Disorders related to GRIN gene mutations, called GRINpatia, are minority neuropediatric disorders, with only 500 diagnosed cases worldwide. This genetic disorder alters the brain development and causes severe problems, such as intellectual disability, alterations in the motor activity and social behaviour, digestive diseases and epilepsia. A team of researchers, led by Xavier Altafaj, from the Bellvitge Institute for Biomedical Research (IDIBELL), and David Soto del Cerro, lecturer at the Faculty of Medicine of the UB, has worked on a project to study the functional range of these disorders and design customized therapies. This therapeutic strategy, which counts on the participation of the team led by the researcher Àngels García Cazorla, from Hospital Sant Joan de Déu, and Mireia Olivella, from Pompeu Fabra University, was used to successfully treat a patient, who has improved notably regarding motor and communicative skills.

Aiming to translate this successful strategy to thirty patients, from Spain and ten European countries, the researchers started a campaign in the FECYT platform Precipita. The fundraising campaign will be active until June 23, 2019, to raise 25,500 euros. “This funding will enable understanding molecular alterations derived from mutations caused by this disease, getting a molecular and functional diagnostic and assessing several therapeutic strategies for its translation into clinical practice”, says David Soto del Cerro, who is also member of the Institute of Neurosciences of the UB.

Studying each mutation individually

The study, developed by these researchers and other research groups, showed that GRIN gene mutations cause a change in the functionality of NMDA receptors. In certain cases, the mutations cause a lower function, while in others, the function is exacerbated. Both situations cause an imbalance in the synaptic transmission of neurons and therefore affect the development of the brain and its proper functioning.

The genetic cause and clinical manifestation of GRINpaties are variable. However, although in some cases alterations can be light, most children with a GRINpatia show a severe intellectual disability and severe hypotonia (state of low muscle tone). This variability makes it necessary to study each mutation individually to diagnose the specific disease of each patient and therefore design a treatment. “When talking about customized medicine we have to understand the consequences of the mutation, to give a treatment that normalizes the function of the NMDA receptors”, notes Xavier Altafaj.

Improving the living conditions of thirty patients in Europe

This therapeutic strategy received its first positive results in a pilot study in which the researchers showed the benefits of a customized treatment with adverse effect-free amino acid. After the treatment, the researchers observed a significant improvement both in communicative skills and the motor activity of the patient with GRINpatia.

Seeing these results, thirty families asked for the analysis of the mutations of their children, the so-called functional molecular diagnostic, which enables the identification of the impact of the mutations. The identification of the mutation and its effects could enable the design of customized therapies to improve the symptoms and life conditions of the patients and their families, who suffer from the severity of this minority disease, which is not studied enough.

The objective of this campaign is to provide people who suffer from these diseases with customized studies within the frame of the national health services and without extra costs for the patients.

“Now we have the methodology and knowledge to categorize the consequences of each type of mutation, but we need the means to study each specific case and assess the customized treatments. The donations from this initiative will be fully used to hire research support staff who will carry out the functional assessment of the GRIN gene mutations”, says David Soto.

A predictive algorithm to accelerate the diagnostic

Also, the study will contribute to another objective in the long run: the creation of a predictive algorithm to predict functional consequences of the mutations to be identified in the future. “This algorithm could speed up the molecular diagnostic and the beginning of a customized treatment for patients with GRIN gene mutations, with which the negative consequences of the disease would be significantly attenuated”, concludes Xavier Altafaj.

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