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Project FAVA

Project FAVA is a non-profit patient advocacy group that promotes awareness of fibro-adipose vascular anomalies, educates patients, their families, and the global community, and provides helpful resources to those with FAVA. They also work with scientists, medical providers, and pharmaceutical companies to advance research and move the needle towards more effective and less invasive treatment options.

Visit Project FAVA’s website and sign up (https://www.projectfava.org/join-now) to stay on top of the latest news and breakthroughs in FAVA care.

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The Prize “Gagna A. & Ch. Van Heck Prize for Incurable Diseases” has been awarded to Prof. Guillaume CANAUD

This Prize, amounting to 75.000 €, is a triennial and international Prize, granted by “Fonds de la Recherche Scientifique – FNRS” (F.R.S.-FNRS) to reward a scientist or a medical doctor, in recognition of a research work which has contributed to the treatment of a disease currently incurable, or which has raised hopes for curing the disease.

The 2021 Prize was awarded to Prof. Guillaume Canaud of the Necker Hospital, University of Paris, for his contributions to the therapeutic treatment of PIK3CA-related overgrowth spectrum (PROS), which includes a broad range of rare disorders caused by a PIK3CA mutation.

Objectives, progress and highlights of the COZY project in 2020

The overall aim of the COSY project is to improve the medical care of patients with overgrowth syndromes. To this end, we intend to improve the genetic diagnosis; identify new genes involved; understand how the disease develops and progresses; identify new therapeutic targets; improve patient care (one-day-care concept); develop new imaging tools to improve patient’s follow-up; increase awareness of these syndromes within the medical community and promote a better patient integration through dissemination in appropriate communication channels.

The project started nearly at the same time as the global COVID-19 pandemic, however, it did not impact our motivation, and we have been able to move forward despite the international context. In fact, we have identified new genes in OS patients, and we are currently trying to demonstrate their contribution to the development of these syndromes. We have also made progress in understanding the molecular mechanisms of these syndromes, about which several scientific publications will be published soon. A new tool to assess patient bone abnormalities will be delivered later this year as well as new modalities for imaging analysis.

Finally, our hospital care level improved through an increasingly smoother patient journey. This first year allowed us to lay the foundations of our project.

The coming year shall see several deliverables being reached. To be continued!

Call for research projects: “Human and social sciences & rare diseases”

The Foundation for Rare Diseases is launching its 9th call for research projects: “Human and social sciences & rare diseases”.

As part of the Foundation’s participation in the RHU project ‘COSY’, 4 projects addressing the challenges of patients affected by Overgrowth Syndromes (OS) will be supported for up to 12 months and with a maximum budget of €20,000.

All projects should formulate a research question, the benefits of which being transposable to other pathologies, involving at least a research team in Humanities and Social Sciences (HSS), a medical team specialized in rare diseases and a patient advocacy group. Finally, the bearer must be an expert in the HSS field. All rare diseases of children and adults are concerned.

Click here to find more about this projects call: https://fondation-maladiesrares.org/wp-content/uploads/2021/05/SHS9-Call.pdf

Interview of Dr. Stéphanie Baulac

Inserm research directoris and head of the research team at the ICM (Paris Brain Institute in French Institut du cerveau – ICM)


→ Who are you?

I am a geneticist intrigued by mosaic mutations in epilepsies with cortical malformation.

→ What is your role in the project?

I am the leader of WP2, which aims to tackle the genetic etiology of these syndromes and to contribute to the genetic diagnosis. Using the latest generation sequencing tools, we are looking for mosaic mutations that are only present in a small number of cells.

I am also involved in WP3 which aims to understand the physiopathological mechanisms of these syndromes. The goal is to develop preclinical mouse models, modelling somatic mutations in vivo in order to test new pharmacological targets.

→ Currently, what are you working on?

We are now working on a cohort of young patients with a cortical malformation (particularly focal cortical dysplasia), who have undergone resection of the epileptogenic focus to control their epileptic crises. 
Using a targeted sequencing panel, we have identified numerous somatic mutations in various genes (MTOR, RHEB, PIK3CA, AKT3, TSC1 / 2) of the mTOR signalling pathway, which controls cell growth and proliferation. These mutations are “brain-specific”, they appear during brain development. Thus, somatic mosaicism is gaining more importance in several diseases besides cancer.

→ What are your first discoveries?

Our recent work has shown that there is a gradient of mosaicism correlated with the size of the dysplastic lesion in the brain. The earlier a mutation occurs in brain development, the larger the fraction of cells and the lesion will be extensive (Lee * Baldassari * et al. 2021). By laser microdissection of cells, we have demonstrated that only abnormally large cells carry the mutation. 
We were also interested in a subgroup of cortical malformations, “mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)” and showed that somatic mutations in the SCL35A2 gene, which codes for a galactose transporter are responsible (Bonduelle et al. 2021).

→ What is the impact of your work on the project?

This work makes it possible to offer a genetic diagnosis to families, a reclassification of these cortical malformations based on genetic etiology, but also to evolve towards precision and personalized medicine, which is based on the understanding of deregulated signalling pathways.

What is next?

The remainder of the work consists of looking for new genes by a so-called “whole exome sequencing” approach in patients who are panel-negative, in order words who do not carry mutations in genes known to date

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Publications

〉 Frequent SLC35A2 brain mosaicism in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) – Bonduelle et al. acta neuropathol commun
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〉  Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia – Annals Clinical and Translational Neurology
Click here

The detection of the mutation PIK3CA

Interview of the Pr Guillaume Canaud


→ What is a gene panel? 

A gene panel is a test that analyzes multiple of genes at once. The goal is to identify a mutation that explains the disease. In such analyze we are focusing on a subset of genes known to be associated with overgrowth syndromes. Having a negative test does not exclude a mutation. This can be due to the sensitivity of the test that is not sufficient or the biopsy ran could have be performed in an area that is less/not affected by the disease or the disease can be related to a new gene that is not know yet.

In case of a negative test, we perform a second or a third biopsy. If on these subsequent tests we don’t find any genetic explanation we perform a whole exome sequencing (i.e. we explore all the genes and not only the ones from the panel). 


→ Which medical centers can run this test?

Each medical center has his own panel. Most of them are dedicated to oncology since the genes involved in overgrowth syndromes are similar (PIK3CA, AKT, mTOR, RAS….). However, usually that kind of panels do not allow to explore very low frequency variant. Dedicated panel to overgrowth syndromes are indeed mandatory.


→ Is there a universal gene panel for all overgrowth patients?

Absolutely not! This is our goal. We aim to purpose a panel to all medical centers taking care of patients with overgrowth in order to cover more than 90% of the genes involved.


→ Which type of samples is necessary to run this test?

This is mandatory otherwise you will miss the mutation. As stated above, a negative test does not exclude the presence of a mutation. Sometime, a second or a third biopsy is required. 


→ Can PIK3CA mutation always be detected by using a gene panel?

It depends on the design of the panel. Most of the time yes.


→ What other mutations can it detect? 

We have two different panels that we are using now. The first one is used daily to detect mutations in patients with overgrowth and/or vascular anomalies. In this panel we test the following genes:AKT1 AKT2 AKT3 BRAF GNAQ KRAS MAP2K1 MTOR NRAS PIK3CA PIK3R1 PIK3R2 RASA1 TEK TSC1 TSC2 GNA11, GNA14, HRAS, MAP3K3, KRIT1, EPHB4, PTEN. The second panel is a research panel exploring more than 50 genes involved in the PIK3/AKT/mTOR pathway.

At the end of the project by merging the data obtained from these 2 panels we will be able to provide an optimized test for patients with overgrowth.


→ What have you already discovered?

We found new mutations but they are currently under investigation to validate their pathogenic potential. We also found that few patients are carrying additional mutations.