Dr. Stephanie Dooves, Liza Kok and colleagues performed a study aiming to enhance our understanding of the disease mechanisms behind 4H leukodystrophy. This study, performed under the supervision of Dr. Vivi Heine and Prof. Nicole Wolf, provides the first insights into the cellular mechanisms underlying 4H leukodystrophy.

4H leukodystrophy is a severe genetic disorder affecting brain functionality, characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Patients experience challenges with motor skills and muscle coordination. Although it is known that 4H leukodystrophy is caused by mutations in RNA polymerase III, it is not clear how these mutations lead to specific 4H phenotypes. To develop new treatment options for 4H patients we are in need of a better understanding of disease mechanisms.

Connecting patients and the laboratory

In the collaborative effort between the Stem Cell Lab at the Emma Children's Hospital & Vrije Universiteit Amsterdam and the Amsterdam Leukodystrophy Center, the research group successfully utilized patient-derived stem cells to model brain development. This translational study has opened up new possibilities for investigating the disease at a cellular level and has provided critical insights into the mechanisms underlying 4H leukodystrophy.

The role of interneurons

By examining the brain cells of 4H patients and comparing them to controls, the research group identified significant deviations in a specific type of brain cells known as interneurons. These interneurons displayed reduced connectivity with other neurons, resulting in an increased activity. Moreover, alterations in interneurons were also observed in brain tissue from two 4H patients, reinforcing the notion that these cells play a crucial role in the disease's mechanisms. These novel findings shed light on the cell types affected by 4H leukodystrophy, offering valuable insights for the development of future treatment options.

Unraveling cellular mechanisms of 4H leukodystrophy

This collaborative research represents a significant step forward in unraveling the cellular mechanisms associated with 4H leukodystrophy. Through the use of patient-derived stem cells, the study highlighted the involvement of interneurons and their disrupted connectivity, leading to increased activity levels in 4H patients. This understanding is instrumental in paving the way for the development of innovative treatment strategies in future investigations.

This research is published in a research article in Brain.