Huntington's disease: evidence of altered brain development even before birth

                                                                              07/09/2020

This discovery - recently published on 'Science' - may have important implications on the nature of future treatments and on the appropriate time to begin them. Huntington's disease causes the degeneration of nerve cells in the cortex, the outer layer of the brain, the one that controls thought, behavior and memory, and in the striatum, the part that controls motor functions and cognition.

While researchers have long believed that Huntington’s involves normal brain development followed by a degenerative phase, during which symptoms appear, increasing evidence suggests that the disease may also affect prenatal neurodevelopment.

The Institute of Neuroscience of Grenoble, France, has published  the results of a study conducted by a team of researchers that have analyzed the cortex tissue from eight 13-week-old human fetuses donated by parents following medical terminations of pregnancy, including four diagnosed with Huntington and four healthy.

Researchers Humbert and Alexandra Durr observed that, compared to healthy fetuses, the cells of fetuses with the Huntington mutation had several defects, including an abnormal localization of mHTT and proteins involved in keeping progenitor cells together and impaired intracellular transport. All of these anomalies result into an abnormal maturation of brain structures already in the fetal phase. The alterations found in the human fetus were then also confirmed in laboratory on animal models.

It is important to emphasize that these defects have also been observed in fetuses with a lower CAG repeat , which would typically cause a later disease onset.

But how do you explain, then, the absence of symptoms up to a certain point in life? Researchers have hypothesized that the brain can activate, even very early, mechanisms that compensate for changes in neuro-development, in order to allow normal functions to be carried out until the first symptoms appear. "The research of the Grenoble group is very consistent with our discovery of biological, clinical and brain structure alterations found in children carrying a very extensive mutation (Fusilli et al., Lancet Neurol 2018)", comments Ferdinando Squitieri : "In that case, a very toxic mutation shows developmental alterations of the nervous system already in childhood".

In Humbert's words, this important discovery entails the fact that "once disease-modifying therapies for Huntington’s are developed, we should treat pre-manifest patients as early as possible or differently compared to those who are at symptomatic.”

However, It will be necessary to gather further insights on this point.