Diagnosis X: Zeroing in on a new condition

For decades, the mutant genetic blueprint slipped past the most ardent gene stalkers -- even those familiar with fragile X syndrome and CGG expansions, mutations and premutations. Though unnoticed, it continued its habit -- repeating and replicating, expanding until its errant ways could no longer be masked.

Then came the symptoms. The slight tremor, the falls, the difficulty writing. Some blamed it on age, some on culprits such as Parkinson's. Still, those who carried this genetic anomaly got worse, not knowing why.

It was Randi J. Hagerman, MD, a pediatrician and director of the MIND Institute at the University of California, Davis, who first became suspicious. She began linking patterns and patients after the mothers of children with fragile X syndrome complained about the health of the kids' grandfathers. An uncanny similarity in the complaints of those in the older generation -- mostly tremor and balance problems -- led her, along with biochemist husband, Paul J. Hagerman, MD, PhD, a UC-Davis professor, to explore the genetic links.

"Randi ... made the connection in 2000," Dr. Paul Hagerman says. "Then it was solidified at the National Fragile X Conference. We were giving a presentation and asked if anyone's dad had this problem. At least a third of the mothers in the audience raised their hands and it was at that moment I decided to get seriously involved."

The pair, along with a cadre of researchers from UC-Davis, University of Colorado Health Sciences Center in Denver, San Diego State University and Rush-Presbyterian St. Luke's Medical Center in Chicago, began unmasking the effects of the rogue genetic behavior.

By 2001, the researchers had discovered and named a new, progressive neurological disorder: fragile X-associated tremor/ataxia syndrome or FXTAS (pronounced fax-tas). Findings of the research were published in the Jan. 28, 2004, issue of the Journal of the American Medical Association.

"It's exciting. You hardly ever discover a new disease," says fellow researcher Maureen A. Leehey, MD, associate professor of neurology and director of the movement disorders program at Colorado's health science center.

What it is

Even though fragile X syndrome and FXTAS are two different disorders affecting opposite ends of the life cycle, both are caused by mutations on the FMR1 gene -- the mental retardation gene all humans possess. The protein FMR1 produces, FMRP, is important for brain development.

The newly recognized disorder predominantly affects men older than 50 and carriers of a premutation on FMR1. Nearly one in 800 men and one in 250 women are carriers. Research suggests that as many as 30% of male carriers -- roughly one in 3,000 men -- might develop FXTAS later in life. It is still unclear how many women are affected.

Until this discovery, it was believed that carriers of the FMR1 premutation did not display any emotional, intellectual or behavior effects. "Originally, we thought that those with the premutation were in the clear," Dr. Randi Hagerman says.

Commonly misdiagnosed as Parkinson's disease, atypical Parkinson's, Alzheimer's disease, associated tremor or spinal cerebellar degeneration, patients often wander from neurologist to neurologist in search of answers.

"FXTAS may be one of the most common causes of tremor and balance problems in the adult population," Dr. Randi Hagerman says. "Yet it is being misdiagnosed, because neurologists are not aware they need to look for a family history of fragile X in grandchildren or to check for the presence of the premutation in the fragile X gene."

The premutation is easily diagnosed with a standard DNA test, developed in 1991.

"We recommend that primary care physicians ask older men with balance or tremor problems about their grandchildren," Dr. Leehey says. But even in the absence of family history, the researchers recommend screening older men who exhibit such signs as tremor, falls, rigidity of movement, short-term memory loss or dementia.

Exploring FMR1

Here's what's known. Normally, FMR1 produces a protein that maintains the proper functioning of nerve cells in the brain. Fragile X and FXTAS occur when a particular segment of DNA is repeated too many times. The repetition is called a CGG repeat because it contains the same trio of DNA building blocks, with a pattern that goes cytosine, guanine and guanine. The average person has 30 CGG repeats in the FMR1 gene. The appearance of 200 or more CGG repeats is a marker of fragile X syndrome and results in the creation of little or no protein, which has a serious impact on brain development.

Fragile X syndrome is the most common inherited cause of mental retardation and has been known in the pediatric population for 50 years. The spectrum of intellectual impairment ranges from minor learning disabilities to severe mental retardation and autism. Behavioral problems include attention deficit disorders, speech disturbances, hand biting, hand flapping, autistic behaviors, poor eye contact, and aversion to touch and noise. It is common for males to have noticeable physical features such as enlarged ears, a long face with a prominent chin, and large testicles. Still, these characteristics are often not present until after puberty.

Because females have two X chromosomes, the impact of the full mutation is often diminished; the normally functioning gene compensating for the nonfunctioning one. At this point scientists believe patients with the full mutation will not get FXTAS.

Conversely, FXTAS is identified by 55 to 200 CGG repeats, which is considered a relatively small mutation or premutation. Early studies indicate elevated levels of mRNA, which have been consistently observed in the blood of premutation carriers. "Further study of these cellular processes can lead to a better understanding of the mechanisms leading to fragile X syndrome and offer new targets for developing treatments," Dr. Paul Hagerman says. "If we could identify the inciting event, we could develop specific molecular interventions."

Male premutation carriers are at high risk for developing FXTAS as well as for passing on the gene mutation to all of their daughters. In turn, the daughters can pass on both the full mutation and premutation to their offspring. That's why genetic counseling is important, scientists say.

Constellation of symptoms

Appearing later in life, FXTAS does not inhibit life and career goals and many patients have a long list of impressive accomplishments.

"FXTAS is an enigma," Dr. Randi Hagerman says. "The disorder appears later in life in men who are generally healthy throughout childhood and early- to mid-adulthood and have normal to above-average intelligence, yet it is caused by a defect in a gene known to cause mental retardation usually diagnosed in childhood."

Onset age varies: Men older than 50, women older than 30. Of the 192 individuals (all had grandchildren with fragile X) studied, only 17% of the men had FXTAS in their 50s. But the percentage of individuals with tremors and balance problems increased with each decade of life: 38% of men in their 60s, 47% in their 70s, 75% in their 80s.

The initial appearance of this progressive disorder can involve difficulty with writing, using eating utensils or pouring water; problems with balance; with frequent falls. These initial symptoms generally progress over years, or even decades, until carrying out many tasks of daily living, and walking without assistance, become difficult or impossible. Other features might include sensory loss in the feet or lower legs, difficulties with short-term memory, impotence, moodiness, anxiety and irritability.

Initially Dr. Leehey examined and videotaped eight patients, many diagnosed with Parkinson's disease. "It wasn't at all Parkinson's. They all had this unique constellation of symptoms I had not seen before," she says. "Action tremor, imbalance, gait ataxia and atrophy on brain scans." Since then, Dr. Leehey has reviewed more than 70 FXTAS cases. "We are trying to figure out the course of the disease," she says. "We'd like to pin down the phenotype. ... How often do they have tremor? How often is it just dementia? How fast does the disease progress? We want to know, what are the consistent clinical signs?"

Today and tomorrow

Currently there is no cure and no specific treatment, so doctors are focusing on the alleviation of symptoms. "We are very interested in doing more clinical trials to see what interventions work," Dr. Randi Hagerman says.

Some physicians have had limited success with prescribing Parkinson's drugs such as amantadine for tremor and antidepressants for anxiety, depression and reclusive behavior. Despite few treatments, patients are optimistic. "They tell me, 'Look I'm falling down, I can't feed myself,' " Dr. Paul Hagerman says. "An accurate diagnosis gives them a sense of understanding, and they have become advocates for research. Ideally, because it is a late-onset disorder, if onset could be blocked or delayed 20 years, symptoms would essentially disappear."

One of Dr. Leehey's patients, John Kinna, PhD, has FXTAS. He also has two grandchildren with fragile X. The 67-year-old was superintendent of schools in Fairfield, Mont., for several decades. He was also chief of staff for Montana's governor in 1988. But in 1989 he noticed his handwriting changing. There were tremors, falls and balance problems.

"They tell me it will progress slowly," he says. And Dr. Kinna is doing what he can to slow its movement. "I work out physically with weights, I walk on the treadmill and do flexibility exercises," he says. "One of my former students is a physical therapist, and he is working real hard to help me over the obstacles. I found a doctor who knew what was going on. It's extremely important to get educated and stop diagnosing this as Parkinson's."

FXTAS not only provides a powerful new key to understanding the FMR1 gene and fragile X syndrome, it informs clinical practice, says William Rhead, MD, PhD, section chief of medical genetics at Children's Hospital of Wisconsin in Milwaukee. "As we talk to patients, we have a more balanced, more complete picture," he says. "When people like the Hagermans tell us something like this, we listen."