Opening Up the Ivory Tower

Emery-Dreifuss MD: A Search For Answers

A Woman Pursuing a Personal Mystery
Finds Some Clues in an MDA Research Lab

Jill Dopf

I feel like a spy who's gained entrance to a top-secret research facility, as I await the start of an informal research meeting at Katherine Wilson's lab in Johns Hopkins University's Department of Cell Biology and Anatomy. Around the table on this summer morning sit a half-dozen scientists, each armed with a pile of papers that represents the culmination of years of research and data. I sense their sideways glances as I awkwardly circle the table and draw a chair up beside them. I don't resent their curiosity — I welcome it.

I scan a newly published research article describing the 53 people in the world who share my diagnosis of autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). I'm comforted to learn that one to two new cases are being discovered each week, yet I feel alone as I recognize that my family is one of a handful in the United States known to be affected by AD-EDMD. I contemplate the stories hidden beneath the cumbersome text. Black circles and squares. Lives stretched to the limits of human endurance, now reduced to geometric simplicity.

I trace my finger over the description of a young woman, similar to me. I think about this person living far away, yet in a strange way, inhabiting the same body as mine. I wonder what she does for a living, whom she loves and what her family is like. Most of all, I long to meet her someday. I imagine traveling to a small cafe in a distant country and out of the crowd of bustling patrons, eyeing someone with the same waddling gait as mine. Oblivious to the passage of time, I would speak endlessly to her like a woman reunited with a child given up for adoption.

But, as I strum my fingers over the brief description, the text becomes too real. The age, the surgical history, the pattern of muscle weakness... I finally realize I'm looking at a description of myself.

My journey to Johns Hopkins in Baltimore in the summer of 2000 had actually begun long ago. As a child with an unclassified diagnosis of muscular dystrophy, I had few concerns. True, I walked with an awkward gait and stumbled frequently, but for the most part I blended in with others my age. Infrequently I was confronted by children who asked what was wrong with me, and I'd simply shrug my shoulders and say, "I was just born this way."

I recall swimming in a public pool with my sister Janet when I was 8 and she was 6. Enjoying the sparse collection of swimmers in the final five minutes before the pool closed, we took turns diving into the deep end. As I surfaced after a dive I heard the snickering of two boys. I called my sister.

"It was nothing," she insisted, as she stuffed our towels and suntan lotion into her bag. Though 26 months my junior, Janet had already surpassed me in both height and weight.

"Tell me," I insisted as I noticed the boys now doubled over laughing and clutching the stainless steel rungs of the diving board ladder.

"He said you look like a white Ethiopian," she finally whispered in my ear.

Though I never can recall being teased for my waddling gait or obvious muscle weakness, my tiny limbs had not escaped the attention of my classmates. At the lunch table at school I frequently brushed the hands of students away. However, every once in a while I wasn't quick enough and I'd feel the fingers of a classmate wrap around my biceps or ankle. As I approached adolescence the curious glances became more frequent. I recall a sixth-grade orchestra practice as the girl beside me slowly moved her eyes up and down my torso.

"When was your accident?" she asked.

"I don't understand," I stammered.

"Your car accident," she insisted. "Your neck's all funny-looking and stiff."

I ignored her question and pretended to be occupied with tightening the strings of my violin bow. Yet I found myself glaring into my music stand. Studying the bloated image of my face in the chrome, I eased my head forward, attempting to rest my chin on my chest, yet found the joint mysteriously locked like bone meeting bone. Almost overnight, I'd noticed my back had stiffened to the point where I could no longer recline into the pew at church.

I searched for answers during the annual MDA Labor Day Telethon, yet I didn't recognize anyone with symptoms similar to my own. I was especially discouraged when my yearly visits to the Mayo Clinic in Rochester, Minn., offered no explanation for my bizarre symptoms. Though an elevation of creatine kinase in my bloodstream was indicative of muscular dystrophy, the neurologists who examined me claimed never to have seen another case such as mine.

Yosef Gruenbaum, Jill Dopf and Kathy Wilson in Wilson's lab at John Hopkins

Digging Deeper

Confusion regarding a precise diagnosis had lingered in my family for several decades. My father demonstrated the same type of weakness, though as a child of the 1950s, his symptoms were readily attributed to polio. A diagnosis of muscular dystrophy wasn't assigned until I began to show the same symptoms at age 4.

Although the quest seemed futile, I knew I needed to search for answers on my own. As I completed my first year of college at Drake University, my introductory genetics professor arranged an internship for me at the Human Gene Therapy Research Institute in Des Moines, Iowa. Through my studies there, the once-baffling world of DNA came to life and I found myself able to follow the articles in medical journals. Armed with my new vocabulary, I transferred to Iowa State University in Ames to pursue a degree in genetics, and searched the Internet for clues.

I was inspired by the 1992 film, "Lorenzo's Oil," in which a father and mother desperately search for, and eventually discover, a treatment for their son's debilitating neurological disorder. I thought of this movie often as I spent more and more time in the dark, musty tiers of the ISU library. I wondered if someday I, too, would occupy a dark circle on a genetic chart catalogued on a dusty library shelf.

In the library, I stumbled upon photographs of people with Emery-Dreifuss muscular dystrophy. Though it was a rare disorder, typically seen only in males, I could readily identify with the bizarre symptoms unique to this form of MD, which included contractures of the Achilles tendons, elbows and neck.

Clutching an armful of research articles, I suggested EDMD as a diagnosis for my condition during my yearly neurological exam in the fall of 1995. I'd hoped my doctor would share my enthusiasm and offer to write to a team of Italian scientists who'd already identified the causative gene for the more common X-linked form of EDMD.

"You don't have Emery-Dreifuss, though your symptoms are strikingly similar," my doctor insisted, suggesting that the absence of cardiac symptoms excluded such a diagnosis.

One-on-One With Researchers

Unpersuaded, I decided to write to the Italian scientists myself, describing my symptoms and suggesting my family as potential participants in their research. As I proofread my letter, I was aware of the blank space following my name. No M.D., no Ph.D. I didn't think anyone would believe me, a 20-year-old college student.

I also enclosed a photo of myself to show my symptoms, and a recent family Christmas picture showing my two sisters and two brothers (three of whom are also affected by EDMD, though with a wide variation in symptoms), as well as my parents and me.

Fortunately, the Italian scientists were pleased with my offer, and a linkage study, based on blood samples from members of my family, confirmed a diagnosis of AD-EDMD in March 1999. The same year, scientists found the gene involved in the autosomal dominant form of the disease. My father also received a pacemaker to treat the cardiac symptoms that he now realized were associated with his EDMD.

Shortly following this exciting update, I received a call from cell biologist Kathy Wilson at Johns Hopkins. She had come across my name in correspondence with a colleague and contacted me to inquire whether my family and I wished to be analyzed as part of her MDA-funded research regarding the inner nuclear membrane and its role in hereditary disease. I inquired whether I might come join her lab as a summer volunteer.

I was eager to meet the researchers behind the published papers who were working 12-hour days in an effort to help people like me and my family. And I was hoping they'd grow to understand me — not just as a research subject, but as a friend. Wilson offered me a paid internship and arranged for me to reside with two visiting colleagues, Yosef Gruenbaum and Merav Cohen from Hebrew University in Jerusalem.

Entering the Lab

As I arrived for my first day at work, words of the evening news anchor echoed through my mind: "Is the cure for cancer within reach?" I thought of movie plots such as that of "Medicine Man," depicting a maverick scientist in the jungles of South America — Sean Connery alone possessing a single rare herb or drug to cure any variety of cancer.

The author (lower right) joins colleagues at the Johns Hopkins cell biology lab where she worked as an intern. Wilson is at the top, second from right.

I quickly learned that no one studies "cancer" or "muscular dystrophy," but an individual scientist may spend an entire career studying a tiny piece of the puzzle. I realized the cure for cancer or muscular dystrophy wouldn't be identified by a single person, but rather would occur as the culmination of hundreds of scientific studies whose results were shared in journals and research conferences. I felt at ease as I joined in conversation with the graduate students in the lab, most of whom were under 30.

Later in the day, Kathy Wilson ushered me into the break room to discuss the progress in EDMD research. She explained that AD-EDMD occurs when the protein lamin is missing or defective. Lamin is normally found in the membrane surrounding the cell nucleus, where it functions like a tethering system to expand and contract the chromosomes of each cell, in a manner similar to the way a computer compresses and stores information. A genetic mutation in nuclear lamin causes certain genes to become either overexpressed or underexpressed. However, the overall effect is to subdue gene expression.

Wilson explained that the genetic code may be thought of as a gigantic cookbook, each cell type using only the specific "recipes," or genes, it requires. Many of the muscular dystrophies such as limb-girdle MD are caused by defects in genes used by muscle cells only. EDMD is unusual in that the nuclear lamin "recipe" is required by virtually every cell type from skeletal and cardiac muscle to brain and many internal organs. Remarkably, however, EDMD's effect is limited primarily to skeletal and cardiac muscle.

I followed Wilson through the dim hallways, several floors above the lab. The pungent smell of mice scurrying in rows of plastic cubes filled the air. She drew a cage from the floor and I peered inside. Two mice huddled in the corner, seemingly unaware of eight tiny newborn mice, the size and color of fuzzy pink erasers. At this point, they appeared indistinguishable, yet in only a few weeks, roughly one in four would produce the telltale signs of Emery-Dreifuss MD — splayed hind legs, waddling gait, and stiffened forearms and hind legs.

Wilson explained that these mutant mice would yield a wealth of information regarding which genes are over- or underexpressed in EDMD. A computer technique known as microarray analysis can screen thousands of genes at a time and identify abnormalities. She said that these results could someday help pharmacologists develop drugs to target the proteins that are flawed in EDMD.

Each evening after my day in the lab, I returned to a flight and a half of concrete steps leading to our apartment in suburban Baltimore. Merav and Yosef assisted my tedious ascent up the stairs, and I paused at each of three staircase landings to catch my breath.

Teaching Each Other

Michael Zastrow, a graduate student in Wilson's laboratory, served as my mentor during my stay.

"I have all these articles and pictures of patients with their eyes darkened, who appear either angry, or frightened, or both, but it makes all the difference to talk to you face to face," he explained, gesturing to the tall stack of research articles beside him.

He continued to trace the advances in EDMD research across the dry erase board but paused momentarily as he stroked his goatee.

"You know all this already, don't you?"

I simply smiled.

Jill Dopf is completing her first year of graduate school at Iowa State University with an emphasis in creative writing. She also teaches a freshman composition course. She plans to pursue a career as an author and creative writing instructor upon graduation in May 2002. And she stays in contact with the EDMD researchers at Johns Hopkins and at Hebrew University via e-mail.

She'd like to correspond with others who have neuromuscular diseases; write to jdopf@aol.com or Jill Dopf, 7501 Bryn Mawr Drive, Urbandale, IA 50322.