BOSTON Hydrocephalus, or water on the brain, occurs when the cerebral ventriclesfour interconnected cavities of the brain that are filled with cerebrospinal fluidbecome enlarged, but its cause is unknown in many cases. A better understanding could lead to improved treatments for hydrocephalus, which is the leading reason for brain surgery in children and is associated with neurodevelopmental disability. To provide insights, a team led by investigators at Massachusetts General Hospital (MGH) and Yale University analyzed variations in genetic sequences and gene expression patterns in the brains of patients with congenital hydrocephalus. The research, which is published in Nature Neuroscience, indicates that hydrocephalus does not result from a defect of cerebrospinal fluid plumbing but rather arises because primitive cells in the brain do not behave properly during development.
In patients with hydrocephalus, continued accumulation of fluid dilates the cerebral ventricles, increases pressure in the skull, and compresses the surrounding brain structure. This compression can cause acute symptoms such as vomiting and headache, and even coma or even death. In the long-term, brain compression can lead to neurocognitive issues and neurodevelopmental disabilities in children, even when a medical device called a shunt is surgically placed in the brain.
Neurosurgical shunting of cerebrospinal fluid addresses some consequences of the disease but does not target the underlying mechanisms, says senior author Kristopher T. Kahle, MD, PhD, director of Pediatric Neurosurgery at MGH and director of the Harvard Center for Hydrocephalus and Neurodevelopmental. Knowing the molecular cause of disease could be very helpful towards clinical decision making.
To provide insights, Kahle and his colleagues genetically sequenced cells from 483 children with hydrocephalus and their unaffected parents, using a profiling technology that uncovers gene mutations in patients across the entire genome. By combining the genetic sequence data with gene expression data, the team found that many hydrocephalus-associated genes converge not in fluid circulation components but instead in neuroepithelial cells, which are the earliest stem cells of the brain that arise during the first several weeks of development. These cells go on to generate all of the neurons and support cells of the brain.
This began to hint to us that rather than affecting fluid circulation, hydrocephalus gene mutations may be disrupting the earliest processes of human brain development to cause hydrocephalus, says colead author Phan Q. Duy, an MD/PhD student at Yale University School of Medicine.
The most frequently mutated gene in the studys patientscalled TRIM71codes for a protein that is part of a pathway that regulates the timing of stem cell development. When the investigators bred mice to express TRIM71mutations, the mice developed fetal-onset hydrocephalus similar to human patients. Mechanistically, stem cells in the brains of the Trim71-mutated mice prematurely generated neurons, leading to a deficient pool of stem cells to support brain growth and development. This caused deficient expansion of brain tissue and underdevelopment of the cerebral cortex.
The scientists note that the resulting altered structure of the brain is not capable of holding the pressure exerted by cerebrospinal fluid, and thus the brain deforms and its ventricles passively expand. The site of pathology is therefore not happening in the fluid itself, but rather the vesselor the brain tissuethats holding the fluid, says Duy.
The findings suggest that treatment strategies for hydrocephalus should go beyond draining fluid in the brain. A more nuanced treatment approach may include not only cerebrospinal fluid diversion but also other approaches more tailored towards improving neurodevelopmental function, says Kahle. In the long-term, with continued gene discovery and better understanding of how other gene mutations disrupt brain development to cause hydrocephalus, we may be able to develop drug treatments or even gene therapy to correct the gene mutations months before the birth of patients.
Beyond providing a better understanding hydrocephalus, this work may offer additional insights into other pediatric brain disorders. In fact, ventricular dilation is a common feature in developmental neuropsychiatric diseases such as autism and schizophrenia, and many of the processes involved with hydrocephalus may also be relevant for other structural brain malformations.
This work was supported by the National Institutes of Health, Rudi Schulte Institute, and the Hydrocephalus Association.
About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Instituteconducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in theU.S. News & World Reportlist of "Americas Best Hospitals." MGH is a founding member of the Mass General Brigham health care system.
Nature Neuroscience
Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus
4-Apr-2022
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Genetic analysis provides insights into the cause of hydrocephalus, or water on the brain - EurekAlert
