I’m a Buddy!

Interestingly enough, I slightly groaned about working in a bank and how unrewarding it is yesterday in my post.  Then the head of personnel called me not two hours later and asked if I wanted to be a buddy. 

My ears perked up and replied, “A buddy?  What is that??” 

The bank started a new program where new hires get teamed up with someone who isn’t a new hire that they can lean on if they have questions or what not.  It’s kind of like a mentor.  She told me that she knew that I had just barely passed my one year mark here (May 30!) but I was so good with people that she knew I would be a good buddy.  Sweet!! Out of 160 people she thought of me (job security??!!).

So later that day she assigned me to my buddy and we get a free luncheon next Tuesday at the Marriot so we can meet and stuff.  I love helping people out so this is right up my alley.  I’m already thinking of the little gifts I’ll get her when she hits her 1 year mark and what I’ll get her for a little xmas present.  I know…I’m a nerd…but I’m good at it!!

Article 2: Raise the bar on FXTAS: Recognize It

I have two articles related to fragile X syndrome that I found this morning that I wanted to share.  Because I think they are both informative and both deal with different aspects of the syndrome I’m posting them separately.  Here is the second one about fragile x tremor ataxia syndrome (FXTAS). It can be found here.

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	April 01, 2007 Vol. 3 No. 4 Raise the Bar on FXTAS: Recognize It Myra Partridge
	Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset progressive neurological disorder, is found in carriers of a fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats). Studies are showing that the disorder affects up to 1 in 3000 adult men older than 50 years and is less common in women.Although FXTAS was first recognized and reported in 2001 by Randi J. Hagerman, MD, professor and director of the M.I.N.D. Institute at the University of California, Davis,1 she said many physicians are still unaware of the condition. That’s why she and other researchers from the M.I.N.D. Institute collaborated with the CDC to send informational postcards on FXTAS in February to all practicing neurologists and geriatric psychiatrists in the United States.”There are some neurologists who read the journals and are right on top of this issue, but some patients have told me horror stories about physicians who have not heard of FXTAS and are unwilling to test their patients for the disorder,” she said. “I knew of a family where the grandmother was being treated by neurologists at a local HMO in California. “She began having symptoms of tremor and ataxia, then couldn’t walk, and is now bedridden. Her daughter, who has a son with fragile X, asked the neurologist whether the issues could be related, and the neurologists would always answer ‘no.’” That’s when family members discovered information about FXTAS on the National Fragile X Foundation’s Web site (www. fragilex.org/html/fxtas.htm). “They brought papers on FXTAS to the grandmother’s neurologist who said ‘I’ve never heard of fragile X syndrome or FXTAS.’ This is astounding, because fragile X syndrome is the most common cause of autism or retardation,” Hagerman said. “Unfortunately, physicians in the autism field tend to ignore the fragile X component too. They often do not test families for this disorder. So, in general, there seems to be resistance to testing, even though it is so cheap,” Hagerman said. She discovered FXTAS through her research on fragile X, which brought her into contact with many patients with the disorder and their families. By talking to these family members, she discovered that many grandfathers of children with fragile X seemed to have the same neurological symptoms. “We decided to look into this issue because I kept hearing the same story about a lot of the grandfathers,” she said. “After seeing 6 of these grandfathers, we realized that they all had the same behavioral phenotype and tremor/ataxia.” But she had no idea how prevalent these symptoms were until she presented her hypothesis to the International Fragile X Foundation meeting in Los Angeles in 2000. “I presented the 6 cases to a roomful of families and asked whether any other people had seen these kinds of issues in the grandparents. About one third of the people in the room raised their hands, and I suddenly realized this could be a very common problem.” This prompted Hagerman to report on FXTAS in 2001 with colleagues at the M.I.N.D. Institute.1 Since that time, the team has collaborated with researchers from other institutions to learn more about FXTAS. SIGNS AND SYMPTOMS In many patients with FXTAS, the disorder is misdiagnosed as another neuropsychiatric or movement disorder, such as Parkinson disease (PD), essential tremor, ataxia, Alzheimer disease, normal pressure hydrocephalus, or stroke. According to Hagerman, genetic testing is important in all patients presenting with risk factors of FXTAS because many may not know they are FMR1 premutation carriers. Hagerman suggests that testing should be performed in persons 50 years or older presenting with any of the following symptoms or combinations of symptoms: unexplained gait ataxia; dementia with action tremor; action tremor, dementia, or parkinsonism; family history of developmental delay or autism; or premature menopause. MRI will show generalized atrophy, white matter changes, and distinctive T2 hyperintensities in the middle cerebellar peduncles (Figures 1 and 2), according to a study that also showed FXTAS symptom severity corresponds with the degree of MRI changes.1 However, a small study led by Danuta Z. Loesch, MD, PhD, senior research fellow in the School of Psychological Science at La Trobe Universtity, Melbourne, Australia, showed that only 3 of 9 patients with fxtas studied had close correspondence between clinical features and MRI status.2 Loesch and colleagues suggested that MRI changes precede manifestations for some patients with FXTAS. Normally, there are approximately 5 to 44 CGG repeats on the front end of the FMR1 gene, while minor instability can be associated with 45 to 54 repeats from generation to generation. Carriers of a FMR1 premutation have 55 to 200 CGG repeats, and those with fragile X syndrome have more than 200 CGG repeats. The prevalence of the premutation in the general population is approximately 1 per 259 men and 1 per 810 women. The prevalence of fragile X causing mental retardation is approximately 1 per 4000 men and 1 per 6000 women.3 While most premutation carriers have a normal IQ, premature ovarian failure occurs in approximately 21% of women who are carriers, and FXTAS occurs in approximately 38% of older men who are carriers. Some carriers also have been shown to have lower FMR1 protein levels, in addition to features of fragile X syndrome, and all have elevated FMR1-mRNA. The full mutation of the FMR1 gene is clinically associated with features of fragile X syndrome, including prominent ears, long face, hyperextensible finger joints, and cognitive deficits, such as learning disabilities and mental retardation.4 Genetic testing for FXTAS is underused, although it is simple and inexpensive, according to Hagerman. The FMR1 DNA test is available at most clinical and molecular laboratories, and it may be called the “Fragile X” or “FXTAS” gene test. When results of a test are positive for the FMR1 premutation, physicians should talk to the patient about FXTAS and refer the patient and his family to a genetic counselor. Patients and their families may also want to contact the National Fragile X Foundation at 800-688-8765 (www.FragileX.org) for more information and a list of FXTAS experts. TREATMENT Although no specific treatments have been established for patients with FXTAS, there is anecdotal information that points toward the effectiveness of certain medications. In a recent study conducted by Deborah A. Hall, MD, assistant professor in the Department of Neurology at the University of Colorado Health Sciences Center at Denver, and colleagues, 56 patients with FXTAS completed a questionnaire to determine whether medications had been effective for neurological symptoms.5 All known patients with FXTAS who were seen at the University of Colorado, Rush University, and University of California, Davis, were included in the study.Of these patients, the mean age was 69.1 years and 73% were men. Eleven patients had definite FXTAS; 70% were being treated for neurological symptoms. Of the remaining 45 patients with possible or probable FXTAS, 70% did not receive medications. There were no therapies that were found to be uniformly effective for intention tremor, ataxia, parkinsonism, memory loss, or anxiety.The most commonly prescribed medications were for memory or anxiety. Cognitive decline was slowed in 2 of 6 patients taking venlafaxine (Effexor) and in 3 of 9 taking acetylcholinesterase inhibitors. Of patients with anxiety, 2 of 6 improved with venlafaxine and 5 of 8 with benzodiazepines. Of those patients who were treated for intention tremor, 3 of 6 reported mild to moderate improvement with primidone, 3 of 8 had moderate improvement when treated with ß-blockers, 2 of 8 had moderate improvement with benzodiazepines, and 1of 8 improved with memantine (Namenda). Of those patients with parkinsonism, 2 of 8 improved with carbidopa/levodopa and 1 of 2 with pramipexole (Mirapex). No patients improved with treatment using bromocriptine or gabapentin (Neurontin), although the gabapentin helped with pain. Hall and colleagues concluded that patients with possible or probable FXTAS are not usually treated for neurological motor signs, while those with definite FXTAS are more likely to receive medications, suggesting that those patients with milder FXTAS may not find their symptoms to be intrusive enough to warrant treatment with medication. They also showed that patients with FXTAS can derive improvement from medication for some of their symptoms. Similar results were reported in a recent study of patients with essential tremor, of whom only 6% were taking medication.6 Hagerman said that her studies and clinical experiences have shown that a variety of medications can be used for FXTAS. “Patients with anxiety and depression respond very well to selective serotonin reuptake inhibitors. But there are no controlled trials out; this is all anecdotal information,” she said. “These patients have a lot of nerve pain, and some of it is associated with neuropathy. For some of the women, there may be a fibromyalgia-like component. We think that gabapentin helps with this nerve pain problem. The tremor can sometimes do well with other agents, such as primidone. Amantadine may be helpful for balance problems. And the more traditional PD treatments may be helpful, such as carbidopa/levodopa.” Some controlled trials are beginning to explore these treatments, but results from these studies will not be published for a few years, according to Hagerman. Recent reports have shown that some patients with FXTAS may have a testosterone deficiency. “We also think testosterone and thyroid should be routinely tested,” Hagerman said. It is crucial that physicians correctly diagnose FXTAS so the patients can receive the best interventions, Hagerman noted. “But the most important reason to identify those with FXTAS is for genetic counseling,” she said. “Once you find someone with the genetic condition, there is a whole family tree that you have to think about. Men with the premutation will be carriers themselves. All of the daughters are carriers, because they inherit the gene from their father. And they are at very high risk of having a child with fragile X—having a 50/50 chance. So this is critically important. And when you do a family tree, there are usually many people affected by the full mutation or the premutation. That varies from psychiatric problems to gynecological problems.” In the past few years, more research has focused on fragile X, and molecular mechanisms of involvement have been identified, including RNA toxicity in premutation carriers. Phenotypes have also been broadened, said Hagerman. “There are a whole slew of proteins that we think cause dysregulation of function for the neurons, which causes the neuron to die more readily and leaves the neuron more vulnerable to oxidated stress,” she said. “That understanding has led us to seek more funding looking at neuroprotective agents and agents to decrease this problem.” Hagerman’s team plans to conduct further research focusing on neuroprotective agents for patients with FXTAS and targeted treatments for children and adults with fragile X syndrome. REFERENCES 1. Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology. 2001;57:127-130. 2. Loesch DZ, Litewka L, Churchyard A, et al. Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats. J Clin Neurosci. 2007;14:245-248. 3. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome—an older face of the fragile X gene. Nat Clin Pract Neurol. 2007;3:107-112. 4. Grigsby J, Brega AG, Leehey MA, et al. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord. In press. 5. Hall DA, Berry-Kravis E, Hagerman RJ, et al. Symptomatic treatment in the fragile X-associated tremor/ataxia syndrome. Mov Disord. 2006;21:1741-1744. 6. Benito-Leon J, Louis ED, Bermejo-Pareja F; Neurological Disorders in Central Spain (NEDICES) Study Group. Population-based case-control study of cognitive function in essential tremor. Neurology. 2006;66:69-74.

Article 1: Michael R. Tranfaglia

I have two articles related to fragile X syndrome that I found this morning that I wanted to share.  Because I think they are both informative and both deal with different aspects of the syndrome I’m posting them separately.  Here is the first one about a parent and pioneer in research for fxs.

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News

Michael R. Tranfaglia

Published On 6/4/2007 8:57:16 AM

By ADITI BALAKRISHNA

Crimson Staff Writer

Michael R. Tranfaglia ’82 was never just an average Harvard pre-med.

“He was kind of unusual,” says his wife Katherine N. Clapp ’82. Her first memories of Tranfaglia include a characteristic Marine Corps haircut acquired during a summer spent in boot camp “just for an experience,” and another summer souvenir—a single sunburned side picked up during a cross-country bike trip and debuted the following fall.

While at Harvard, Tranfaglia kept himself busy with a concentration in biology, an unofficial minor in psychology, and a host of extracurricular sporting activities.

Michael R. Tranfaglia ‘82

He says he was a young man with no “great aspirations” as a collegiate, simply wishing to become a small town psychiatrist with a comfortable middle class life. However, he says, those modest plans “jumped the tracks big time” about 10 years after commencement, when Tranfaglia and Clapp learned in 1992 that their first child, Andrew, had Fragile X syndrome.

Fragile X is a genetic disorder resulting from a mutation on the X chromosome, and according to the Centers for Disease Control, the disorder is “the most common known cause of mental retardation and developmental disability that can be inherited.”

A FRAGILE X FOUNDATION

Tranfaglia and Clapp were left frustrated as they brought a then three-year-old Andrew from pediatrician to pediatrician—repeatedly failing to find someone who could successfully diagnose their son’s developmental problems. Though the doctors tested Andrew for a number of conditions, none of these preliminary screenings could provide the answers the family was looking for.

“Fragile X is probably the first thing they should have tested for, but it really was missed in the first couple of passes,” Tranfaglia says.

For a genetic disorder, Fragile X is quite common—affecting one in 4,000 males and one in 6,000 females—says Tranfaglia. However, he says, at the time, familiarity with it was limited even in medical circles.

Upon receiving the Fragile X diagnosis, Clapp and Tranfaglia set out to educate themselves about the disorder.

“I’m a psychiatrist, so I had heard of [Fragile X], but I had never actually seen a patient with it,” Tranfaglia says. “In textbooks, mentions were so brief that they were almost meaningless…I had heard the term bandied about, but not discussed in any meaningful way.”

Yet the more Tranfaglia and his wife learned about the disorder, the more compelled they felt to help address this gap in knowledge.

The couple, with the help of Kathy May (another Fragile X parent), founded FRAXA in 1994, a nonprofit foundation that aims to broaden biomedical research efforts dedicated to finding better treatments and possibly a cure for Fragile X, says Tranfaglia.

Since its founding, FRAXA has capitalized upon technological advances ranging from the booming biotech industry to the advent of the internet, allowing it to develop a large but diffuse community of Fragile X parents and researchers dedicated to the study of the disorder.

According to Tranfaglia, in the early 1990s the idea that the disorder could be treated at all was controversial, as its main symptom is mental retardation. With mental retardation commonly perceived as irreversible and largely untreatable, many are reluctant to seek medical treatment for it, Trafaglia explains. Many are inclined to view Fragile X as “just the way these kids are,” he says—an inclination FRAXA looks to combat.

SEARCHING FOR A CURE

FRAXA gathers donations primarily from personal contacts of Fragile X relatives, and—in turn—considers research proposals submitted by scientists looking to receive these funds from the organization.

Proposals are reviewed by the foundation’s volunteer Scientific Advisory Board—a body made up of 20 prominent scientists, including Harvard Provost Steven E. Hyman. The board claims three Nobel Laureates—James Watson, Eric Kandel, and Susumu Tonegawa—among its members, as well as “several future winners,” says Tranfaglia.

“We’ve been so successful on the science that we’re in a phase now where we’re transitioning; raising the bar on what we’ll fund,” Tranfaglia says. “We’re only funding translation research…designed to translate basic science findings into clinical applications.”

He adds that a goal for the near future is to work closely with pharmaceutical groups to develop actual treatments for the disorder and bring them to clinical trial.

Fragile X is caused by a mutation of the FMR1 gene on the X chromosome. The gene regulates synaptic plasticity in the brain—the ability for neural connections in the brain to adapt over time as a result of experience. Plasticity is thought to be especially important in the areas of learning and memory.

A possible solution to the disorder—the replacement of the defective gene with a normal copy—has proven difficult to make a reality, as scientists have yet to find a way to physically place a new copy of the gene into brain cells.

At present, FRAXA-funded researchers have made progress in identifying the signaling pathways in the brain that are disrupted because of Fragile X-caused genetic mutations. If these disrupted pathways can be brought back to normal with drug treatment, a wide array of autism spectrum disorders that share in their pathology this interrupted signaling pathway may be treatable.

“Autism folks are skeptical that [Fragile X and autism] are related, but as a psychiatrist, the first thing you realize is that there are a lot of people who look and act like they have Fragile X, but don’t have it,” Tranfaglia says. “By identifying this pathway, we can also identify ways of testing those other folks to see who might respond to those same treatments.”

A GLASS HALF FULL

Since FRAXA’s founding, Fragile X “certainly has become better known and better understood in some circles,” Tranfaglia says. Pediatricians are diagnosing the condition earlier and special education specialists are better understanding how to address it, he says.

Nevertheless, Fragile X still has yet to receive the public address it may warrant, in large part because of the overarching stigma associated with mental retardation, Tranfaglia says.

“There really is a bias against mental retardation, and that bias is actually more common in the higher strata of society than in the general population,” he says. “I know of other physicians and psychiatrists who have kids with Fragile X, and they don’t want to step forward and be counted because they’re afraid of the stigma, that it somehow reflects badly on them.”

As a result of his experiences, Tranfaglia advises current undergraduates to “push themselves in ways they might not expect.”

“Don’t be afraid to try, even if you’re not great at it,” he says. “You have to be flexible, adaptable, able to take on new challenges.”

Clapp recalls how her husband always pushed the boundaries. Their first real date, she says, was an 85-mile biking trip to a cabin in New Hampshire.

“He liked adventures like that,” she says.

Former roommate Jeffrey T. Wu ’82 recalls a young man that always seemed to take things in stride, citing Tranfaglia’s appreciation of dining hall food amidst a sea of complaint from peers. Classmates always “got a kick out of Mike because he was so unfussy,” Wu says. “He would always say ‘Mmm…not bad.’”

“I think he has approached a lot of his life that way—he was a glass-half-full sort of person, and that has carried over to what he has done,” Wu says. “When Mike and Katie learned what Andy was up against, a lot of people would have felt bad for themselves, and seen obstacles—and I’m sure he did see those at first—but what he also saw was opportunity to do something significant.”

A FAMILY MAN

Tranfaglia, Clapp, and their two children—Andrew, 17, and Laura, 15—live about 40 miles outside of Boston in West Newbury.

According to Laura Tranfaglia, her father is “smart,” “helpful,” and “always seems to be right.” She says her father is also quite the multitalented individual—with interests ranging from carpentry to cooking to playing with remote controlled cars with his son.

Laura Tranfaglia says that in his downtime, her father can often be found watching “Mythbusters” or playing fighter-jet computer games.

“He wanted to be a pilot, but decided to be a doctor instead,” she says. “It’s ironic because he would be killing people as a fighter pilot, but instead he’s saving people.”

Though living with a brother with Fragile X has been tough at times, Laura Tranfaglia says, medical advancements and the simple passage of time have made her brother’s condition more manageable.

“I guess I really wouldn’t understand people like him as much—I wouldn’t see them as as normal as I do now,” she says.

Also, she jokes, “It’s the reason why I have an ‘A’ in biology.”

—Staff writer Aditi Balakrishna can be reached at balakris@fas.harvard.edu.

http://www.thecrimson.com/article.aspx?ref=519071