An Australian-led international research collaboration has delivered a promising breakthrough in the quest to better understand and treat childhood dementia.
Recently published in one of the world’s most preeminent scientific journals, Nature Communications , the study uncovered a fundamental mechanism underlying Sanfilippo syndrome, a common form of childhood dementia, revealing how hyperactive and dysregulated synaptic circuits emerge in the brain tissue of children impacted by this devastating disease.
Sanfilippo syndrome is a rare genetic condition that causes fatal brain damage. Children typically reach early developmental milestones before rapidly losing cognitive skills, speech, and mobility. Early symptoms often include hyperactivity, erratic behaviour, and sleep disturbance.
In Australia an estimated 1400 children currently live with childhood dementia, with hundreds of thousands of cases worldwide.
Families managing the condition are the driving force behind the need for urgent research. Caring for a child with dementia is heartbreaking and relentless.
Twins Jobe and Tate were inseparable from birth, crawling, walking, and learning side by side. But at around 18 months, Jobe’s development began to slow, and just after their second birthday, Jobe was diagnosed with Sanfilippo syndrome.
Since then, Jobe’s mum, Tenille Koistinen says life has been a mix of love, loss, and constant adaptation. Now nine, Jobe can no longer count to five, write his name or draw a circle, and struggles to remember the names of family members. While Tate continues learning to read, spell and ride bikes, Jobe’s world is becoming increasingly confusing.
“It’s like grieving your child’s life in front of your eyes, before they’ve even started it,” Mrs Koistinen says.
“There’s not a day that goes by that you don’t wake up and think about this terrible disease and wish that there was a cure — not just for Jobe, but for the kids yet to be born.”
“One of the things that breaks our hearts the most is knowing that it’s not just us grieving for Jobe, but also his twin and best friend.”
Tenille says she’s desperate for progress, access to clinical trials, and a future where no family must face such immense pain.
It’s stories like these that inspire lead researcher Professor Cedric Bardy, who heads the Laboratory for Human Neurophysiology and Genetics at the South Australian Health and Medical Research Institute (SAHMRI) and Flinders University, to solve this incredibly complex problem.
Professor Bardy says the findings of this latest study represent significant progress, having identified that chronic overactivity in the brain appears to be a fundamental mechanism contributing to cognitive deterioration in children with Sanfilippo syndrome.
Using human stem cell-derived cortical neurons and advanced electrophysiological and molecular methods, the team demonstrated for the first time that excitatory synapses in affected children’s neurons become abnormally active during early brain development and get stuck in overdrive.
"What we see in these children’s neurons is an escalation of excitatory activity that overwhelms the brain’s natural balance," says Professor Bardy.
In this study the researchers observed that although these neurons appeared to develop and function well initially, over time they became increasingly overactive. As the brain cell networks matured, they showed bursts of intense, highly synchronised electrical activity, mirroring the hyperactivity and neurological symptoms seen in children with the condition.
"This hyperactivity offers a clear biological explanation for early behavioural changes, and it brings us closer to understanding the complex mechanisms contributing to childhood dementia."
The team also found that these neurons are especially vulnerable to stress. When exposed to mild nutrient deprivation, excitatory synaptic abnormalities intensified, suggesting that common illnesses or physiological stressors may accelerate neurological decline.
"Our research shows that disrupted synaptic communication is not simply a byproduct of degeneration. It is an early driver of the disease," Professor Bardy says.
Childhood Dementia Initiative CEO and founder, Megan Maack, who leads world-first action and awareness for all children with dementia, has been involved in guiding the project since its inception.
“This research is significant not just for Sanfilippo syndrome, but for the field of childhood dementia as a whole,” Ms Maack says.
“By identifying the precise cellular mechanisms driving the disease, we are moving towards a personalised medicine approach — the kind of targeted treatment strategy that has transformed outcomes for children with cancer. Children with dementia urgently need progress of this kind."
Researchers are now screening drugs that are already on the market for use in other conditions, which could potentially be repurposed for childhood dementia.
"Encouragingly, we’ve already demonstrated that these synaptic imbalances can be corrected with the use of certain medications in the laboratory, which means they represent a genuine therapeutic target,” adds Professor Bardy.
"We now have a new preclinical tool to screen therapeutics that may help manage difficult symptoms in these children and potential slow or stop the progression of this deadly disease.”
“There is a lot more to do to help these kids, but this collaborative effort really put us on the right track.”
This research was an made possible through an outstanding combined international effort featuring children and families affected by this disease, paediatric neurologists and scientists, including Dr Nick Smith, Professor Kim Hemsley, Professor Mark Hutchinson and more.
The article, Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks (2026) by Paris Mazzachi, Ella McDonald, Dr Zarina Greenberg, Alejandra Noreña Puerta, Dr Jenne Tran, Dr Manam Inushi De Silva, Cade Christensen, Robert Adams, Sebastian Loskarn, Dr Helen Beard, Michael Zabolocki, Meera Elmasri, Megan Maack, Dr Kristina L Elvidge, Prof Mark R. Hutchinson, Cara O’Neill, Prof Kim M Hemsley, Lisa Melton, Dr Nicholas Smith and Prof Cedric Bardy has been published in Nature Communications , DOI: 10.1038/s41467-026-71112-9
Collaborating organisations included SAHMRI, Flinders University, Adelaide University, the Women’s and Children’s Health Network, the Childhood Dementia Initiative, Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation, supported by the Medical Research Future Fund (MRFF).
Nature Communications
Experimental study
Cells
Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks
7-Apr-2026