New Ultra-Rare Neurodevelopmental Disease Identified

The multi-center study involved 5 patients in 3 countries. The findings in the journal Nature Communications

A new, hitherto undiagnosed, ultra-rare disease characterized in the most severe cases by microcephaly, brain atrophy and skeletal abnormalities. It was identified by researchers at the Bambino Gesù Pediatric Hospital as part of a multi-center study involving 5 patients in 3 countries (Italy, France and the United States). The researchers identified the causes of the disease in the mutations of the ARF gene and studied their impact on embryonic development through the use of the experimental zebrafish model. The findings were published on the scientific journal Nature Communications.

The study involved five patients recruited at a multi-center level and was funded by the “Patients without diagnosis” program of the Bambino Gesù Foundation, by the Ministry of Health and by the Ministry of University and Research. Researchers have identified mutations in the ARF3 gene as responsible for the disease. It is a gene not previously associated with developmental disorders. The research was coordinated by Dr. Marco Tartaglia, head of the Genetics and Rare Diseases Research Area of the Hospital, in synergy with Dr. Antonella Lauri, young PI of the European program “Marie Sklodowoska Curie”, and involved the institutions of 3 countries (Italy, France and the United States).

The researchers studied the impact of single mutations in the gene implicated in the freshwater fish zebrafish, which shares more than 70% homology with human genes. These small fish also have the characteristic of being transparent in the early stages of development. This allows to study with high resolution techniques and in a short time the processes of embryonic development and tissue-specific alterations, otherwise difficult to access and explore.

Thanks to the use of cellular systems and zebrafish, it was possible to understand the mechanism of action of the various mutations implicated in this disease. It has also been shown that the mutation have a deleterious impact both on the functionality of the protein encoded by the mutated gene, and on the normal activity of the Golgi apparatus, an organelle present in cells that plays a key role in managing traffic flows in and out the cells.

Molecular and high-resolution microscopy analysis of zebrafish embryos allowed researchers to reveal perturbations in stem cell proliferation and increased mortality during brain development, thus helping to elucidate the mechanisms underlying the microcephaly found in patients.

The study confirmed the importance of the functional integrity of the Golgi apparatus in regulating the processes of brain development – explains Marco TartagliaIt was therefore possible to assign this disease to the group of so-called “golgipathies”, that is, to diseases caused by the malfunctioning of the Golgi apparatus”. According to Bruno Dallapiccola, Scientific Director of the pediatric hospital “Thanks to the discovery of the mutations of the ARF3 gene, we now have biomarkers which, in addition to identifying the disease by allowing its diagnosis, offer potential targets for future targeted therapies”.

“The dream of Bambino Gesù Hospital,
the dream of the Pope, is to help bring
science and humanity to all children with
very severe diseases who need to be treated”
Pope Francis