Kleefstra syndrome (KLEFS1) is a rare genetic condition caused by haploinsufficiency of the EHMT1 gene on chromosome 9q34, meaning one working copy of the gene is lost, either through a deletion of genetic material in that region or through a smaller sequence variant that disables the gene. EHMT1 helps regulate how other genes are switched on and off during brain development, and the condition it causes is estimated to affect fewer than 1 in 1,000,000 people, according to a 2026 international clinical guideline. People with Kleefstra syndrome typically have intellectual disability, developmental delay, low muscle tone, and distinctive facial features, along with an elevated likelihood of autism-related traits and epilepsy. But one of the syndrome's most clinically important features has nothing to do with early childhood: in late puberty or early adulthood, some individuals with Kleefstra syndrome experience a sudden loss of previously acquired daily-living skills, a pattern of regression that can resemble, and sometimes overlap with, a treatable psychiatric condition called catatonia. New research is now connecting this regression to a specific brain mechanism, and pointing toward a medication that may be able to help reverse it.
What does the clinical picture of Kleefstra syndrome look like?
A 2025 study in Clinical Genetics examined a large clinical cohort of 65 individuals with Kleefstra syndrome (40 female, 25 male; mean age 9.3 years) treated at a dedicated Kleefstra Clinic at Boston Children's Hospital. Genetically, 17% had large 9q34 deletions of at least 1 megabase (Mb), 29% had smaller deletions under 1 Mb, and 54% had sequence variants in EHMT1 itself. Clinically, across the full cohort, global developmental delay or intellectual disability was documented in 77%, autism spectrum disorder in 38%, and epilepsy in 15%. When the researchers compared the two main genetic subgroups, those with a 9q34 deletion (combining the large- and small-deletion groups) had significantly higher rates than those with sequence variants alone of developmental delay or intellectual disability (p=0.037), motor impairment (p=0.01), epilepsy (p=0.004), and cortical visual impairment (p=0.003). In other words, the type of genetic change, not just the Kleefstra syndrome diagnosis itself, carries real information about what a family might expect and plan for.
Coping strategies for individuals and families
- Expect the emotional impact of diagnosis to be real, and to hit hardest early on. A 2025 interview study of parents of children with Kleefstra syndrome found that the emotional weight of diagnosis was especially profound for parents of younger children. Naming that impact openly, rather than minimizing it, is a reasonable and expected response, not a sign that something is being handled wrong.
- Plan for the practical toll that behavioral and psychiatric symptoms can take on daily life. The same study found that behavioral and psychiatric symptoms had a major impact on parents' employment, activities, and emotional wellbeing. Building in flexibility at work, and lining up support before a crisis hits rather than during one, can soften that impact.
- Ask early about respite care options. Parents in the study specifically identified a need for better access to respite care. Looking into local and national respite programs before they're urgently needed makes them easier to access when they are.
- Advocate for schooling tailored to the person's specific needs. Specialized schooling was another need parents named directly. Kleefstra syndrome's genotype can predict some of what a child may need, so sharing genetic test results with educators and therapists can help shape a more individualized plan.
- Seek emotional support that's tailored to this specific diagnosis, not just general parenting resources. Parents in the study wanted support specific to the diagnosis itself, delivered at the time of diagnosis, rather than generic resources offered later. Condition-specific family organizations and Kleefstra syndrome clinics are often better positioned to offer this than general-purpose services.
A closer look: late-onset regression and catatonia in Kleefstra syndrome
Parents of children with Kleefstra syndrome consistently name one fear above all others: the possibility of future regression and lifelong dependency. A 2025 interview study in the European Journal of Medical Genetics, built on 12 semi-structured interviews with 15 parents of children and young adults with Kleefstra syndrome (ages 8 to 25) in the Netherlands and Belgium, found that this fear is not abstract. Unlike many genetic syndromes where developmental trajectories are relatively stable once early childhood challenges are addressed, Kleefstra syndrome carries a distinctive and clinically underrecognized risk: in late puberty or early adulthood, some individuals lose previously mastered daily-living skills over a relatively short period of time. This regression can resemble, or directly overlap with, catatonia, a condition marked by immobility, mutism, odd posturing, or agitation that is treatable but frequently missed, especially in people who already have intellectual disability and limited verbal communication. A 2025 case report in the Journal of Visualized Experiments described a 17-year-old male with Kleefstra syndrome who developed catatonia and was successfully treated with scheduled lorazepam, the first published case of its kind. The case illustrates why recognizing catatonia specifically, rather than attributing a sudden loss of skills to the underlying syndrome and leaving it unaddressed, matters so much: it is one of the few presentations in Kleefstra syndrome with a clear, fast-acting treatment.
Mental health care considerations
Beyond catatonia, a 2026 study in the Journal of Clinical Investigation identified a biological mechanism behind the broader pattern of neurodevelopmental regression in Kleefstra syndrome, along with a promising treatment. Researchers studied an international cohort of 54 individuals with Kleefstra syndrome, 16 of whom had been treated with the antipsychotic medication olanzapine for regression-related symptoms. Of those 16, 10 showed a clear beneficial response with improved adaptive functioning, and 4 showed temporary improvement. To understand why, the researchers turned to laboratory models, including brain cells grown from stem cells (induced pluripotent stem cells, or iPSCs) and mouse brain tissue, and found that cells lacking a working copy of EHMT1 show elevated levels of S100B, a marker of neuroinflammation produced by support cells called astrocytes. This elevated S100B appeared to drive neurons into a state of hyperactivity. Olanzapine reduced S100B levels and reversed this hyperactivity in the lab models, offering a plausible biological explanation for why it helped reverse regression symptoms in some patients. This is still early-stage evidence, not a guaranteed treatment for everyone, but it is a genuinely hopeful and mechanistically grounded finding for a symptom that has historically been poorly understood and difficult to treat.
Tips for supporting someone with Kleefstra syndrome
- Watch for the specific signs of regression during adolescence and early adulthood. Because this life stage carries a distinctive risk in Kleefstra syndrome that most other genetic syndromes don't share, knowing to watch for a sudden loss of previously mastered skills, rather than assuming gradual decline is inevitable, allows for faster recognition and action.
- Learn to recognize catatonia specifically, and know that it's treatable. Immobility, mutism, odd posturing, and agitation can be mistaken for a permanent worsening of the underlying syndrome. Because catatonia has shown a fast, clear response to treatment, raising the possibility with a clinician promptly is worth doing rather than waiting to see if it passes.
- Ask about EHMT1-specific genetic testing and what the result means. Knowing whether someone has a 9q34 deletion or a sequence variant, and the size of a deletion if present, can help anticipate the likelihood of developmental delay, motor impairment, epilepsy, and visual impairment, and shape care planning accordingly.
- Connect with Kleefstra syndrome-specific patient organizations. Groups focused specifically on Kleefstra syndrome, rather than intellectual disability or autism in general, can offer more relevant guidance, connect families to specialists experienced with the condition, and reduce the isolation that often comes with a very rare diagnosis.
- Ask your care team about the new international guideline for Kleefstra syndrome. A 2026 international guideline, developed by a consortium of specialists across 15 countries, lays out 66 recommendations for coordinated care. Bringing it to appointments can help ensure that monitoring for regression, epilepsy, and other known risks isn't left to chance.