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Treatment of Congenital Hydrocephalus Should Optimize Brain Development

Key findings

  • Previous works have identified numerous gene mutations associated with congenital hydrocephalus (CH), and this study took a convergent neuroscience approach to define the mechanisms that link gene mutations to hydrocephalus
  • An integrative genomics analysis mapped 93 CH risk genes to human neural tube neuroepithelial cells that are the stem cells of all neurons and macroglia of the human brain
  • A humanized mouse model of hydrocephalus harboring a patient-specific missense mutation in TRIM71 clarified that genetically encoded dysregulation of neuroepithelial cell development is the primary pathology driving CH
  • The disruption in neural stem cells compromised the mechanical stability of the brain, leading to a passive accumulation of cerebrospinal fluid responsible for enlargement of the ventricles

The classical dogma about hydrocephalus is that ventricular expansion is attributable to the dysregulated flow of cerebrospinal fluid (CSF). Neurosurgical shunting to reduce CSF volume has long been the default treatment, but some patients have minimal benefit and others have substantial morbidity due to shunt infection or complications.

As a way to understand the disease better, previous studies investigated the genetics of patients with idiopathic congenital hydrocephalus (CH). The results suggested some cases might arise not from primary CSF overaccumulation but rather from aberrant neurodevelopment.

Now, researchers at Massachusetts General Hospital have uncovered mechanisms that link CH gene mutations to hydrocephalus. Kristopher T. Kahle, MD, PhD, a neurosurgeon in the Department of Neurosurgery and director of Pediatric Neurosurgery at Massachusetts General Hospital, Phan Q. Duy, MD, PhD, a research student in Dr. Kahle's laboratory, and colleagues report the details and their implications for treatment in Nature Neuroscience.

CH Genetic Risk and Neuroepithelial Cells

The researchers began by analyzing genetic data on 483 patients who underwent surgery for therapeutic CSF diversion and 578 of their family members. They identified 93 CH-associated risk genes.

Those genes were mapped to large-scale gene expression atlases of normally developing human brains. The CH risk genes were:

  • Involved in biological processes affecting brain development, such as synapse organization and neuron projection development
  • Unrelated to CSF circulation
  • Expressed across all prenatal cortical regions during post-conception weeks 8 to 24, a key period for fetal brain development
  • Highly expressed in neural tube neuroepithelial cells, stem cells that line the embryonic ventricles of the brain

Selecting a Prototype Gene

The research team focused the remainder of the study on just one of the CH risk genes, TRIM71, which helps regulate embryonic brain development. Of all 93 CH risk genes, TRIM71 was the one most specifically expressed in neuroepithelial cells and had the most de novo mutations.

Among the 483 patients studied, all TRIM71-mutant patients exhibited hydrocephalus at or soon after birth, and ventriculomegaly had been apparent in most of them on prenatal brain imaging.

Humanized Mouse Model

Using gene editing, the researchers created a humanized mouse model of hydrocephalus harboring a patient-specific missense mutation in TRIM71. The model clarified that genetically encoded dysregulation of neuroepithelial cell development is the primary pathology driving CH.

A secondary effect of the disruptions in neural stem cells was a compromise of parenchymal–CSF biomechanics. CSF normally generates a positive pressure in the ventricles that must be counteracted by the surrounding brain parenchyma. In the mouse model, underdevelopment of the cortex resulted in a "floppy brain" that couldn't resist the pressure exerted by CSF.

Thus, although there was no primary defect in CSF flow, the ventricles became dilated. Continued expansion of the parenchyma eventually compressed the midbrain, leading to secondary aqueductal stenosis that contributed to progressively worsening abnormalities in CSF circulation.

Future Directions

This study demonstrates that some forms of CH are part of the spectrum of neural tube defects. In fact, the researchers found genetic evidence of overlap between CH and other congenital brain malformations, including microcephaly.

Strategies for managing CH need to optimize brain development beyond the current approach of simply draining brain fluid:

  • Prenatal imaging may be useful for clinical decision-making
  • Even in patients who receive a molecular diagnosis of a primary neurogenic deficit, prospective monitoring of biomechanical markers (brain stiffness and viscoelasticity) may inform the timing and modality of surgical intervention
  • Behavioral interventions designed to improve cognitive and neurobehavioral function should start from the time of diagnosis
  • In the very long term, it might be possible to develop in utero personalized gene therapy or pharmacologic treatment to provide a definite cure

Learn about Pediatric Neurosurgery

Learn about research in the Department of Neurosurgery

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