Oculopharyngeal muscular dystrophy
This 68 year-old man experienced a late onset of symptoms, with isolated ptosis, diplopia, and dysphagia beginning in the sixth decade and progressing slowly thereafter. His symptoms were described as more prominent near the end of the day, as is seen in most neurological disorders; however, he did not relate the rapid use-dependent worsening and relief of symptoms with brief rest that are characteristic of myasthenic fatiguability. Unlike acquired myasthenia, his disorder was familial, with a dominant inheritance of similar disease suggested on the paternal side. His ethnic background was French-Canadian. Clinical and ophthalmologic evaluation, as well as swallowing evaluation (results listed under "Endoscopy" or "X-rays" in this menu) documented findings compatible with the history given. These features, taken together, strongly suggest a clinical diagnosis of oculopharyngeal muscular dystrophy (OPMD). After extensive discussion, the patient elected to defer genetic testing (see comment under "Genetic Testing," Poly(A)-Binding Proteins) as a final confirmatory measure.
Several disorders may mimic aspects of OPMD. This disorder is frequently mistaken for myasthenia gravis because of the prominent ocular and bulbar involvement, and it is not unusual for patients without a clear family history to have received unnecessary immunotherapy. In this patient, the fixed nature of deficits, lack of clinical fatiguability, and a negative acetylcholine-receptor antibody screen argued strongly against myasthenia. In evaluating patients with continued diagnostic suspicion for a neuromuscular junction disorder, low-frequency repetitive stimulation of the spinal accessory or facial nerves may detect decrementing responses, and occasionally single-fiber electromyography may be helpful in supporting this diagnosis. Due to risk of symptomatic bradycardia, we do not recommend the routine use of intravenous edrophonium (Tensilon) as a diagnostic screening test in older patients or patients with significant risk factors for cardiovascular disease.
Mitochondrial disorders may also present with chronic progressive external ophthalmoplegia (CPEO). Many of these disorders are maternally inherited, through transmission of the mitochondrial genome, although some genes encoding mitochondrial proteins are found within the cellular genome and may exhibit non-maternal inheritance patterns. However, this patient lacked evidence of unexplained multisystem disease, and had a normal serum lactate screen, so we did not further pursue this alternative. In patients with higher suspicion for mitochondrial disease, muscle biopsy and histochemical analysis to screen for "ragged-red" fibers, muscle enzyme activity assays, mitochondrial DNA sequencing and exercise testing have all been used to support a diagnosis of mitochondrial disease. Inflammatory myopathies, most frequently dermatomyositis, may also present with unexplained dysphagia. However, the degree of ocular involvement, lack of a characteristic rash, and normal serum creatine kinase (CK) assay would be inconsistent with dermatomyositis as an alternative diagnosis, particularly in view of the protracted clinical course. Distal myopathic variants of the oculopharyngeal myopathies have been described, but were not suggested by this patient's examination.
Oculopharyngeal muscular dystrophy (OPMD) is a disease of generally late onset, that initially presents with progressive ptosis and dysphagia. Taylor noted this syndrome in 1915, describing four members of a Canadian family with late-onset ptosis and progressive swallowing difficulties, leading to death by starvation. In the early 1960s, Robert Hayes was able to follow up on that same family, and identified members of two subsequent generations who had also developed the disorder. Oculopharyngeal muscular dystrophy was the name given to this disease in 1962 by Maurice Victor, Robert Hayes, and Raymond Adams.
OPMD is more commonly found in certain ethnic communities, particularly among French Canadians and Bukhara Jews living in Israel. The largest cluster of OPMD patients is found in the Canadian Province of Quebec, with an estimated frequency of more than 1 per 1000 individuals. Other clusters of OPMD have been seen among Bukhara Jews, Uruguayans, and Spanish Americans living in New Mexico.
The disease usually presents during the fifth or sixth decade with initial symptoms of ptosis, dysphagia, and dysphonia, involving the striated muscles of the pharynx and upper third of the esophagus. Later developments may include limitations of ocular movements, facial weakness, and proximal limb weakness. Disease-specific morbidity and mortality in OPMD is generally attributed to complications of bulbar dysfunction, particularly malnutrition and aspiration pneumonia.
Both autosomal dominant (OMIM 164300) and recessive (OMIM 257950) forms of OPMD have been reported. The dominant gene locus was first mapped by Brais et al. (1995) to chromosome 14q11.1, by completing a linkage analysis of French Canadian families. They identified short (8-13) GCG repeat expansions in the polyadenylate-binding protein nuclear gene 1 (PABPN1), strongly associated with clinical disease status. Currently, a polymerase chain reaction study is available to establish the carrier status of an affected individual. Gene dosage appears to affect the age of onset as well as the severity of disease presentation. The most severe forms of OPMD are found in individuals who are homozygous for a dominant OPMD mutation, with onset of symptoms about two decades earlier than that of heterozygotes.
Prior to discovery of the genetic mutations in OPMD, diagnosis was dependent on the clinical presentation and pathologic review of muscle specimens. Muscle biopsies may reveal loss of muscle fibers, with variation in fiber size and an increase in the number of nuclei and amount of interstitial connective tissue, as is seen in many myopathies. Rimmed vacuoles as well as small, angulated fibers have been described. However, the most significant finding is that of accumulations of intranuclear tubular filaments with an 8.5-nm outer diameter and a 3-nm inner diameter, which are unbranched, and often course rectilinearly.
The mechanism of disease is currently unknown, although a gain-of-function pathogenesis has been proposed, with pathogenic mutations causing abnormal accumulation or localization of PABPN1 and other nuclear proteins, and interference with normal cellular processes. A transgenic mouse model has been developed and reported (Davies et al., 2005), with progressive muscle weakness and intranuclear aggregates, further suggesting that abnormal expansions of trinucleotide repeats in the PABPN1 gene are pathogenic. Current investigations are aimed at using protein chaperones or targeted knockdown of the PABPN1 gene to reduce accumulations of abnormal intranuclear protein, in the hope of ameliorating disease.
At this point, there is no definitive medical treatment for OPMD. Diet modification and supplementation are recommended as needed. Blepharoplasty, with resection of the levator palpebral aponeurosis and frontal suspension of the eyelids, is recommended once the ptosis interferes with vision or when neck pain becomes a complication due to compensatory dorsiflexion of the neck. Cricopharyngeal myotomy should be considered once patients develop severe dysphagia or recurrent aspiration pneumonia. Unfortunately the procedure will only temporarily alleviate the symptoms, as the dysphagia will eventually recur with time. Gastrostomy may allow for adequate nutrition, but its value in preventing recurrent aspiration remains debatable.
We thank Dr. Nguyen for presenting this interesting case for discussion, and the patient for consent to use his case documentation in the online presentation. We thank the Muscular Dystrophy Association and the Department of Neurology at Baylor College of Medicine for providing the venue for clinical care of this patient. As noted in the discussion, myasthenia gravis is frequently the initial diagnosis rendered in patients with oculopharyngeal muscular dystrophy, and thus careful determination of the family history and a detailed clinical examination are often critical to making an accurate diagnosis.
Several respondents wrote to comment on the paucity of diagnostic testing performed in this patient. Although electrodiagnostic and muscle studies had been performed years earlier in another family member, these results were conveyed only by word of mouth and were not available for our review at the time of presentation. Thus, we presented the case to emphasize the importance of recognizing the clinical phenotype of OPMD using the history and physical examination, with limited use of screening assays.
-- Dennis R. Mosier, M.D., Ph.D.
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