Pediatric News

Hydrocephalus is a potentially life-threatening neurological condition characterized by abnormal accumulation of cerebrospinal fluid (CSF) within the ventricular system, resulting in increased intracranial pressure and progressive brain injury. Congenital hydrocephalus occurs in approximately 1 per 1,000 live births and represents a major cause of long-term neurodevelopmental morbidity in children.¹ Disruption of CSF circulation or absorption underlies the condition, and nearly 40% of cases are attributed to single-gene mutations affecting CSF homeostasis.²

The current standard of care for hydrocephalus relies predominantly on surgical diversion of CSF, most commonly through ventriculoperitoneal shunt placement. Although effective in relieving pressure, shunt surgery is invasive and associated with significant complications, including infection, obstruction, and the need for repeated revisions throughout life.³ These limitations underscore the need for disease-modifying, non-surgical therapeutic strategies.

A recent preclinical study published in Molecular Therapy explored the feasibility of preventing hydrocephalus at the molecular level using RNA-based therapy.⁴ The investigators focused on Schinzel-Giedion syndrome, a rare neurodevelopmental disorder caused by gain-of-function mutations in the SETBP1 gene. These mutations lead to excess protein expression, impaired CSF regulation, and a high incidence of hydrocephalus.⁵

Using a genetically engineered mouse model, the researchers administered an antisense oligonucleotide designed to suppress the pathological effects of the SETBP1 mutation. Treatment resulted in a substantial reduction in the incidence of hydrocephalus, with affected offspring decreasing from approximately 75% in untreated controls to 25% in the treated group.⁴ This finding demonstrates that targeted RNA therapy can significantly alter disease trajectory when applied early.

Although Schinzel-Giedion syndrome is exceedingly rare, this study provides proof of concept that RNA-based therapeutics may prevent genetically driven hydrocephalus. Such an approach has the potential to reduce dependence on lifelong surgical management and opens new avenues for precision medicine in paediatric neurology.⁶

References:

1. Schrander-Stumpel C, Fryns JP. Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling. Eur J Pediatr. 1998;157(5):355–62.
   
   
2. Kahle KT, Kulkarni AV, Limbrick DD, Warf BC. Hydrocephalus in children. Lancet. 2016;387(10020):788–99.
   
   
3. Riva-Cambrin J, Kestle JRW. Complications of cerebrospinal fluid shunt surgery in children. Semin Pediatr Neurol. 2017;24(2):70–6.
   
   
4. Ernst C, et al. RNA-based therapy prevents hydrocephalus in a mouse model of Schinzel-Giedion syndrome. Mol Ther. 2026;34(2):XXX–XXX.
   
   
5. Hoischen A, et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet. 2010;42(6):483–5.
   
   
6. Bennett CF, Krainer AR, Cleveland DW. Antisense oligonucleotide therapies for neurodegenerative diseases. Annu Rev Neurosci. 2019;42:385–406.