OPMD and Advancements in Genetic Research
Matthew Wicklund, MD, a professor of neurology at the University of Texas Health Science Center San Antonio, discussed the genetic basis of oculopharyngeal muscular dystrophy, as well as the primary challenges in diagnosing and treating the condition.
Matthew Wicklund, MD
Credit: UT Health
A rare, autosomal dominant disorder, the symptoms of oculopharyngeal muscular dystrophy (OPMD) include progressive weakness in muscles controlling eye movement, swallowing, and limb strength. Although some treatments focused on management of the symptoms exist, there are no currently available treatments that target the root genetic cause of the disease.
CGTLive®'s sister site NeurologyLive® recently spoke with Matthew Wicklund, MD, a professor of neurology at the University of Texas Health Science Center San Antonio, who chaired a session on clinical and preclinical advances in OPMD as part of the “Lab to Life Track” at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19, in Dallas, Texas. Wicklund gave some background information about the disease itself and then discussed some of the preclinical efforts that are currently ongoing to develop targeted treatments for OPMD.
NeurologyLive: Can you give an overview of OPMD, its genetic basis, and some of the primary challenges that clinicians currently face in diagnosing and treating this condition?
Matthew Wicklund, MD: OPMD is oculopharyngeal muscular dystrophy and we name things by what they are. What that tells you is that involvement includes the eyes: they develop ptosis; pharyngeal: they have difficulty swallowing, dysphagia; and then they also have a dystrophy: they have proximal weakness, usually in the legs, more than the arms. It's a later onset disorder, so the onset usually is in the 40s or the 50s, usually with ptosis first followed by dysphagia, and then by the weakness in the legs. It's due to a trinucleotide repeat in a gene called PABPN1. In this gene, if you have a repeat size of 10 of these repeats, you do not have disease. If you have 11, you are recessive and anything above that you will have dominantly inherited disease.
There are pockets where OPMD is much more likely to be seen, and those include in the northeast of the United States, which really means Quebec, Canada because there's a French Canadian founder mutation; there is a group in the southwest of the US, and that's a Hispanic population of Texas, New Mexico, Arizona, and California. Then there are the Bukharan Jews over in Israel. As such, there are places where you'll more likely see OPMD, and probably there are about 15,000 to 20,000 patients with OPMD, if you look sort of in that North America, Europe, and Israel population.
That describes OPMD clinically. The challenge is we don't have definitive disease-targeted treatments yet. There are treatments for OPMD. Very simply, the first thing they usually develop is ptosis. You can develop slings that will help pull the eye up or the eyebrow up and there are multiple ways that you can do that to alleviate ptosis. For the dysphagia, that comes on gradually. You can do swallow studies and you can have speech and language pathologists work with them to help their swallowing. You can have issues with either dilating the esophagus, which allows for food to flow more smoothly down. Occasionally, you can have somebody that will actually do botulinum toxin of the esophageal muscles, and that will work in some patients of limited time frame. Then the current definitive therapy, if you just cannot swallow, and is a myomectomy. Then obviously, for the muscular dystrophy, we do not have anything at this time.
What recent preclinical research has shown promise in understanding the underlying mechanisms of OPMD, and how is this knowledge potentially guiding future therapies?
In OPMD, you have this trinucleotide repeat that leads to inclusions. One of the early things that they're trying to do is—you want to produce the protein which is involved in developing a poly(A) tail and you must have that poly(A) tail. But the goal is, if you can produce the normal protein, but not produce the abnormal protein, then theoretically, you would solve the problem. There are preclinical models that are working on that, and that includes CRISPR/Cas9 and other methods to knock down one and/or give a replacement normal copy. The other thing is that there are other techniques out there where you can actually try to silence the abnormal RNA or act at the ribosome, so that the ribosome will not create protein from the RNA that comes to it that is abnormal. So there are a number of strategies all along that pathway that can be targeted.
