Human genetics and molecular mechanisms of pediatric neurosurgical disorders
Stained mice brains with Hydrocephalus
Kahle Lab, Yale University
About Our Research
The Kahle Lab conducts both human genetic and basic science research. Our research relies on the enthusiasm and generosity of the patients and families who volunteer to be a part of our work. Participants who contribute to our research gain knowledge about their own condition and enter a community of committed caregivers, passionate scientists, and other concerned parents. The overarching goal of our work is to translate basic science advances into better options for the diagnosis, management, and treatment of pediatric neurosurgical diseases and, in the process, train the next generation of neurosurgeon-scientists.
We are interested in the fundamental mechanisms directing human brain development that are relevant for pediatric neurosurgical diseases. These historically understudied conditions, treated with invasive and often morbid brain surgeries, include congenital hydrocephalus, Chiari malformation, cerebrovascular anomalies, and other structural brain malformations. By studying individuals and families affected with these conditions, and identifying the associated genes and their mutations, we can learn about the biological mechanisms that are important for development of the human brain, and identify potential therapeutic targets.
We necessarily employ a multidisciplinary approach that brings together neurosurgeons, neuroradiologists, pediatricians, neurologists, and basic scientists. We use human genetics (next-generation sequencing) coupled with the modeling of discovered mutations in systems such as mouse and fish. In these animals, we utilize physiology, cell biology, and biochemistry to study the pathogenic mechanisms and therapeutic vulnerabilities of specific patient mutations, including those of patients we treat in our own operating rooms.
Arachnoid cysts (ACs) are pouches of cerebrospinal fluid surrounded by a membrane of arachnoid cells and collagen. ACs are typically found on the surface of the brain or spinal cord, and constitute about 1% of intracranial masses. Though most cases begin during infancy, many patients are not diagnosed until much later in life.
An arteriovenous malformation (AVM) occurs when there is a direct connection from an artery to a vein rather than the normal connection of artery to capillary to vein, creating an abnormal connection with high blood speed and turbulent flow. An AVM can occur anywhere in the body. Approximately 1 in 100,000 people has an AVM within the brain or spinal cord. This abnormal connection and high-speed flow can lead to rupture and bleeding, which can be especially devastating in the tight confines of the skull. Half of all brain AVMs are found after they have ruptured as a hemorrhagic stroke.
Chiari Malformations (CM) describe a spectrum of structural variations of the cerebellum which can cause many symptoms that negatively impact quality of life. There are several different types of CM that may be associated with other disorders, such as but not limited to syringomyelia, myelomeningocele, hydrocephalus, and Ehlers Danlos. There is some evidence to suggest that the development of CM may be in part genetic, however, the genes that cause CM are currently unknown.
Congenital hydrocephalus, the expansion of the developing cerebrospinal fluid(CSF)-filled ventricles of the brain, affects 1 in 1,000 newborns and is empirically treated with morbid surgical CSF shunting. Although hydrocephalus remains a major cause of morbidity and mortality in children, its cellular and molecular etiology is largely unknown and treatment options are limited.
Vein of Galen Malformation
Vein of Galen Malformations (VOGMs) are a rare type of developmental brain arteriovenous malformation (AVM). Interestingly, true VOGMs are, in fact, abnormal connections to the median prosencephalic vein. This median prosencephalic vein is the embryonic precursor of the mature Vein of Galen, and thus a true VOGM does not affect the Vein of Galen proper. Although this is a semantic misconception that persists in modern medical literature today, the pathogenic mechanisms of VOGM are also ill-conceived. This disease can be lethal if untreated and often leads to developmental delays with other neurologic abnormalities.