by Dan Stimson

San Miguel County, in northern New Mexico, about 25 miles east of Santa Fe, is steeped in Native American and Spanish history.

Before Spanish explorers arrived in the 16th century, the area was a thriving center of trade between nomadic Apache tribes to the north and agrarian Puebloan tribes to the south. The Spanish built some of the first Catholic missions in the southwestern United States here.

Though signs of this rich cultural heritage are abundant, another part of the area’s heritage has, until recently, remained hidden. It’s oculopharyngeal muscular dystrophy (OPMD) — a rare genetic disease that causes muscle weakness primarily around the eyes and in the throat — and it may have been introduced to the area by the Spanish.

Charlie Chavez (pictured with his wife, Carol) has OPMD, as did his mother, Felicita (below).

Charlie Chavez, a 57-year-old supervisor at a trucking company, lives in Albuquerque but grew up in rural San Miguel. He recalls that when his mother was in her 60s, she began to have frequent choking spells during meals. Chavez and his siblings didn’t see this as unusual or disturbing; an uncle had the same problem.

But in 1998, when Mrs. Chavez was hospitalized for terminal lung cancer at age 87, doctors noticed the swallowing problems and other symptoms, and determined that she had OPMD.

Chavez, who had always been athletic and used to eating meals on the go, developed similar problems a few years later, and quickly found it hard to maintain his weight. He received an OPMD diagnosis in 2002.

OPMD has been identified in “clusters,” some as small as single families, in just a handful of countries. As people like Chavez sought help, researchers at the University of New Mexico (UNM) Hospital and the New Mexico Veterans Affairs Health Care System in Albuquerque began to see the outlines of a large OPMD cluster among Hispanic families, many of them living in rural parts of the state with limited access to health care.

In a study published in the Journal of the American Medical Association (JAMA) in 2001, researchers reported finding 216 cases of OPMD in New Mexico, spanning four generations in 39 families — one of the largest OPMD clusters in the world.

Even now, “patients and some practitioners in rural areas might not recognize [OPMD] as a disease. They just think, ‘Grandma had this problem and so do I.’ They don’t realize there are some interventions that can help,” says MDA research grantee Mark Becher, a neuropathologist formerly at UNM and an author on the 2001 JAMA study. Fortunately, the study has raised awareness of OPMD across the United States and contributed to a boom in research seeking more effective treatments.

Neurologist Leslie Morrison, director of the MDA clinic at the University of New Mexico Carrie Tingley Hospital, and David Bear, a protein biologist at UNM, are exploring the New Mexico cluster of OPMD.

UNM researchers now have identified 99 Hispanic families with OPMD in New Mexico, and for every known patient, it’s suspected there are two more whose OPMD remains undiagnosed. Neurologist Leslie Morrison, director of the MDA clinic at UNM, is helping to spread the word about the disease and available treatments.

As the OPMD cluster emerged, Morrison began setting aside one day of the clinic each month exclusively for OPMD patients. The clinic now serves nearly 500 such patients and has a hotline (see “OPMD Resources”) which has taken calls from as far away as New Jersey.

In November 2003, Morrison invited families to learn more about the disease at a conference at the National Hispanic Cultural Center in Albuquerque, and she plans a similar conference for health care professionals in 2005.

Droopy Eyelids, Trouble Eating

As its name suggests, OPMD primarily causes weakness in the ocular muscles, which control movement of the eyes and eyelids, and the muscles of the pharynx — the tube at the back of the mouth that splits into the esophagus (which leads to the stomach) and the trachea (which leads to the lungs). Thus, the earliest and most common complaints of people with OPMD are ptosis (droopy eyelids) and dysphagia (swallowing problems).

“The droopy eyelids bother them because they can’t see the whole visual field. They might have noticed it years ago,” Morrison says.

Emily Crump Roberts interviews Charlie Chavez about his family’s OPMD history.

Or, “they’ll notice that they have more and more difficulty swallowing dry foods, like breads and meat. It takes a long time for them to get through a meal. They spend a lot of time coughing and clearing their throats, and they tend to lose weight,” she says.

In most cases, these problems begin between ages 40 and 60, and gradually worsen with time. As ptosis worsens, muscles in the back of the neck may become strained and weak from constantly tilting the head back to improve vision. Progressive weakness in muscles that control the eyes’ gaze may cause a partial paralysis of eye movements, called ophthalmoplegia.

This weakness may begin to affect other facial muscles, making it difficult to speak or even smile. The rate at which the disease progresses is variable, as is the involvement of muscle groups other than those in the head and neck. Even relatively early in the course of OPMD, some people experience significant weakness in the limbs, necessitating use of a wheelchair or other mobility aid.

Late in the course of the disease, pharyngeal weakness can become severe, and an inadequate swallow can send food down the trachea and into the lungs, where it can lead to pneumonia. Historically, starvation and pneumonia were common causes of death among families with OPMD, but surprisingly the disease doesn’t seem to shorten life expectancy, Morrison says.

She traces the histories further at the Genealogy Library of the National Hispanic Cultural Center in Albuquerque.

“Instead, people end up living for quite a while with a diminished quality of life,” she says.

At the MDA clinic, a speech pathologist teaches OPMD patients techniques to improve swallowing, while a nutritionist helps them move their diets away from chewy foods. For most people, these modifications eventually become inadequate, but fortunately, there are surgeries that can eliminate dysphagia for many years. Ptosis also can be corrected through surgery (see “Surgical Options”).

Meanwhile, research at UNM is focused on understanding the genetic defect behind OPMD and figuring out how it made its way into New Mexico.

The French Connection

To date, most research on OPMD has been concentrated in Quebec, home of the world’s largest known cluster of people with the disease. In this Canadian province, founded by French colonists in the 17th century, OPMD is as prevalent as Parkinson’s disease, and more prevalent than any other form of muscular dystrophy.

In the 1960s, researchers combed through the extensive records of the Roman Catholic Church in Quebec in an effort to probe the genealogical origins of this mysterious cluster. All French-Canadian families with OPMD, they found, could trace their roots to a single ancestral couple — Jean Aymard and Marie Bineau — whose three daughters emigrated from France to Quebec in 1648. Many people with OPMD living in the United States, especially in New England, probably can trace their heritage to the same couple.

Other studies in the 1960s helped to show how the disease had spread so rapidly through generations of French-Canadian families. OPMD, it turned out, typically is inherited in an autosomal dominant manner, meaning that only one faulty gene is needed to cause the disease and that an affected parent has a 50 percent chance of passing it on to each child.

Emily Crump Roberts, a premedical student at UNM who works closely with Morrison, is conducting similar studies to determine the origins of the disease in New Mexico.

“This work is important not only because of the scientific interest in how OPMD got to New Mexico, but also because it will help medical care providers identify underserved areas in the state that are likely to have large populations of people with OPMD who are still undiagnosed and untreated,” she says.

In her studies, Roberts first interviews volunteers about their family histories, then traces the histories further at the Genealogy Library of the National Hispanic Cultural Center, which has census records, birth and death certificates, and copies of the baptismal and marriage records of the Catholic archdioceses in Santa Fe and Taos, N.M. (The center doesn’t conduct research or provide medical care, but offers its library facilities to researchers.)

The two prevailing theories are that OPMD was brought to New Mexico by Spanish colonists in the 1500s or by French-Canadian fur trappers in the 1800s. Another possibility is that the genetic defect that causes OPMD — which has proven to be the same kind of mutation in the same gene everywhere the disease is found — arose in this population independently.

The OPMD Gene

Some experiments suggest that the PABPN1 protein normally sticks to RNA long enough to attach a protective poly(A) tail. Extra material in PABPN1 might make it abnormally sticky and lead to the clumps of cellular debris observed in OPMD-affected muscle cells.

A Canadian team led by MDA research grantee Guy Rouleau, a geneticist at McGill University and Montreal General Hospital, reported discovery of the OPMD gene in 1998. With support from MDA, these researchers had collected DNA from hundreds of patients living in Canada and 19 other countries, and found that all of them had mutations in the same gene.

The gene makes a protein called nuclear poly(A)-binding protein 1, also known as PABPN1, which is found in nearly every cell in the body. Most of the PABPN1 in cells is located in the nucleus — the cellular command center where DNA is stored.

Rouleau and his colleagues were surprised to find that the PABPN1 gene (originally called the PABP2 gene) was behind OPMD. They had expected to find a gene with a function specific to muscle cells.

They were equally surprised by the kind of mutation they found. The chemical code of DNA is divided into three-letter phrases, called trinucleotides, and this mutation looked like a stutter of the three-letter phrase “GCG.”

Normally, the PABPN1 gene contains six consecutive repeats of GCG, but in people with OPMD, it contained eight to 13 such repeats. This type of mutation — known as a trinucleotide repeat expansion — has been found in other genes, and is associated with more than a dozen hereditary disorders, including Huntington’s disease.

At the time of his discovery, Rouleau says, “There was no example of a muscle disease caused by a repeat in the coding part of a gene [the part that forms the direct instructions for making a protein].”

Before any gene (actually, a stretch of DNA) can be used to make any protein, it must first be copied into a string of chemicals called RNA. During this process, PABPN1 and other proteins normally latch onto the newly formed RNA and fit it with a chemical tail called poly(A).

Eventually, when RNA gets shipped out of the nucleus and into the main part of the cell, the poly(A) tail protects it from attack by enzymes. Even in OPMD-affected cells, this function appears to be intact. Nevertheless, the researchers knew something had to be going wrong, and it had to involve PABPN1.

In every part of the world where OPMD has been found, including New Mexico, GCG-9 (nine GCG repeats) has turned out to be the most common mutation in the PABPN1 gene. Repeat expansions of other sizes have been found, which seems to explain why some people with the disease experience a broad distribution of weakness while others have few symptoms beyond ptosis and dysphagia. Longer-repeat expansions tend to be associated with a more severe disease course with weakness in more muscles.

In general, the total number of repeats seems to determine the severity of the OPMD. By far, the majority of people with OPMD have one mutated copy of PABPN1 and one normal copy. But it’s possible to get a double “dose” of defective PABPN1 — two mutated copies of the gene (one from each parent). The mutated copies can be identical, or they can be a combination of two different repeat sizes. Either way, the resulting disease tends to be more severe and to begin at an earlier age.

Then there’s a GCG-7 mutation, found in 1 percent to 2 percent of North Americans, that causes OPMD only when it’s present in both copies of PABPN1, or when it’s combined with a longer repeat expansion. Apparently, seven repeats in one copy of the gene isn’t enough to cause OPMD.

A Sticky Situation

OPMD Resources MDA Web site www.mda.org/disease/opmd.aspx OPMD e-mail support group http://health.groups.yahoo.com/group/opmd/ University of New Mexico OPMD hotline (505) 272-OPMD http://hsc.unm.edu/som/programs/opmd

Whatever the exact number, extra repeats in the PABPN1 gene ultimately elongate its protein and alter its function in ways that aren’t fully understood. Figuring out what’s wrong with the mutated protein, researchers believe, could lead to the development of drug treatments for OPMD.

“In the trinucleotide repeat diseases in general, we believe the proteins have a novel, abnormal function as opposed to just losing their normal function,” Becher notes.

Some experiments suggest that the repeats in PABPN1 normally provide a surface for sticking to RNA and other proteins, so extra repeats might make the protein abnormally sticky. Consistent with this idea, the elongated protein has been shown to accumulate in the nuclei of muscle cells, forming heaps of cellular debris called intranuclear inclusions.

Notably, inclusions like these are a hallmark of trinucleotide repeat diseases in general. The mutated protein that causes Huntington’s disease, for example, accumulates in the nuclei of brain cells.

“The prevailing hypothesis is that these inclusions trap important proteins and RNA, and that the trapping mechanism keeps the cell from functioning normally,” says MDA grantee David Bear, a protein biologist at UNM who has been studying PABPN1 for more than 10 years.

(It was actually Bear who provided the driving force behind the 2001 JAMA study. In 1998, after learning that PABPN1 had been linked to OPMD, Bear contacted Morrison, and the two formulated a plan to search for PABPN1 mutations in what they thought was a small group of Hispanic New Mexicans with the disease.)

On the other hand, Bear says, “The inclusions may be a byproduct of the disease, and not a cause. It could be that they’re just a mechanism of packaging up bad proteins in order to keep them from damaging the cell.”

In that case, what else might be causing OPMD?

Last year, Bear made the surprising discovery that PABPN1 doesn’t merely hitch itself to RNA that’s already been made. It also interacts with RNA polymerase — a protein essential for copying RNA from DNA. Bear says it’s possible that in OPMD, the elongated version of PABPN1 interferes at the earliest stage of RNA production rather than just sticking to formed RNA later on.

The Search for Drugs

Whether PABPN1 inclusions are harmful or protective, their presence in muscle tissue is a clear indicator of OPMD. They’re visible under a microscope, and long before they were known to contain PABPN1, they served as a tool for diagnosing OPMD. (Nowadays, direct genetic testing also can be used to diagnose OPMD.)

The percentage of nuclei that contain inclusions has been shown to parallel the severity of the disease. Thus, a major research strategy is to find drugs that are capable of clearing away the inclusions.

In order to test candidate drugs, Rouleau has created laboratory-grown cells that develop PABPN1 inclusions. He and other researchers also have independently created mice that carry trinucleotide repeat expansions in the PABPN1 gene.

Similar research on Huntington’s disease has revealed drugs that might be useful for treating a number of trinucleotide repeat diseases, including OPMD.

For example, researchers at Harvard Medical School in Boston recently gave mice with Huntington’s disease abdominal or cerebral (brain) injections of Congo red, a dye that’s attracted to accumulated proteins and is used to examine postmortem brain tissue. Those injections cleared away inclusions in the animals’ brain cells and improved their neurological symptoms.

“We’re profiting a lot from research on Huntington’s,” says Mark Becher, who recently relocated from UNM to Vanderbilt University in Nashville, Tenn., where he’ll continue to study OPMD.

“In the Huntington’s world, they’re concentrating on agents that are already approved for use by the Food and Drug Administration, so any drug candidates they find could move rapidly into clinical trials.” The same sorts of drugs are being evaluated in cell and animal models of OPMD, Becher says.

Meanwhile at UNM, Bear and Morrison are continuing their outreach efforts and designing clinical studies to improve treatments for OPMD patients.

“In addition to understanding the biology of the disease,” Bear says, “our major goal is to characterize the OPMD population in New Mexico and surrounding areas. The population is largely elderly, and they tend to have other health problems besides OPMD. We want to understand how OPMD affects those problems, and how those problems affect OPMD.”

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Surgical Options in OPMD

At some point, most people with OPMD find that they need surgery to correct ptosis or dysphagia, or both. There are different types of surgery for each problem, and it’s important to choose the right one at the right time.

To treat ptosis (droopy eyelids), surgeons can either remove a section of the levator palpebrae superioris muscle, which normally opens the eye, or they can connect the upper eyelid to the frontalis muscle, which normally lifts the eyebrow. The circular orbicularis oculi closes the eye.

Ptosis

Ptosis is caused mainly by slackening of a muscle called the levator palpebrae superioris, which literally means “lifter of the upper eyelid.” In levator resection surgery, a section of this muscle is removed so that it becomes shorter and more effective at pulling up the eyelid.

But, since the levator muscle continues to weaken over the course of OPMD, ptosis probably will return within five to 15 years after the surgery.

Therefore, many surgeons recommend a frontal suspension or frontalis sling, in which a bridge is passed from the upper eyelid to the frontalis, a large muscle in the forehead that stays relatively strong in OPMD. Surgeons usually advise delaying either procedure until ptosis seriously interferes with vision, so that the tendency for progressive weakening and relapse is less likely. (For more about eye surgery, see “Keeping Your Focus: Eye Care in Neuromuscular Disorders,” December 2000.)

Darlene Nilsson of Temecula, Calif., now 69, learned she had OPMD in 1984, and has had both procedures. After a levator resection in 1994, her ptosis improved remarkably, but it returned after about six years, at which point she opted for frontalis slings.

Since then, her vision has remained good, her neck is no longer sore from tilting her head back, and she’s happy with her appearance.

“The day I came home from the surgery, I looked at myself and said, ‘I really do have blue eyes!,’” Nilsson recalls.

Dysphagia

Weakening the circular cricopharyngeus muscle in the throat, or slicing through it, can remove the obstacle to swallowing when the pharyngeal muscles aren’t strong enough to push food past it. Widening the opening to the esophagus is another approach.

There are surgical and nonsurgical treatments for patients who find that swallowing therapy alone is no longer effective for dealing with dysphagia.

Most of these interventions center around the cricopharyngeus, or CP, a muscle that forms a ring around the opening of the esophagus.

When a person isn’t swallowing, the muscle stays tight, helping prevent esophageal reflux — food and digestive acids coming back up the esophagus. During the swallowing process, muscles above the CP contract to push the food toward the esophagus, and in turn, the CP loosens to let the food pass.

In OPMD, the “pushing” pharyngeal muscles become weak, while the circular CP remains strong, becoming an obstacle to a good swallow.

One method surgeons have developed to get around the CP is to inject it with the muscle-paralyzing agent botulinum toxin. (Botox is a popular brand name.) Another procedure, called cricopharyngeal myotomy, involves slicing through one side of the CP muscle. Finally, an operation called pharyngeal dilatation involves inserting a tube or inflating a balloon in the pharynx to widen the esophageal opening.

The Botox procedure is noninvasive, but its effects only last a few months. Another down side is that the toxin can spread from the injection site and reach the larynx, or voice box.

“One of the main side effects is that people tend to lose their voice temporarily,” says Carol Romero-Clark, a speech pathologist at UNM. “The second complaint is that if anybody has heartburn or reflux, we’ve paralyzed the muscle now, so there’s nothing to stop [food and acids] from coming back up.”

In the dilatation procedure, there’s a risk that the tube or balloon could expand too quickly and puncture the esophagus, but the procedure is generally safe and its effects last for five to six years, Romero-Clark says. CP myotomy usually produces a longer-lasting improvement — about 10 years — but carries the risk of cutting the nerves to the voice box, she says.

Nilsson had a Botox injection in April 2002, and she’s thinking about getting another one.

“I still have to watch what I eat, but it helped immensely,” she says.