/or ptosis. Disorders in the differential diagnosis with a known genetic etiology are summarized in .

Table 4.

Genes of Interest in the Differential Diagnosis of Oculopharyngeal Muscular Dystrophy

Gene(s) | Disorder | MOI | Swallowing Difficulties | Ptosis | Other Key Features / Comments

CNBP | Myotonic dystrophy type 2 | AD | Gastrointestinal complications common; can incl dysphagia | Not present | Caused by a CCTG tetranucleotide repeat expansion

DCTN1

| Distal hereditary motor neuropathy (See CMT Hereditary Neuropathy Overview.) | AD | Vocal cord palsy in children | Not present | Distal motor weakness i...

Source: GeneReviews — "Oculopharyngeal Muscular Dystrophy"

Therapies Under Investigation

Several therapeutic strategies, developed and tested in OPMD models (mammalian cells, nematode, drosophila, mouse) are currently under investigation . The majority of them are pharmacologic approaches to reduce cell toxicity 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 [, , , ] and improved muscle weakness in both mouse and Drosophila OPMD models [, , , , ]. 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.

Source: GeneReviews — "Oculopharyngeal Muscular Dystrophy"