Semblance of a Whole

The Story of the Tell-Tale X: or, Mind Your C's and G's

About fifteen years ago or so, we began noticing some odd things about my father. An avid skier all his adult life, his friends noticed he suddenly seemed to be having balance and coordination problems on the slopes. My mother was troubled when he seemed to lose interest in many of his favorite activities, including working on wood carving, carpentry, or electrical projects in his workshop, and even, god forbid, the computer. Running, skiing, and other active pastimes fell by the wayside. He seemed increasingly tired and lethargic, but the change was gradual. After a few years, we realized he had come to spend most of his day dozing in his favorite chair.

My mother took him to the doctor, but they couldn't identify any particular ailment. The symptoms only grew more alarming as time went on. The changes were so gradual, we wouldn't realize he was getting worse until were suddenly faced with the reality that another daily life activity had joined the list of things my father could no longer do. I remember vividly the day I realized my father could no longer drive safely. One day my mother came home from work to find my father lying in the bedroom, where he had apparently been most of the day, unable to get up. There were more doctors, but still no answers.

Even more frightening than the physical changes were the cognitive ones. The man who so enjoyed, as he put it, "shooting the bull" with friends and always had to be dragged away from parties by my mother became silent and non-communicative. The man who taught me calculus (usually when he was supposed to be helping me with my algebra, natch), could no longer do simple arithmetic. The man who tried so hard for years to convince me that learning a computer programming language should be just as fun as the other foreign languages I so loved to study no longer even entered his office, let alone tinkered with database programs that used to enthrall him so entirely, and didn't show any interest in hearing all about my excitement in discovering how fun it was to work with XML and XSLT at my new job at the YMCA Archives. There was a trip to the Mayo Clinic to see yet more doctors. They could see that there were changes in my father's brain, but still no explanation for his neurological problems.

There was a walker. Then there was a wheelchair.

My mom sold their home of 33 years, the house on Medicine Lake where I grew up, to move to a place that was wheelchair accessible.

Gradually, my dad's activities became more and more limited. He could no longer walk even a few steps unassisted, and he began to suffer from incontinence. His communication was limited to answers to direct questions (and then often only with prodding), and his behavior could only be described as childish. Travel was out of the question, and even outings to restaurants, plays, ball games, friends' homes, or other places they enjoyed became increasingly difficult. My mom struggled to get him in and out of chairs and cars. Still the doctors had no explanation. It wasn't Alzheimer's. They didn't even call it dementia. My dad, they said, simply had a degenerative neurological condition.

The wear and tear on my mother reached a breaking point, and ultimately, about a year and a half ago, she was forced to move my father to a nursing home. He was 65 years old. Since then he has continued his slow decline, speaking even less, and losing either the ability or the will to feed himself.

Meanwhile, my sister and I discovered we had both been diagnosed with another problem, equally inexplicable if less debilitating than my dad's. My doctor offered no explanation for Primary Ovarian Insufficiency (POI, also known as "Premature Ovarian Failure"), other than "it happens to some people." My own research, however, suggested there are indeed some known causes. In particular, I came across two that caught my eye:
1) POI can be caused by an autoimmune reaction. My dad has suffered from rheumatoid arthritis, which is an autoimmune disease. Could there be a connection?
2) POI can be caused by the Fragile X premutation. A cousin on my father's side has Fragile X Syndrome. Could there be a connection? And what the heck was a "premutation," anyway?

I mentioned these possibilities to my doctor, who ordered some tests. The results showed no sign of any autoimmune reactions. They also showed I didn't have Fragile X, which we were pretty certain of, anyway, as even though it affects males more significantly than females, the symptoms are usually pretty evident. The doctor didn't seem inclined to pursue it any further, but I wasn't convinced that we had fully explored or understood the possible Fragile X connection.

A couple of years went by. My regular doctor was on leave when I was due for a routine exam, so I ended up seeing a different doctor. I was given the usual medical history forms to fill out before my appointment. I checked off the usual response after the usual list of conditions like heart disease, stroke, cancer, diabetes, etc. When I got to the blank line with "other" before it, I decided to write in Rheumatoid Arthritis and Fragile X, since I wanted the new doctor to know about these pieces of my medical history, just in case they were significant. Sure enough, she latched right on to them. It seemed that the research I had been reading about had started to trickle down to the general practitioners. Whereas previously, my doctor had seemed complacent about finding a cause for my POI, now she took a muchmore aggressive approach, referring me to an endocrinologist to investigate the possibility of either an autoimmune condition or some connection with Fragile X.

The endocrinologist ordered more autoimmune tests, but they came back normal. He also did some research on Fragile X. I learned that it is caused by changes to the FMR1 gene on the X chromosome. The gene has a DNA sequence called CGG repeats. A normal FMR1 gene has up to 50 CGG repeats. An individual with over 200 repeats has Fragile X. If you have between 50 and 200 repeats, you are considered to carry the Fragile X premutation. Fathers with the Fragile X premutation can pass it on to their daughters (not to their sons, since it is on the X chromosome), and mothers who carry it can pass it on to their offspring as well. When passed from mother to child, the number of repeats can expand, potentially to the point of becoming full-blown Fragile X in their sons or daughters. Whereas the full mutation can cause mental retardation, autism, or learning disabilities, until recently, the premutation was believed to have no affect on its carriers. What researchers now know is that female carriers of the Fragile X premutation can, like my sister and I, develop POI. Although the test my doctor had done earlier showed I did not have Fragile X, it did not rule out a Fragile X premutation.

The endocrinologist also mentioned one more thing to me, almost as an afterthought. Recent research has revealed that older men who carry the Fragile X premutation can suffer from certain neurological problems.

Bingo! I started searching the Internet for research on Fragile X and neurological problems in men and there was the description of my father's problem: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Ironically, my father had been asked about six years ago by doctors familiar with my cousin's case to participate in a study that would check to see if he carried the Fragile X premutation. The study was being conducted in California, so my parents arranged to have a blood sample sent there. However, they never heard anything back and they never pursued it.

After I told my mother about what I had learned, she started looking at the research herself. In one of the articles, she found the email address of the doctor who had asked for the blood sample six years ago. She contacted him and got a response back almost immediately. After reading a description of my dad's symptoms, he agreed it sounded likely that the Fragile X premutation could in fact be the culprit. He had a colleague check back through the records to see if they still had the results of my dad's test. They did. And guess what? My dad has
95 CGG repeats.

So now we know. My dad almost certainly has FXTAS. There is a name for his problem. A known cause. There is no treatment, but although my father probably won't benefit, there may soon be one. The doctor who conducted that study just received a grant of almost $22 million to develop one.

And now I wonder: Whereas Fragile X affects only 1 in 6000 males and 1 in 4000 females, about 1 in 259 women and 1 in 800 men carry the Fragile X premutation. That's a lot of people. How many of these men have been (mis)diagnosed with Alzheimers, Parkinsons, or some other non-specific dementia?

Posted by ldfs at April 3, 2008 05:40 PM | TrackBack