Oculopharyngeal muscular dystrophy (ORPHA:270)
A rare, adult-onset, progressive myopathy characterized by progressive eyelid ptosis, ophthalmoplegia, dysphagia, dysarthria and proximal limb weakness.
Epidemiology
Oculopharyngeal muscular dystrophy (OPMD) occurs worldwide with varying prevalence rates. The estimated prevalence rate in Europe is 1/100,000-200,000. The highest prevalence rate of 1/1,000 is found in French Canadians in Quebec and 1/600 in Israel's Bukharan Jews.
Clinical description
Disease onset occurs in the fifth to sixth decade of life. Early signs include ptosis, ophthalmoplegia without diplopia, limb weakness, dysarthria and dysphagia. Symptoms usually begin after the age of 45 years, and ptosis is the most common presenting feature. Other signs that occur as the disease progresses include tongue weakness and atrophy, proximal upper and lower extremity weakness, dysphonia, dysarthria, facial muscle weakness, and limitation of upward gaze. In several cases, limb weakness has preceded dysphagia. In 5-10% of patients, the disease is more severe, with ptosis and dysphagia presenting before the age of 45 and incapacitating distal leg weakness occurring before the age of 60. The manifestations of autosomal recessive OPMD usually present later (after the age of 60) than those of the autosomal dominant form.
Etiology
OPMD is caused by an expansion in the polyalanine tract in the PABPN1 gene (14q11.2), which leads to overexpression of a mutant protein, polyadenylate-binding protein 2, and consequently to the accumulation of nuclear aggregates in the muscles.
Diagnostic methods
OPMD is diagnosed by genetic confirmation of a mutation in the PABPN1 gene. Supportive evidence comes from the family history, late-onset clinical characteristics, and muscle biopsy findings (tubulofilamentous inclusions in the nuclei of myocytes using electron microscopy, as well as muscle fibers containing rimmed vacuoles). However, a muscle biopsy is not needed for diagnosis and is nowadays rarely performed. Creatine kinase (CK) levels can be slightly elevated and electromyogram (EMG) studies may suggest a mild myopathic process.
Differential diagnosis
Differential diagnoses include first and foremost myasthenia gravis, mitochondrial myopathies, and myotonic dystrophy type 1. Other less likely but possible differential diagnoses are oculopharyngodistal myopathy, proximal myotonic myopathy, congenital fibrosis of extraocular muscles, blepharophimosis-epicanthus inversus-ptosis syndrome, and autosomal dominant distal myopathy.
Antenatal diagnosis
Prenatal diagnosis is possible, but as this condition presents in adulthood, it is very rarely performed.
Genetic counseling
OPMD is inherited autosomal dominantly in the vast majority of cases, but can be found recessively in certain regions. Genetic counseling is possible when a PABPN1 mutation has been identified in a family.
Management and treatment
No pharmacological treatment is presently available, but surgical treatments are offered that can help with ptosis and dysphagia. A blepharoplasty can treat ptosis when the eyelids cover more than 50% of the pupils or when neck pain is present. A cricopharyngeal myotomy or botulinum toxin injection of the cricopharyngeal muscle can be performed to achieve normal swallowing, but dysphagia usually recurs years after surgery. The intake of dietary supplements and a diet of foods that are soft and easy to swallow are often necessary. Some patients may need a wheelchair if muscle atrophy is severe.
Prognosis
Ptosis and dysphagia typically recur within five to fifteen years after surgery. There is usually no decrease in life expectancy, but quality of life can be reduced in those where the disease is debilitating. Premature death, if it happens, is usually due to aspiration pneumonia or malnutrition (with severe weight loss) in elderly patients.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Pr John VISSING