Preprint links metabolic collapse to developmental regression in Kleefstra syndrome
FDG-PET/CT imaging in people with Kleefstra syndrome and a Drosophila model both point to impaired glucose metabolism as a mechanism underlying the adolescent-onset developmental regression seen in this rare neurodevelopmental condition.
A preprint posted to bioRxiv reports convergent evidence that altered glucose metabolism may drive the severe developmental regression that occurs in some individuals with Kleefstra syndrome (KLEFS1), a rare neurodevelopmental disorder caused by haploinsufficiency of EHMT1.
Kleefstra syndrome is characterised by intellectual disability, childhood hypotonia, and distinctive facial features. A subset of affected individuals experience marked regression — loss of previously acquired skills — during adolescence or early adulthood, often preceded by severe sleep disturbance. The mechanisms underlying this regression have not been well understood.
The research team combined two lines of evidence. First, they used FDG-PET/CT imaging — a technique that maps glucose uptake across tissues — in individuals with KLEFS1, finding patterns consistent with impaired cerebral metabolism. Second, they used a Drosophila model of EHMT1/G9a loss to investigate metabolic phenotypes experimentally, observing that flies with reduced G9a function showed evidence of metabolic vulnerability under stress conditions.
The authors propose that EHMT1's known roles in metabolic regulation and stress responses may leave affected individuals with insufficient metabolic resilience to sustain normal brain function during the physiological demands of adolescence, potentially explaining the timing of regression episodes.
This work has not yet been peer-reviewed. The preprint is available at bioRxiv (DOI: 10.64898/2026.08.28.747020). It is relevant to researchers in neurodevelopmental genetics, rare disease biology, and clinical geneticists and genetic counsellors who support families affected by Kleefstra syndrome.
Plain-language version
For patients, families, and general readers. Educational only — not medical advice.
Kleefstra syndrome is a rare condition caused by a change in a gene called EHMT1. People with this condition often have learning difficulties and low muscle tone from early childhood. Some individuals — though not all — experience a period of developmental regression, meaning they lose skills they had previously gained. This often happens in the teenage years or early adulthood, and sleep problems frequently come first.
Researchers have used a type of brain scan called FDG-PET/CT — which shows how the brain uses sugar for energy — in people with Kleefstra syndrome, and also studied flies with a similar gene change in the laboratory. Both lines of evidence point to the brain having difficulty managing energy during times of physical and developmental stress, which the researchers suggest might help explain why regression happens when it does.
This is very early research and has not yet been reviewed by other scientists. It does not change current care, but it offers a possible explanation that the research community will investigate further.
This is an educational summary, not medical advice. If anything here raises questions for you, please speak with your GP or a clinical professional.
Sources
Read the original reporting — these are the public sources this summary draws from.
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Primary sourcePreprint bioRxiv (Cold Spring Harbor Laboratory) · 2026-08-31Metabolic collapse as a mechanism of developmental regression: convergent evidence from Kleefstra syndrome FDG-PET/CT imaging and Drosophila modelling