Years-long search unlocks deadly genetic disease
Ann Messer knew something was wrong while she was still pregnant with her second child. Her baby didn’t move, except sometimes to roll over to one side of her body, leaving her stomach flat.
Her fears were confirmed when her son, Andrew, was born. “He had a very weak cry, very little muscle tone, he had contractures in his knee joints,” Messer recalled.
The doctors diagnosed congenital muscular atrophy. Andrew died at 5 months of age, in 1985.
Two months later, a first cousin of Messer’s, living in Evansville, Ind., gave birth to a baby boy with similar characteristics. That baby died at 10 months of age. “My mother saw him one time and said he was floppy, very limp, didn’t move,” Messer recalled.
And unbeknownst to Messer at the time, yet another cousin, in a third branch of the family, this one living in New Orleans, had earlier given birth to two baby boys with the same condition. One died at 18 months and one lived to 18 years, although he needed a feeding tube and was confined to a wheelchair for all his short life.
In all, four baby boys with the same condition were born in roughly a five-year span. They all died.
Several years later, doctors were able to give the disease a more specific name: autosomal recessive spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder occurring in children that involves severely weakened muscles and usually results in death within two years, often because muscles of the respiratory system can no longer support breathing. The X chromosome-linked form of the disease is passed unsuspectingly by healthy mothers to their sons.
SMA made sense to Messer and her family, but they were baffled by the autosomal part of the diagnosis.
“I’m not a genetics person, but I know that autosomal recessive means that both mothers and fathers have to be carriers 1/8of the gene that causes the disease 1/2,” Messer said. “We started scratching our heads. What are the odds that all of us would have married somebody with the same recessive gene and our two mothers and our grandmother? I don’t calculate odds very well, but I can tell that that’s just a staggering amount.”
At about this time, another cousin, Patti, living in Houston, married and wanted to have children but was terrified after watching the devastation of her family. She sought genetic counseling.
Enter Lisa Baumbach-Reardon, associate research professor of pediatrics and neurology at the University of Miami Miller School of Medicine, who was already researching a similar family in South Carolina.
Baumbach-Reardon would spend 15 years searching for the genetic root of these family tragedies.
“We started investigating and found all these other families, and then we spent many years trying to map the gene where it was on the X chromosome, and we were very sure about where it was, but we had no great breakthroughs or clues,” Baumbach-Reardon recalled. “It was probably the biggest scientific experience of my career, and many times we were told to give up, but we didn’t give up, because we knew in the end what we were working on was this terrible disease.”
This week, Baumbach-Reardon and her colleagues published the results of their quest in The American Journal of Human Genetics. A gene known as UBE1 is the cause of this rare, X-linked form of SMA. The gene lies at the top of a major biological pathway, the same pathway that has been implicated in Parkinson’s and other neurodegenerative disorders.
“It’s the beginning of a pathway. If that doesn’t work in the beginning, then nothing else works,” Baumbach-Reardon explained.
Tragically, all six women in Ann Messer’s generation were carriers of the mutation – a mutation that was enough to cause the disease, regardless of their husbands’ genetic makeup.
On Dec. 7, Baumbach-Reardon flew to Houston to meet with nine members of the family and tell them the scientists had finally located the gene responsible for their losses.
“We met in a Sunday school room in my cousin’s church,” Messer said. “Dr. Baumbach flew in from Miami, bless her heart. She’s sitting there looking at nine blank faces trying to explain Genetics 101.”
For the family, Messer said, “it gave a meaning and purpose to all of this heartache we’ve all gone through and gives us so much hope for so many more families, the diagnosis and the therapies that I’m sure they’ll eventually develop, and prevention.”
Because the gene has links to Parkinson’s disease, that offers hope that more progress will be made in preventing and treating that disease and others like it.
“The thought of the agony and anguish that we went through, the sadness, that we can be a part to help thousands of families is just huge for us,” Messer said.
The knowledge gained from the Miami researchers’ work has already benefited the family. One of Messer’s nieces was found not to carry the mutation. “She can have children and not worry about it,” Messer said.
Dr. E. Darrell Crisp, associate professor of internal medicine and pediatrics at the Texas A&M Health Science Center College of Medicine and director of pediatric neurology at Scott & White Hospital in College Station, cared for Andrew Messer 23 years ago, although he was not involved with the new study.
“Having a gene localization and a way of making a diagnosis … helps differentiate whether this is truly SMA or another disorder,” Crisp said. “Another thing is, if it’s the X-linked form of SMA, it can tell us whether a person in the family may be a carrier and if they are at risk.”
On the Web:
www.ninds.nih.gov/disorders/sma/sma.htm. The U.S. National Institute of Neurological Disorders and Stroke has more information about SMA.
Short chat with doc can curb problem drinking
Ten minutes of discussion with a doctor about drinking may help at least one in six problem drinkers change their ways, but most physicians don’t understand that, a new data review finds.
The systematic review of 10 related studies is published in the February issue of the American Journal of Preventive Medicine.
According to the researchers, brief alcohol screening and counseling may rank among the top five most cost-effective preventive services a doctor can offer, along with Pap smears and bowel cancer screening.
Screening for problem drinking, combined with a doctor’s advice, reduced problem drinking by 17.4 percent over a period that varied from six months to two years, according to the particular study.
The research team defined problem drinking as consuming more than seven drinks per week for women or more than 14 for men – or drinking more than three drinks on one occasion for women or four drinks on one occasion for men. Approximately one in four people between the ages of 18 and 54 are problem drinkers, said the researchers.
Problem drinking can include binge drinking or drinking and driving; serious alcohol-related choices but not severe enough to be considered alcoholism.
“Reviewing this data and stepping back, it really struck me how truly important this finding is,” lead author Dr. Leif Solberg, associate medical director for care improvement research at Health Partners in Minneapolis, said in a prepared statement. “It’s a service most physicians don’t offer … I think most of my fellow physicians would think that their impact on alcohol use is close to zero.”
According to the researchers, physicians may believe a short talk with a doctor will not help alcoholics quit or that people who are not alcoholics don’t need advice on controlling drinking.
“The effectiveness does not depend on stopping drinking, it’s reducing the quantity or the number of times there is binge drinking,” study co-author, Michael Maciosek, research investigator at Health Partners, said in a prepared statement.
The researchers found that screening and counseling cost about $10 per patient but saved money in terms of reduced need to treat injuries or other alcohol-related health problems.
On the Web:
www.niaaa.nih.gov/FAQs/General-English/default.htm. The U.S. National Institute on Alcohol Abuse and Alcoholism has more information on alcohol abuse.
Transplant drug shrinks tumors in women with rare lung disease
Women who are struck by a rare lung disease could find their tumors shrink by 50 percent with the help of the transplant drug sirolimus, a new study suggests.
The Cincinnati researchers who made the discovery also demonstrated the drug might improve lung function in some patients over time.
Lymphangioleiomyomatosis (LAM), a disease that exclusively targets women, is characterized by progressive loss of lung function due to the invasion of abnormal muscle tissue that obstructs airways. In its early stages, LAM can be confused with emphysema because of its effects on breathing. People with LAM often need oxygen treatments and lung transplants as the disease continues its course. According to the American Lung Association, as many as 250,000 women worldwide might have the disease.
The new treatment was also effective in reducing tumors in patients suffering from tuberous sclerosis complex (TSC), a rare genetic multi-system disease.
The two diseases share a genetic mutation that affects the activation of the enzyme mTOR, which is responsible for controlling the growth and spread of cells. Sirolimus, a drug that is usually prescribed to prevent the rejection of transplanted organs, also prevents mTOR activity, according to the researchers. Sirolimus is also known as rapamycin (Rapamune).
Publishing in the Jan. 10 edition of the New England Journal of Medicine, the researchers concluded that sirolimus has the potential to help patients with either disease avoid surgery for the tumor angiomyolipomata, common to both conditions.
“Less-invasive therapies are clearly needed to treat the angiomyolipomata that people with TSC and LAM develop, and a drug that maintains or shrinks tumor size may reduce the need for procedures such as surgery,” study author Dr. John Bissler, a physician/scientist in the division of nephrology and hypertension at Cincinnati Children’s Hospital, said in a prepared statement. “Our data suggest that mTOR inhibition with sirolimus may hold promise for treating these and other disease manifestations in patients with TSC and LAM.”
Bissler and his colleagues treated 20 patients who had angiomyolipomata tumors with sirolimus for 12 months. They reported that, at the end of the year, the tumors shrank by about half. Eleven of the patients who had LAM and took sirolimus for the year also showed a 10 percent to 15 percent improvement in expiratory air flow, a standard measure of lung function.
The researchers followed up with 18 of the original patients after a year without the sirolimus treatment. They found that tumor size had increased to about 85 percent of original pre-treatment size.
Tumors in five of the original patients, though, were 30 percent smaller than their original size after a year without the medication. The study authors theorized that this could be a result of apoptosis, a kind of programmed cell death.
After a year without treatment, the patients’ lung function declined but was still better than what could be expected from similar patients after two years without any intervention, the researchers said. The improved lung function could be because of the lessening of obstructions and trapped gas in the lungs, the researchers noted.
Patients reported side effects from the sirolimus treatment that included mouth sores, diarrhea, upper respiratory infections and joint pain.
The researchers acknowledged that the small study needs further follow-up. A phase III clinical trial of the drug as a treatment for LAM patients is planned, they said.
On the Web:
American Lung Association has more information about LAM.
Eye care lacking in many who buy contact lenses online
Buying contact lenses online may save time, but people who do so tend not to follow proper eye care, new research shows.
Time saved with an Internet purchase may translate into more trouble down the line, warned the investigators, who found that people purchasing lenses from wholesale clubs or optical chains were also less likely to follow the healthy eye-care practices most doctors would recommend.
“We found that a pattern exists regarding the method of contact lens purchasing and following recommendations from the Food and Drug Administration,” lead author Joshua Fogel, assistant professor of behavioral sciences at Brooklyn College, said in a prepared statement. “Those who bought contact lenses at their doctor’s office followed a number of FDA recommendations, more so than those who bought contact lenses elsewhere.”
A Brooklyn College team surveyed 151 university students about Internet use, contact lenses, time pressure, and FDA recommendations for purchasing contact lenses online.
When they analyzed the data, the researchers found that 86 percent of people who bought their lenses from an eye doctor also had a yearly eye exam, compared to 76.5 percent of people who shopped online. An annual exam is an important part of maintaining eye health, noted the researchers. Continuing to use contact lenses based on an old prescription may lead to eye discomfort, tiredness, poor vision and headaches, they warned.
The researchers also found that while 15 percent of people who wore contacts and saw their doctor regularly did not check to see if they had a current prescription, 32 percent of Internet shoppers used a prescription that had not been updated.
People who purchase contact lenses from a doctor are asked to return for a follow-up appointment to check the fit of the lenses. More than half (57 percent) of people who bought lenses from the doctor returned for a check-up, while only one in three (27 percent) of online shoppers saw a doctor after purchase.
More than 30 million people wear contacts, according to the Contact Lens Institute.
People who bought lenses at their doctor’s office or a store expressed greater confidence in that purchase than those who shopped online, the researchers said.
The study was published in the January issue of Optometry: Journal of the American Optometric Association.
On the Web:
http://www.aoa.org/x8024.xml. The American Optometric Association has more information about the proper care of contact lenses.
Antidepressants help HIV-infected patients stick to treatment
People with HIV who suffer from depression are much less likely to stick with their treatment regimens, new research shows.
However, treating their depression with widely used selective serotonin reuptake inhibitor (SSRI) antidepressants can get them back on track, the researchers said.
A team from Kaiser Permanente in Oakland, Calif., analyzed the mental health, disease progression and treatment data of almost 3,400 HIV-infected patients nationwide between 2000 and 2003. All patients were starting a new, highly active antiretroviral therapy (HAART).
Reporting in the current online issue of the Journal of Acquired Immune Deficiency Syndromes, they found that almost half of the study participants (42 percent) had depression during the 12-month study. Those who were depressed were less likely to take their medications and had worse viral response than people who were not depressed. However, when depressed people took prescribed SSRIs – which include drugs such as Celexa, Paxil, Prozac and Zoloft – they had the same health outcomes as patients who were not depressed.
“The take-home point of this study is that depression carries a worse prognosis for HAART in HIV patients. However, we also found that SSRIs can reverse this and improve outcomes for HIV-depressed patients,” lead author Dr. Michael A. Horberg, director of HIV/AIDS for Kaiser Permanente, said in a prepared statement. “HIV and depression often go hand in hand. If you are HIV-infected, you should be screened regularly for depression, and if you are depressed, and you are going to go on HAART, it’s very worthwhile to treat your depression.”
On the Web
http://familydoctor.org/online/famdocen/home/common/mentalhealth/depres sion/046.htm. The American Academy of Family Physicians has more information about depression.