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A research team from Mannheim, Göttingen, Varna, and Princeton has discovered in animal studies with mice that the growth factor recombinant human erythropoietin (rhEPO) can significantly improve cognitive and social problems of Primrose syndrome. Primrose syndrome is a very rare and severe disease caused by changes in the ZBTB20 control gene. The study, which has now been published in the Journal of Clinical Investigation Insight, provides the first evidence that an already approved drug could counteract the severe neurological symptoms of this rare disease.
Primrose syndrome is an extremely rare congenital developmental disorder. Affected children often exhibit delayed mental and linguistic development and usually have distinctive facial features and progressive thickening of the bones, particularly in the skull and hands. They also often have an enlarged brain (megalencephaly) and characteristics of the autism spectrum, including attention deficits, repetitive behaviors, and self-harm. Only a few hundred cases have been reported worldwide to date, which is why the syndrome is classified as an ultra-rare disease and is often only recognized after a long diagnostic search.
Primrose syndrome: A genetic model for autism and intellectual disability
In most cases, the disease is caused by changes in the ZBTB20 gene, a transcription factor that plays an important role in controlling many other genes in the early development of the brain and other organs. To understand the underlying biological mechanisms, an international team of researchers led by Hannelore Ehrenreich, Manvendra Singh, and Klaus-Armin Nave studied mice that carried an inactive copy of Zbtb20, mimicking this human mutation.
The researchers subjected male and female mice lacking one of the two copies of the Zbtb20 gene to a series of behavioral tests and MRI scans. The animals exhibited core characteristics of autism: they were less sociable, vocalized less, displayed repetitive behaviors, and had impaired cognitive flexibility, pronounced hyperactivity, and reduced sensitivity to pain.
MRI scans of the males revealed an enlarged volume of the hippocampus, cerebellum, brain substance, and entire brain, which is comparable to megalencephaly in some patients. The females had a reduced olfactory bulb and also an increased volume of the hippocampus and cerebellum, which normalized after treatment. “These observations confirmed that the mice we used are a good model for Primrose syndrome,” says Prof. Dr. Dr. Hannelore Ehrenreich, head of Experimental Medicine at the Central Institute of Mental Health (CIMH) in Mannheim and one of the last authors of the study.
Erythropoietin reverses behavioral and structural deficits
The team had previously shown that injections with rhEPO cause the ZBTB20 gene to become more active in certain nerve cells in the hippocampus. RhEPO is a genetically engineered variant of the natural hormone erythropoietin, which, in addition to its role in blood formation, can also influence the development and protection of nerve cells.
Based on this finding, the researchers administered rhEPO to the experimental mice every other day for three weeks starting on day 28 of life. The treatment significantly improved the animals’ social skills, vocalization, working memory, exploratory motivation, and cognitive flexibility. In a behavioral test of spatial learning and memory, the treated mice performed just as well as normal wild-type mice. The drug rhEPO also normalized pain sensitivity and reduced hyperactivity in both sexes.
“The ability of rhEPO to normalize such a wide range of deficits in our primrose model is remarkable,” says last author Ehrenreich. At the cellular level, rhEPO was found to specifically stimulate the important control gene ZBTB20 in young nerve cells in the hippocampus. According to the researchers, this indicates that the drug can promote the maturation and adaptability of brain cells. MRI images also showed that rhEPO partially reversed changes in brain structure in female animals. The hippocampus and cerebellum became smaller, and enlarged brain ventricles regressed.
Promising, but still preliminary
However, the researchers emphasize that rhEPO has not yet been tested on patients with Primrose syndrome and should not be used in exceptional cases without clinical trials. “Many of the behavioral benefits occurred in a mouse model and may not be fully transferable to humans,” explains researcher Ehrenreich.
Manvendra Singh, Experimental Medicine, Central Institute of Mental Health (CIMH) in Mannheim, added: “We are only at the beginning. ZBTB20 is a key regulatory protein in the brain, but we do not yet know exactly which genes it influences and how rhEPO can compensate for the loss of function caused by the genetic mutation. We now need to clarify this step by step.“
Next, the researchers want to investigate which molecular processes ZBTB20 triggers and whether more advanced rhEPO drugs offer similar benefits. Since Primrose syndrome is extremely rare, they hope that international collaboration will enable future studies. Until then, this study offers a glimmer of hope: a drug that is already used clinically to treat anemia could one day improve the lives of people with Primrose syndrome.
About CIMH
The Central Institute of Mental Health (CIMH) stands for internationally outstanding research and pioneering treatment concepts in psychiatry and psychotherapy, child and adolescent psychiatry, psychosomatics and addiction medicine. The CIMH clinics provide psychiatric care for the population of Mannheim. At the CIMH, mentally ill people of all ages can rely on the most advanced treatments based on international standards of knowledge. Educating people about mental illness, creating understanding for those affected and strengthening prevention is another important part of our work. In psychiatric research, the CIMH is one of the leading institutions in Europe. Since 2021, it has been a site of the German Centre for Mental Health. The CIMH is institutionally linked to the University of Heidelberg through jointly appointed professors from the Medical Faculty Mannheim. The CIMH is a member of the Health + Life Science Alliance Heidelberg Mannheim.
Hindermann M, Wilke JBH, Curto Y, Oline SN, Gastaldi VD, Butt UJ, et al. Erythropoietin alleviates syndrome-associated intellectual disability and autism-like behavior in Zbtb20-haploinsufficient Primrose syndrome mouse model. JCI Insight. 2026;11(4):e200021. DOI:10.1172/jci.insight.200021
https://doi.org/10.1172/jci.insight.200021.
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