T-A T-A to A-T?

SRxA’s Word on Health is delighted to share news that could change the lives of the 500 or so children and families in the US, dealing with a rare and deadly disease.  The breakthrough, announced this week in the online edition of Nature Medicine, suggests that scientists may have found a way to prevent and possibly reverse the most debilitating symptoms of ataxia telangiectasia (A-T) a rare, progressive childhood degenerative disease that leaves children, unable to walk, and in a wheelchair before they reach adolescence.

As regular readers of this blog know, A-T is a cause close to our hearts, and the courage of these children and their families inspire us daily.

Karl Herrup, chair of the Department of Cell Biology and Neuroscience and his colleagues at Rutgers have discovered why this genetic disease attacks certain parts of the brain, including those that control movement coordination, equilibrium, muscle tone and speech.

When the team examined the brain tissue of young adults who died from A-T, they found a protein (HDAC4) in the nucleus of the nerve cell instead of in the cytoplasm where it belongs. When HDAC4 is in the cytoplasm it helps to prevent nerve cell degeneration; however, when it gets into the nucleus it attacks histones – the small proteins that coat and protect the DNA.

What we found is a double-edged sword,” said Herrup. “While the HDAC4 protein protected a neuron’s function when it was in the cytoplasm, it was lethal in the nucleus.”

To prove this point, Rutgers’ scientists analyzed mice, genetically engineered with the defective protein found in children with A-T, as well as wild mice. The animals were tested on a rotating rod to measure their motor coordination. While the normal mice were able to stay on the rod without any problems for five to six minutes, the mutant mice fell off within 15 to 20 seconds.

However, after being treated with trichostation A (TSA), a chemical compound that inhibits the ability of HDAC4 to modify proteins, they found that the mutant mice were able to stay on the rotating rod without falling off – almost as long as the normal mice.

Although the behavioral symptoms and brain cell loss in the engineered mice are not as severe as in humans, all of the biochemical signs of cell stress were reversed and the motor skills improved dramatically in the mice treated with TSA. This outcome proves that brain cell function could be restored.

Neurological degeneration is not the only life-threatening effect associated with A-T. The disease, which occurs in an estimated 1 in 40,000 births, causes the immune system to break down and leaves children extremely susceptible to cancers such as leukemia or lymphoma. There is no known cure and most die in their teens or early 20s.

Herrup says although this discovery does not address all of the related medical conditions associated with the disease, saving existing brain cells and restoring life-altering neurological functions would make a tremendous improvement in the lives of these children.

 “We can never replace cells that are lost,” said Herrup. “But what these mouse studies indicate is that we can take the cells that remain in the brains of these children and make them work better. This could improve the quality of life for these kids by unimaginable amounts.”

A-T families are cautiously excited by the news. The A-T Children’s Project facebook page notes “This is certainly hopeful news, and we look forward to the results from further studies.”

We certainly do. A cure cannot come soon enough.

Rare but Strong Together

Happy February 29th!  A rare day that comes only once every 4 years. Talking about rare – today is also Rare Disease Day.

In the US, a rare disease is defined as one that affects fewer than 200,000 people.  However, as it turns out rare diseases are actually not all that rare.  In fact there are nearly 7,000 rare diseases affecting almost 30 million Americans. In other words, as many as one in ten Americans are suffering from a rare disease.

Most of my life, I have been involved in some capacity with rare diseases, some of them very rare indeed. While working in the field of transfusion medicine, I became something of an expert in factor II deficiency. This is is an inherited bleeding disorder caused by reduced activity of factor II (prothrombin). Characterized by muco-cutaneous bleeding symptoms, less than 50 people worldwide have been diagnosed.

My work has also brought me into contact with the patients and families affected by a number of rare primary immune deficiency diseases. Most notably among these – ataxia telangiectasia (A-T).  A-T is a progressive degenerative disease marked by ataxia (a lack of muscle control that results in wobbliness and slurred speech); telangiectasia (tiny red spider veins which appear in the eyes, ears or cheeks); immunodeficiencies (low levels of antibodies resulting in increased susceptibility to infections) and a predisposition to cancers such as lymphoma and leukemia.   A-T is thought to affect less than 100 families in the US, and I have been fortunate and humbled to meet most of them. The pictures of some of these children sit on my desk and serve as a daily reminder of why I do what I do. Their daily challenges remind me how inconsequential are my own.

More recently, my EMS work brought me into contact with Hunter syndrome (mucopolysaccharidosis type II). Hunter syndrome is an inherited disease in which the patient lacks an enzyme  (iduronate sulfatase) to break down complex sugar molecules (mucopolysaccharides). As such, sugars accumulate in various body tissues causing severe mental retardation, spasticity, enlarged organs, cardiac defects and deafness. Less than 2,000 people are affected worldwide, fewer than 500 of them in the United States.

Besides dealing with their specific medical problems, people with rare diseases often struggle to get a proper diagnosis and treatment.  Rare Disease Day is about increasing the recognition of rare diseases as a global health challenge and raising awareness of the common challenges and experiences faced by rare disease patients and families.

Rare Disease Day was first observed in Europe in 2008. In 2011, over 60 countries participated and it is hoped that even more will do so this year.

For 2012, the focus of rare disease day is solidarity and the official slogan is “Rare but Strong Together”.  The main aims include:

  • Extensive media coverage
  • Social networking blitz
  • Creating a Rare Disease Physician Database
  • Encouraging patients to share their stories, videos, photos, and blogs including to their local media and through social media
  • Joining hands with others worldwide
  • A three day advocacy and awareness event in Washington, DC at the FDA, NIH and on the Hill
  • Support in-school initiatives in high school biology classes and middle and elementary school classes to implement grade appropriate lesson plans for rare diseases
  • Create tool kits that can help individuals and organizations plan and implement events and awareness activities focused on rare disease day
  • Establishing online photo galleries for the “Handprints Across America” and “Visions of Solidarity” initiatives for patients to express their view of international solidarity in the rare disease community and show the support across the country for this day
  • Update a portal for a user-friendly system to send letters to Congressional Representatives so patients can teach their legislators “Rare Diseases 101”

To find out more about rare diseases and the activities going on today in your area please visit the Rare Disease Day Website.