New genetic variant helps explain rare neurological disease in childhood

Researchers from USP (University of São Paulo) discovered a new genetic variant capable of explaining neurological disease in children. First described in 2018, a condition known as CONDSIAS, an acronym for "stress-induced childhood neurodegeneration with ataxia and seizures", has only been identified once in South America.

The study was published in the journal Neurology Genetics, with support from Fapesp.

Symptoms of CONDSIAS include epilepsy, difficulty with motor coordination (ataxia), developmental delay and progressive degeneration of the nervous system. One of the most characteristic aspects of the syndrome is the considerable worsening of the condition after viral infections such as flu, herpes and Covid. Diseases cause physiological stress, the body's natural immune response, but this can worsen the condition.

The case analyzed by USP researchers is that of an 11-year-old girl who presented typical symptoms and carried two variants of the ADPRS gene (ADP-ribosylserine hydrolase), located on chromosome 1: one already known to cause the disease and another new one, whose clinical relevance was unknown. The main challenge was to relate these variants to the occurrence of the syndrome.

"When you analyze a patient's DNA, it is common to find more than one rare variant", explains the researcher. "The question is whether that variant explains the patient's symptoms or not", explains Nicolas Carlos Hoch, professor in the Department of Biochemistry at the USP Chemistry Institute and coordinator of the study.

He also explains that the advancement of genetic sequencing technologies facilitated the discovery: "In the past, you could describe the symptoms and compare similar patients, but you didn't have a molecular diagnosis", said the researcher.

Discovery also seeks to investigate therapeutic strategies
The research identified that the ARH3 protein acts as a kind of "molecular eraser". Its main function is to remove a chemical modification called ADP-ribosylation, used by cells as a temporary signal when something is wrong, such as DNA damage. Without ARH3, the "signal" is not removed and it remains accumulated, which can compromise cellular functioning, especially in neurons, which are more sensitive to molecular imbalances.

The syndrome still has no specific treatment, which is why researchers have invested in discovering possible therapeutic strategies. From the analysis of the disease mechanism itself, they identified that a possible strategy is to reduce the formation of ADP-ribosylation from the beginning. The researchers are betting on the use of an antibiotic capable of inhibiting the activity of PARP - the enzyme responsible for initiating ADP-ribosylation, but the studies have not yet been completed.

Genetic testing indicates ancestry and risk of diseases; understand

Source: CNN