Research Update on Loeys-Dietz Syndrome and Marfan syndrome

Dr. Hal Dietz, Victor A. McKusick Professor of Institute of Genetic Medicine and Professor of Pediatrics and Investigator of Howard Hughes Medical Institute at The Johns Hopkins Hospital and Chair of the Loeys-Dietz Syndrome Foundation Medical Advisory Council (MAC), presents “Research Update on Loeys-Dietz Syndrome” at the 2012 LDSF Conference in Baltimore, Maryland, USA. Dr. Dietz discusses the latest on LDS mice model research findings.

Advertisements

Dysfunctional TGF-beta signaling contributes to Loeys-Dietz syndrome associated aortic aneurysm

marfan syndrome uk logo squarePatients with the connective tissue disorder Loeys-Dietz syndrome (LDS) are at high risk for aortic aneurysm. LDS results in the presence of missense mutations within either of the genes encoding receptors for TGF-β. LDS-associated mutations are predicted to reduce TGF-β signaling; however, aortic tissue samples from LDS patients indicate that TGF-β signaling may be enhanced.

In this issue of the Journal of Clinical Investigation, Harry Dietz and colleagues at Johns Hopkins School of Medicine developed a mouse model of LDS, in which transgenic animals expressing Tgfbr1 or Tgfbr2 with LDS-associated mutations recapitulated human phenotypes. Using this model, the authors determined that even though the mutated TGF-β receptors were functionally defective, there was evidence of increased TGF-β signaling as indicated by elevated Smad2 phosphorylation. Furthermore, development of aortic aneurysms in these mice was ameliorated by treatment with an Angiotensin II type 1 (AT1) receptor antagonist.

In a companion commentary, Alan Daughtery and colleagues at the University of Kentucky discuss the therapeutic implications of this study on the use of AT1 receptor agonists to treat LDS-associated aneurism.

Source: Journal of Clinical Investigation

Common blood pressure drug reduces aortic enlargement in Marfan syndrome – Update

There were no differences in the rate of aortic dissections (0 in the losartan group and 2 controls) or elective aortic surgery (10 in the losartan group and 9 in controls) and no cardiovascular deaths occurred.

marfan syndrome uk logo squareBy European Society of Cardiology, [RxPG] AMSTERDAM, The Netherlands – A common drug that is used to treat high blood pressure in the general population has been found to significantly reduce a dangerous and frequently fatal cardiac problem in patients with Marfan syndrome.

Results of the COMPARE (COzaar in Marfan PAtients Reduces aortic Enlargement) study reveal that patients treated with losartan (Cozaar) had a significantly reduced rate of aortic enlargement after 3 years compared to patients who did not receive the treatment.

Our study is the first large, prospective randomized study to assess the effects of losartan on aortic enlargement in adults with Marfan syndrome, and confirms previous findings in a mouse model, said lead investigator Maarten Groenink MD, PhD from the Departments of Cardiology and Radiology at Academic Medical Centre in Amsterdam, The Netherlands.

We’re very excited to see that such a commonly used drug that is not expensive and has a familiar side-effect profile could have a significant effect on this very serious and frightening risk factor for these patients. These findings may change standard clinical management.

Marfan syndrome, a heritable connective tissue disorder, affects 2-3 in 10,000 people. It causes progressive enlargement of the aorta, making it prone to rupture, which can be fatal in more than 50% of cases. Currently, the only effective treatment is prophylactic surgical aortic root replacement.

In addition to lowering blood pressure, the main benefit of losartan is believed to be its interference with the biochemical process that causes aortic enlargement.

To assess this, the COMPARE study included 233 participants (47% female) with Marfan syndrome from all four academic Marfan screening centers in the Netherlands.

Subjects were a mean age of 41 years, 27% had previously undergone prophylactic aortic root replacement, and the majority (73%) were being treated with beta blockers.

A total of 117 subjects were randomized to receive no further treatment, while 116 were randomized to receive losartan 50 mg daily, doubling after 14 days if there were no side effects.

Aortic enlargement was monitored with magnetic resonance imaging (MRI) for three years of follow-up.

During the study period, if patients in either arm required prophylactic aortic root replacement the decision was left to the discretion of the attending cardiologists based on existing guidelines and anticoagulation therapy was initiated when appropriate.

The study showed that after 3 years aortic root enlargement was significantly less in the losartan group than in controls (0.77 mm vs. 1.35 mm, p=0.014), and 50% of losartan patients showed no growth of the aortic root compared to 31% of controls (p=0.022).

Read More: rxpg news

Dad’s tragic death may save twin daughters’ lives

  • Tyson Wallis was just 30 years old when his heart ruptured
  • He had a rare genetic syndrome, and now his baby daughters are getting treatment for the same condition

LDS

Tyson Wallis had it all. Seemingly healthy at 30 years old, Tyson and his wife Kristin were deeply in love. After years of trying, they finally had the family they always wanted — twin baby girls, Olivia and Eleanor.

“He kept saying, ‘I finally have everything I’ve ever wanted,'” Kristin Wallis said. “It was just so perfect. It was really perfect.” But tragically, “perfect” couldn’t save Tyson from a silent killer — a killer he had been living with all of his life.

Ten months after their daughters were born, Tyson said goodbye to his wife as she rushed off to work. They said they loved each other, as always. Before Kristin even got to work, a frantic call sent her into a tailspin: Tyson had collapsed. He wasn’t breathing. His heart had ruptured, and within hours, he was dead. Within hours, the life he had worked so hard to achieve was gone.

“Out of the blue, my entire world fell apart,” Kristin says. “He didn’t have heartburn. He didn’t have heart or chest pains. He didn’t have anything. He was perfect. He was fine.”

Tyson Wallis had Loeys-Dietz Syndrome, a condition so rare that only a few hundred people have been diagnosed. For Tyson, his diagnosis came too late, but it may help save the lives of his daughters. The condition enlarges the aorta and tangles smaller blood vessels, weakening them and putting the sufferer at risk for a heart attack or stroke. It is also genetic, and after a few tests, it was determined that Olivia and Eleanor also have Loeys-Dietz Syndrome. Without the tragic discovery of their father’s condition, they may have never known.

Read on: http://www.hlntv.com/article/2012/06/29/dads-death-may-save-daughters-life-loeys-dietz-syndrome

Researchers studying the genetics behind Marfan and Loeys-Dietz syndrome have discovered that there may be a common genetic driver behind almost all allergic diseases

Scientists Reveal Genetic Glitch at the Root of AllergiesAllergies are certainly the result of both genetic and environmental factors, but there is fresh evidence to suggest that at least one major genetic aberration could be behind everything from hay fever to food allergies to asthma.

Allergies — to dust, pet hair or peanuts — are essentially the product of misdirected immune systems, which start to see innocuous objects as potential threats and launch an intensive assault that can translate into sneezing, wheezing, and even potentially fatal seizures. For decades now, rates of allergies and other immune-related diseases such as asthma and eczema have been rising in the U.S., and the rapid increase suggests that it’s more than just genes, or just changes in lifestyle that made us too clean that are at work.

Now researchers studying the genetics behind the rare tissue disorders Marfan and Loeys-Dietz syndromes have discovered that there may be a common genetic driver behind almost all allergic diseases. Reporting in the journal Science Translational Medicine, scientists from Johns Hopkins Children’s Center and the Johns Hopkins Institute of Genetic Medicine say that they were surprised to find that the same mutation they found in the Marfan and Loeys-Dietz patients may also trigger the immune changes responsible for allergies; most of the patients with the two rare disorders also have higher than normal rates of allergies.

More >>> http://english.farsnews.com/newstext.aspx?nn=13920504000189