A group of researchers has discovered a new rare genetic disease severe metabolism characterized by problems in brain and heart development, which affects children. The study has been published in Acta Neurophatologica, and it has been financed with funds from the Carlos III Health Institute, CIBERER and the project of neurological diseases without diagnosis of Catalonia, URD-Cat.
The gene that causes the disease, SHMT2, has been identified by analyzing the genome of 5 Spanish (Sant Joan de Déu), French (Nantes Hospital) and North American (Mayo Clinic) patients. The location of these patients has been possible thanks to the GeneMatcher platform, which connects clinical doctors and researchers from all over the world interested in studying the same genes.
SHMT2 performs the first step in a series of reactions providing one-carbon units covalently attached to folate species in mitochondria: transfers one-carbon units from serine to tetrahydrofolate (THF), generating glycine and 5,10-methylene-THF.
Children with deficiency SHMT2 suffer from cognitive development problems, motor disorders and progressive heart disease that may even require transplantation
Clinical and experimental study
Children with deficiency SHMT2 suffer from cognitive development problems, motor disorders and progressive heart disease you may even need a transplant.
For the analysis of the genome, the IDIBELL group has developed computer tools, sophisticated algorithms aimed at identifying DNA changes in genes most likely to cause disease. “The study of the genome is highly complex and requires powerful computer tools. This algorithm of its own creation -explains Pujol- is trained to navigate among the thousands of variations in the genome that each person has and discern those that best respond to the specific clinic that the patient presents. In the last years, the algorithm has been key to diagnosing hundreds of patients with rare brain diseases, discovering 10 new diseases, and lately, even finding the implication of genes that explain why young Covid-19 patients end up intubated in the ICU ”.
In collaboration with the group led by Udai Pandey at the University of Pittsburg, researchers have been able to corroborate the key role of SHMT2 in the transmission of signals between neurons in a fly model, the Drosophila melanogaster.
The gene SHMT2 directs the production of an enzyme that controls the metabolism of folic acid and amino acids, essential elements for forming proteins, with a key role in brain development
A genetic disorder with metabolic consequences
The gene SHMT2 directs the production of an enzyme that controls the metabolism of folic acid and amino acids, essential elements to form proteins, with a key role in brain development. In the cells of patients obtained by skin biopsy, the researchers have been able to determine the altered function by measuring the metabolites of the pathway in the biochemistry laboratory of the Sant Joan de Déu Hospital (HSJD) directed by Rafael Artuch.
On the other hand, the team of researchers has also found alterations in mitochondria, the organelles responsible for the production of energy and essential for most of the biochemical functions essential for life.
“Thanks to genomic medicine –States Aurora Pujol–, we can now diagnose patients who have not responded for many years, and better understand the mechanisms that govern essential biochemical reactions and the development of organs and tissues ”.
Àngels Garcia-Cazorla, a neuropediatrician who follows the three patients diagnosed in the HSJD and co-responsible for the research, adds that “as these are known biochemical pathways, we are working on experimental treatments to supplement deficient metabolites with the aim of improving the quality of life of the patients”.