Study Links Skill Loss in Kleefstra Syndrome to Astrocytes and Investigates Response to Olanzapine

A new study examines one of the most concerning possibilities for some families living with Kleefstra syndrome: the loss of previously acquired skills (developmental regression). This refers to a decline in functions that the individual had previously attained, such as communication, self-care, participation in activities, or other daily living abilities. The term has no relation to gastroesophageal reflux.

The study, which was published online on June 30, 2026, combined clinical observations from individuals with Kleefstra syndrome type 1 with laboratory experiments. The researchers examined, on the one hand, what had happened to a small group of people who had received olanzapine and, on the other hand, how astrocytes—brain cells that regulate the environment and the activity of neuronal networks—might be involved.

The result constitutes an important research signal, not proof of an established treatment. Human data were observational: olanzapine was not tested in a randomized, placebo-controlled clinical trial for Kleefstra syndrome. Therefore, the study cannot show with certainty how much of the observed change was due to the drug nor which people are most likely to respond.

What did the researchers study

The international clinical team included 54 individuals with molecularly confirmed Kleefstra syndrome type 1. This form is associated with deficiency of one functional copy of the EHMT1: one copy of the functioning gene is not enough to produce the usual amount of functional protein. The EHMT1 encodes an epigenetic regulator involved in the control of gene expression.

Out of the 54 individuals, 16 had received olanzapine, an antipsychotic medication. According to the publication summary, 10 of the 16 showed a beneficial response in terms of daily or adaptive functioning. This term refers to practical skills such as communication, self-care, participation, and the degree of independence; it is not simply a measurement of intelligence quotient. In four of the 16 individuals, the improvement was temporary, highlighting that an initial change is not necessarily stable or long-lasting.

At the same time, the team used human cells generated from patients' induced pluripotent stem cells. They studied neurons and astrocytes, as well as slices of the cerebral cortex from a mouse model with characteristics of Kleefstra syndrome. The combination of clinical and laboratory data allowed the researchers to formulate a biologically testable explanation for what was observed.

The potential role of astrocytes and S100B

Astrocytes were often previously described as cells that simply «support» neurons. Today we know they have a more active role: they contribute to the regulation of the chemical environment, signaling, and the overall activity of neuronal networks. In the experiments of the new study, the networks exhibited hyperactivity when neurons with reduced function EHMT1 were co-cultured with astrocytes that also had reduced function EHMT1.

Olanzapine reversed this laboratory pattern of hyperactivity. The researchers also observed increased levels of the S100B protein in astrocytes with decreased EHMT1. When S100B was pharmacologically or genetically restricted, neuronal network hyperactivity was corrected in the experimental models.

This does not mean that S100B is currently a clinical test for the loss of skills, nor that there is an available treatment targeting it. Correcting a cellular phenotype in the laboratory does not prove that the same intervention will be safe or effective in humans. The finding mainly offers a hypothesis that can be tested in subsequent studies.