Administration of the amino acid D–serine, a dietary supplement, contributes to the improvement of the cognitive and motor capacity of a patient with a mutation that affects glutamate receptors.
A translational, multicenter study unveiled the potential of D–serine to improve the neuronal function of a patient with a mutation of the glutamate receptors associated to atypical Rett syndrome with severe encephalopathy. This collaborative study, led by Dr. Xavier Altafaj (Neuropharmacology Unit, IDIBELL) and published in the journal Biological Psychiatry, opens a new range of therapeutic options for patients with mutations that affect glutamatergic neurotransmission. Likewise, this study has allowed to establish a unique and novel experimental approach that is currently being transferred to an ambitious project that aims to design predictive algorithms that lead to personalized treatments that can be quickly transferred to the clinical practice for other mutations that affect glutamatergic transmission.

"The story begins about three years ago, when Dr. Ángeles García–Cazorla, a neuropediatrician at San Juan de Dios Hospital and professor at the University of Barcelona, ??contacted us regarding one of his patients, who presented an atypical form of Rett syndrome with severe encephalopathy”, explains Dr. Xavier Altafaj, leader of the study and member of the Neuropharmacology Unit IDIBELL–UB, led by Dr. Francisco Ciruela. While assessing the exome of this patient, the geneticists of San Juan de Dios (Dr. Judith Armstrong) identified a mutation that affects the coding gene for a subunit of glutamate receptors of the NMDA type. The team of Dr. David Soto (UB–IDIBAPS) carried out several functional studies that allowed the researchers to prove that the mutation drastically reduces the activity of the glutamate channel.

At the same time, computational studies conducted by Dr. Mireia Olivella (UVic) revealed that the mutation of the glutamate receptor sequence modified the receptor structure, decreasing the size of the canal's pore and thus its affinity for glutamate, as it was subsequently validated at the experimental level. Consequently, if the channel activity of this receptor is impaired, calcium intake could be reduced, leading to a clear decrease in neuronal function.

In order to be activated, NMDA receptors require the simultaneous presence of glutamate and the amino acids glycine or serine, which act as co–agonists. Knowing that glycine also acts on other types of receptors, IDIBELL researchers proposed to administer D–serine – an already commercialized dietary supplement, easy to administer and without side effects – to improve receptor activation and rebound glutamatergic transmission. In vitro studies in cell lines and primary cultures showed that D–serine supplementation enhanced the activity of mutated receptors. These results led Dr. Ángeles García–Cazorla, with the consent of the patient's parents, to start a D–serine supplemented diet.

Follow–up of the patient showed that dietary supplementation with D–serine can be associated with significant improvements in the patient's symptoms, both at a motor and cognitive level. "The patient is able to develop basic motor tasks that were unthinkable of at the beginning of the treatment, 17 months ago. We could say that the patient is connected to the outside world that surrounds her, and this represents a critical and unavoidable step towards establishing new neuronal connections", Dr. Altafaj describes.