Researchers discover a new genetic disease of the nervous and cardiac systems

  • The study, led by scientists from IDIBELL, Hospital Sant Joan de Déu and CIBERER, is published in the prestigious journal ‘Acta Neuropathologica’.
  • Children with ‘SHMT2’ deficiency, the gene that causes the disease, have cognitive development problems, motor disorders and progressive heart disease that may even require transplantation.
  • Researchers are working on experimental supplementation treatments with the deficient metabolites with the aim of improving the quality of life of patients.
Àngels Garcia Cazorla i Aurora Pujol 2

Researchers from IDIBELL and the Sant Joan de Déu Hospital, both members of the Rare Diseases Networking Biomedical Research Centre (CIBERER), have discovered a new serious rare genetic disease of metabolism, characterized by problems in brain and cardiac development, which affects the children. The study has been published in Acta Neurophatologica, a leading journal in neurology, and has been financed with funds from the Carlos III Health Institute, CIBERER, Hesperia Foundation and the project for undiagnosed neurological diseases in Catalonia, URD-Cat.

This new disease has been identified by an international team led by Aurora Pujol, geneticist and ICREA professor (Catalan Institution for Research and Advanced Studies) and head of the Neurometabolic Diseases Group at IDIBELL (Bellvitge Biomedical Research Institute), and by Àngels Garcia-Cazorla and Rafael Artuch, from the Sant Joan de Déu Hospital and the Sant Joan de Déu Research Institute. These two groups are members of the CIBERER.

The gene that causes the disease, SHMT2, has been identified by analyzing the genome of 5 patients from Spain (Sant Joan de Déu), France (Nantes Hospital) and United States (Mayo Clinic). Finding these patients has been possible thanks to the GeneMatcher platform, which connects clinicians and researchers from all over the world interested in studying the same genes.

Clinical and experimental study

Children with SHMT2 deficiency suffer from cognitive development problems, motor disorders, and progressive heart disease that may even require transplantation.

For the analysis of the genome, the IDIBELL group has developed specific computer tools, sophisticated algorithms aimed at identifying changes in the DNA in genes that are most likely to cause disease. “The study of the genome is very complex and requires powerful computer programmes. This algorithm of our own creation -explains Pujol- is trained to navigate among the thousands of variations in the genome that each person has and to discern those that best match to the specific clinical picture that the patient presents. In recent 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, the researchers have been able to corroborate the pivotal role of SHMT2 in the transmission of signals between neurons in Drosophila melanogaster, a fly model.

A genetic disorder with metabolic consequences

The results indicate that SHMT2 gene directs the production of an enzyme that controls the metabolism of folic acid and amino acids, essential elements to form proteins, with a crucial 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 vital for most of the biochemical functions essential for life.

“Thanks to genomic medicine, we can now diagnose patients who have been left unanswered for many years, and better understand the mechanisms that govern essential biochemical reactions and the development of organs and tissues,” emphasizes Aurora Pujol.

Àngels Garcia-Cazorla, a neuropediatrician who follows the three patients diagnosed in the HSJD and co-head of the research, adds that “as these are known biochemical pathways, we are working on experimental treatments to make up for the deficient metabolites with the aim of improving quality of life of patients.”


García-Cazorla, À., Verdura, E., Juliá-Palacios, N. et al. Impairment of the mitochondrial one-carbon metabolism enzyme SHMT2 causes a novel brain and heart developmental syndrome. Acta Neuropathol (2020).

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