Leipzig University Hospital: Investigating the causes of rare diseases in children

The causes of intellectual disability or epilepsy remain unexplained in more than 50 percent of those affected. With international support, researchers at Universitätsmedizin Leipzig have discovered two genes with mutations that are the causes of neurodevelopmental disorders in children. The results have now been published in specialist journals.

Human geneticists at Leipzig University Medicine repeatedly embark on a complicated search for developmental disorders in children because the cause is often not immediately identifiable. The earlier an epilepsy or a mental handicap begins, the more likely it is that there is a genetic cause behind it. When researching the causes, the experts look at the complete coding sequence of the human genome of the sick person. They can make a diagnosis in about 40 to 50 percent of cases.

If the cause remains unclear, the parents of the affected child can be sequenced as part of a research program. The result is compared with the coded sequence of the little patient and it is checked whether genetic changes that have arisen in the child can be found. Or whether there are hereditary causes and the parents have passed on their disposition to their offspring. However, it is also possible that there is a change in a gene that has not yet been linked to a clinical picture.

From clinical discovery to scientific database

Two cases of developmental disorders in children with unknown causes were recently identified in Leipzig University Medicine and researched together with international scientific expertise. In the first case, the parents and a seriously ill child with early onset epilepsy, developmental disorders and a small head circumference were sequenced. The researchers led by study leader Dr. Konrad Platzer two genetic changes in the so-called CHKA gene. Until then, it was not known that this gene is a cause of diseases. Using the “GeneMatcher” database, which scientists use worldwide to exchange information, the Leipzig doctors found five other patients from four families with similar symptoms and the CHKA gene.

Researchers from the University of Halifax in Canada helped demonstrate the connection between the change in the gene and the disease. The experiments confirmed that the enzyme cascade is restricted by the mutations in the gene and important membrane building blocks can therefore not be built. As a result, the patients all have similar symptoms – severe developmental disorders, epilepsy, movement disorders and a head that is too small. “The CHKA gene is part of the Kennedy enzyme pathway. This is a process controlled by enzymes, in which a specific membrane component is rebuilt step by step. There are some genes in this pathway that are already associated with epilepsy, among others. That means it is obvious that another gene in such a signaling pathway triggers a similar phenotype. However, we would not have been able to prove this without the help from Halifax," explains Dr. Konrad Platzer, specialist at the Institute for Human Genetics at the University Hospital in Leipzig.

New cause of developmental disability

Leipzig human geneticists led by study director Dr. Henry Oppermann have successfully solved the second case of a developmental disorder. They included a young patient in the study "Identification and Characterization of Genetic Modifications in Rare Diseases" and were able to identify a mutation in the ATP2B1 gene as a potential cause. Thanks to international cooperation with the Netherlands, New Zealand, Canada, Israel, Italy, USA and France, another twelve subjects with a mutation in the ATP2B1 gene and a developmental delay were found via the “GeneMatcher” database.

Together with the working group of Prof. Dr. Michael Schaefer, Director of the Rudolf Boehm Institute for Pharmacology and Toxicology at the Medical Faculty, and Prof. Frank Gaunitz, Clinic for Neurosurgery, investigated the influence of the mutations on the function of ATP2B1. The gene encodes a calcium pump that transports calcium ions out of the cell. Calcium is an important signaling molecule for neurons because it controls, among other things, the release of neurotransmitters and synaptic transmission. It is therefore important for learning processes and the storage of sensory perceptions in memory. The experiments showed that the mutations in the subjects actually impair the pumping capacity of ATP2B1 and are therefore the cause of the developmental delay. "In summary, we were finally able to solve the Leipzig case and describe mutations in the ATP2B1 gene as a new cause of developmental delay for the first time," says Dr. Opperman.

The study findings from Leipzig have a practical use for physicians all over the world. The new genetic variants that have been identified as causes of developmental disorders have been stored in the international Clinvar database, among others. There, all doctors can check whether their patients have comparable changes in their genetic make-up and whether the symptoms of the disease match them.

Both research papers were created at the Institute for Human Genetics in Leipzig in connection with doctoral theses: on the one hand by Chiara Klöckner (CHKA) and on the other hand by Jacob Rahimi (ATP2B1). After a defense of the results in front of a specialist committee of the medical faculty, both will receive their medical doctorate.

Source: Press release University of Leipzig from April 27.06.2022th, XNUMX