The introduction of this scientific event was made by Prof. Yosef Shiloh of Tel Aviv, the discoverer of the ATM gene in 1995. Here, very short, what he said:

The best known role of the ATM protein is the maintenance of genomic stability by its response to DNA double-strand DNA. But this is not the only, and is involved in many other cellular

The introduction of this scientific event was made by Prof. Yosef Shiloh of Tel Aviv, the discoverer of the ATM gene in 1995. Here is briefly what he said:

The best known role of the ATM protein is the maintenance of genomic stability by its role in the response to DNA double-strand breaks. But this is not the only one, and it is involved in many other cellular functions lost in ataxia telangiectasia, some not being directly related to damage to DNA.

Most teams are working to better knowledge of these functions in an attempt to provide a drug capable of overcoming the absence of ATM. But it remains a question unanswered: which of these functions explains neurodegeneration?

Some work suggests that the ATM protein could actually have a much more subtle role in the response to oxidative stress (which damages DNA) that the repair process of double-strand breaks. And this subtlety may well be the cause of neurodegeneration? But not only ...

There is a new field of investigation that some have already borrowed as Professor Wong of the University of Texas or the team of Dr. Pascale Bertrand CEA, winner of our call to project who explores a very interesting track according to his peers.


Immunity: consensus on handling methods

Although immunodeficiencies are all different in ataxia telangiectasia, recommendations of management of these deficits are now available.

Howard Lederman, who runs the US AT clinic at the John Hopkins Hospital in Baltimore, presented them, stressing in particular on the interest of vaccination for patients who are able to make antibodies and of injections of gammaglobulin for those who are not.

Obviously, the family must also have all its vaccines up to date, especially for seasonal flu!

Major At centers turns these recommendations in detail. Find them here



Immune deficiency can be very variable in ataxia telangiectasiawith different levels of immunoglobulins, antibody response and number of T cell. Some patients with AT have even an immunity almost "normal". Having already shown that the immune deficiency was more pronounced in AT patients producing no ATM protein (some produce low), the immunologist Liz McDermott of Nottingham has noted that the supposed immune stability over time was not verified for a 1/3 of patients with AT with a decrease of B lymphocytes.

In Germany, the team of Prof. Stephan Zielen Frankfurt presented his work on:

  • treatment with growth hormone (GH) in patients with AT.It was hoped, after tests on mice, it would improve the immune characteristics while addressing the problem of growth seen in patients with AT. As expected, one year of treatment (daily subcutaneous injections) has allowed the return of normal growth, but no significant gain on immunity.
  • Another conclusion was to find a mode of GH regulation not completely dependent of the hormone IGF-1.
  • The value of bone marrow transplantation in patients with AT. On the mouse model, a significant improvement was obtained on immunity, life expectancy, growth and performance, but not on the neurological part. Nevertheless, the first transplants should be performed soon on AT young children, more likely to respond favorably to the it. Indeed, it is likely that this solution can't be applied to all immediately.

Dr. Terry Fry (Bethesda, USA) outlined the expectations based on the use of interleukin 7 (see diagram ) to increase the number of T cells (deficient in the AT) and their repertoire diversity. Encouraging trials have been conducted for other diseases with similar effects. Why not for the AT?

Finally, the Japanese team of Shuki Mizutani demonstrated for the low number of T cells in patients with TA: it is due to a lack of control of stem cell precursors of these cells during their "specialization". The ATM protein is part of some process control. When deficient, T cells with non-viable DNA breaks accumulate in the body of patients, causing immunodeficiency and announcing the genesis of lymphomas.


Respiratory complications: FINDINGS AND QUESTIONS

Pulmonary disease are common and often serious for patients with ataxia telangiectasia, but they are of different types that can be simultaneous and not dependent on genotype (John Shneerson, director of adult clinical AT Papworth, UK). It includes: 

  • lower respiratory tract infections
  • interstitial lung disease (non functional alveoli)
  • neuromuscular dysfunction that affect respiratory function. Ex: breathing adult patients with AT during sleep was very irregular. (John Shneerson)

The causes are numerous and include:

  • immune deficiency. Eg patients receiving gamma globulin have an increased risk of having lower respiratory problems (Pr Shannon McGrath-Morrow, Baltimore)
  • false roads, mostly silent
  • problems for rejecting secretions associated with neuromuscular impairments.

But many questions remain, both for the overall process involving the ATM gene and on some questions and findings including:

  • Respiratory capacity declines with age (Pr Shannon McGrath-Morrow, Pr Zielen, Frankfurt and clinical AT Israeli).
  • It also decreases with body mass index (Pr Zielen)
  • What is the best way to measure this ability in a patient with AT?
  • What is the long-term impact of cancer treatments (John Shneerson)?

Thinking ahead is probably the best way to deal with the problems of deterioration of lung capacity in ataxia telangiectasia to identify a risk of decompensation during infections or general anesthesia. (Pr Shannon McGrath-Morrow, Baltimore). Yes, but how, when X-rays, very useful for exploring the lungs, are not recommended in the OT except for emergency and pulmonary function tests are not always appropriate?


Respiratory complications: recommandations

On this point, a team led by the Israeli AT clinic showed that it could be interesting to measure the ability to cough in patients with AT in place of traditional breath tests. The physical exertion required during these tests may even truncate the results, not on coughing. In addition, cough properly is essential in the management of pulmonary infections, which takes to maintain this capacity over time.

In general, everyone strongly emphasized the need to maintain physical ability to breath through  regular training.
Thus, Jayesh Bhatt, chest physician consultant at the AT clinic of Nottingham, favors detection and prevention measures: regular monitoring with measurement of respiratory function, effectiveness of cough and saturation at least twice a year.

Chest physiotherapy is recommended. Started early, it helped increase life expectancy in CF of an average of 3 years. A forthcoming study by Dr Emma Ross (UK) aims to assess precisely in the AT the gain provided by a respiratory muscle training through the daily use of a specific machine on a 12 weeks period..

Another factor that could contribute significantly to degradation is that of pulmonary aspiration. Professor Maureen Lefton-Greif in Baltimore described the mechanisms and the interest of gastrostomy tubes to minimize them. It is reported that they improve patients' lives by providing the correct quantity of food, reducing the duration of the meal without removing the pleasure of eating. Surgeons have however to correctly evaluate the health of the patient at the time of installation. A last point is that there is not yet enough distance to conclude a long-term benefit.


Regarding the treatment of respiratory problems, Jayesh Bhatt summarized what was advocated in the UK facing a lung infection in a patient with AT:

  • Start fast and high-dose antibiotics
  • Chest physiotherapy for 2 to 4 weeks
  • If no improvement, consider x-rays to refine diagnosis
  • Then consider administering intravenous antibiotic treatment
  • The use of corticosteroids early

But he also asks that a unified approach is defined quickly. !


However, the lungs are still not fully understood and even more so the role of the ATM protein in their operation. One poster of the team of Prof. Zielen (Frankfurt) tended to show the immunoregulatory role of ATM in maintaining genome stability and balance of the epithelial barrier, ie in the regeneration and effectiveness of the barrier formed by the lining of the lungs.


Neurology: advances in imaging

The neurology is one of the disciplines of medical research where innovations and discoveries abound, with expectations for ataxia telangiectasia.

First, medical imaging and MRI : Magnetic Resonance Imaging is a non-radiating imaging process: it is not dangerous for patients with AT but particularly effective for exploring the brain.
Two new MRI techniques, presented by Professor Dorothea Auer of Nottingham, could allow a better understanding of the neurodegenerative process in AT: DTI (Diffusion Tensor Imaging) and RsfMRI (Resting State Functional MRI) can indeed demonstrates poor neurons connections due to damage or lack of organization of the neural network.

This explains some paradoxes of AT, as the fact that parts of the cerebellum or basal ganglia are still showing activity when damaged, while others outwardly functionnal are no longer active.

Nora Volkow, Bethesda, USA, famous for his work on the influence of drugs on the brain, measured brain activity in patients with AT using a PET scan and connectivity of neurons as described above with an MRI.

It is in the cerebellum and certain basal ganglia that both parameters were found to be most affected, just as expected.
But she also measured metabolic defect (the use of glucose (sugar) for energy). This defect is also found in the brain, but to a lesser degree and differences between patients with AT. Perhaps a new track to explore?


Neurology: Stem Cells

The discovery of the existence of stem cells for renewal of neurons is recent: it was long thought that there was a capital of neurons diminishing with age.

Rick Livesay Cambridge explained that it was now possible to obtain neurons from stem cells in the laboratory. But even more remarkable was to obtain neural networks based on this differentiation, so that models of degenerative diseases can now be created to study them more easily.

And these models will arrive for AT! The team of Martin Lavin of Queensland, Australia, has in fact obtained stem cells from patients with AT, from their skin and olfactory mucosa. These cells could then be differentiated into neurons!

According to Alastair Wilkins, Bristol, intravenous injection of embryonic stem cell therapies offer many opportunities. Indeed, numerous studies and experiments have shown that they have a regenerating effect on neurons and they protect the cells against oxidative stress (high in the AT and damaging DNA). Another track to explore!


Neurology and Oxidative Stress

The ATM protein is involved when too much oxidative stress (presence of DNA-damaging oxygen compounds, as for the indirect effect of radiation ) occurs in the cell through a complex cascade of reactions. As it is absent in the AT, oxidative stress rises gradually.

Professor Wong of the University of Texas has suggested that all brain cells are affected by stress, including stem cells , which then do not replace the previous any more. This is what causes the neurodegeneration .
The idea is to use a combination of therapy to restore oxidative stress at a "normal" level and also the capacities of the stem cells. This was done with good results in At model mice. A trial is underway in the U.S. on a child.

However, this method only works if there are neurons remaining, which means early in the disease. Later, the only way to replace them would be a stem cell therapy, and we saw that there was also progress.

Finally, many questions still remain in the process that leads to increased oxidative stress and its effects. However, tracks are emerging, with potential therapeutic implications.

Thus, the team of Maria Vinciguerra of the London Research Institute has shown the important role of the ATM protein in cellular metabolism, ie the transformation of carbon compounds (such as carbohydrates) but also of lipids (fats).
This has an important role in the management of oxidative stress and by extension the growth and the functioning of the brain.

Oxidative stress has also a role in aging, accelerated through the AT. The team of Pascale Bertrand, France , just found the reason: the increase of oxidative stress in cells leads to an increase in the essential component of the envelope of the cell nucleus: lamin B1. In doing so, deformation of the shape of this nucleus (usually spherical) are observed, as in the disease "progeria".
This is a key element in explaining the accelerated aging, genome instability during mitosis (cell division) and by extension in neurodegeneration, which is consistent with and complements the research of Professor Wong.

These presentations were among the most hopeful in the search for a neurological treatment.


CANCER in AT: opportunities and challenges

1/3 of patients with AT will develop a malignancy with these elements (M. Taylor, UK, L. Izatt, USA):

  • Most of the malignancies under 16 are met in patients with total absence of ATM activity
  • Most of the lymphoid tumors are exclusive in childhood
  • An increased risk of breast cancer has been identified in female heterozygous ATM carriers and female patients with AT. They should benefit from an enhance surveillance, preferably using MRI for the latter.

Unfortunately, the lack of the ATM protein makes unusable some of the treatments like radiotherapy and some chemotherapies, or they have to be reduced to avoid severe complications. But on the other hand, reducing the drugs quantities might not be sufficient to treat the cancer.

John Sandlund from Memphis, USA, exposed the results of a study on a modified treatment for large B cell lymphoma in AT. You can believe me when I say it is possible to recover from it: our own daughter did it few months ago with the help of the Curie Institute in Paris (F. Bourdeaut).

But standardized treatments are still awaited for malignancies in AT (Jan Loeffen, Netherlands). And this is the aim of one of the project AT Europe is funding.


clinical trials and perspectives

Sometimes treatment tracks appear through fortuitous observations. This is the way Italian have found that some steroids cause an improvement in the neurological status of patients with AT and even in their level of lymphocytes. These processes are still unknown.

A first clinical trial has led however to the following conclusions:

  • little or no side effects
  • 2/3 of the volunteers showed signs of improvement with a majority of female
  • response seemed to depend on the dose, but not on the age, the clinical status of the patient nor the type of mutation


Also on the neurological side, there are the very promising discoveries of Professor Wong already mentioned in this article (a test is on the way on a young patient) and more generally the explanation of the increase in the destructive oxidative stress in AT for which Pascale Bertrand researches are very important.


Professor Karl Herrup of Rutgers University in New Jersey came to expose his team's publication of an encouraging scientific article about the mean in AT mice models to preserve and even reverse the neurodegenerative process.

(from a AT Europe Facebook publication 04/11/12) They showed that a protein, HDAC4 had a destructive effect to the cells of the cerebellum in individuals with ataxia telangiectasia while it protects it in normal times. Treatment of mice with an inhibitory molecule of this protein has allowed them to recover almost all control of their movements.

This is a hopeful step forward, but it is nevertheless to be qualified: symptoms in AT mice are not exactly conform to human symptoms. Also, the tolerance of the inhibitor molecule has to be  checked and it will take a little time.

The indefatigable Professor Richard Gatti also gave an update on his research involving the use of small pharmacological molecules to force DNA coding when protein mutation is of the type codon-stop , ie when the process of production of the protein which is linear is stopped. This is likely to affect 15-20% of patients with AT.
The results are not yet available for ongoing identification of efficient molecules, the field of investigation restricting however. But this principle is tested with encouraging progresses in an attempt to treat cystic fibrosis, according to Professor Andrew Bush, UK.


The meeting in 2012 was very rich and for once hopeful:

  • Scientists have shown a clear commitment to enhanced communication to save time
  • New tools appear to accelerate research and open new tracks, such as stem cells from patients with AT or medical imaging, new techniques also
  • encouraging therapeutic trials are underway

But there seems to be some sort of imbalance between disciplines, the highest advances being made on the neurological part, whereas little was shown in pneumology for example, despite the remarkable efforts of the German team of Pr Zielen .

In addition, man should always be patient and careful regarding research: before being validated for humans, a treatment must be safe and laboratory results do not assume the same effects in humans.

It appears however, strong lines for the future:

  • obtaining and centralization of data is crucial
  • understanding of the level of oxidative stress in the AT should identify pharmacological means to slow the disease progression and improve patient comfort
  • There still lacks effective gene therapy techniques for AT, but this area is improving very quickly

Let's get ready and continue our efforts in this direction!

L' AT, c'est quoi?

L'ataxie télangiectasie (AT) est une maladie rare, neurodégénérative et immunodépressive, maladie héréditaire qui affecte de nombreuses parties du corps et provoque de graves incapacités... SUITE

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