People often talk about translating laboratory discoveries into patient care—but inspiration can flow in the reverse direction, as well. In 1992, an encounter with a toddler whose eyes were frozen in a downward gaze led pediatric neurologist Elizabeth Engle to a trove of previously unrecognized congenital disorders that rob patients of normal control of their eye movements. Exploring the clinical and genetic features of these disorders, Engle and her colleagues have defined a new category of syndromes resulting from errors in brainstem motor neuron development.
Engle had completed her training in pediatrics and neuropathology and was finishing her neurology residency when the toddler was admitted to Boston Children's Hospital. “He was born with a very odd fixed eye position, droopy eyelids that would barely open, and a backward head tilt,” recalled Engle. Ophthalmologists diagnosed the problem as congenital fibrosis of the extraocular muscles, a rare birth defect in which the muscles that pull the eyeball down were believed to be replaced by rigid scar tissue. But Engle, who loves neuroanatomy, genetics, and puzzles of all kinds, was not convinced.
Learning that the boy's extended family had 20 similarly affected members, she entered the Children's Hospital laboratories of Alan Beggs and HHMI investigator Louis Kunkel and began a systematic study, combining clinical and genetic analyses. The family notified her when an elderly relative of the patient died of other causes, and she had the opportunity to examine the eyeball and its surrounding muscles. Her research was spurred on by what she found.
The muscle that pulled the eye down was not a mass of scar tissue; it was simply contracted, keeping the eyeball pointed at the ground. In contrast, the muscles that pulled the eye upward were absent altogether, and so was the nerve connecting them to the brainstem. Muscle fibrosis was not the correct diagnosis after all. Instead, Engle had discovered a genetic disorder involving 1 of the 12 cranial nerves that sprout from the brainstem and control the eyes, face, throat, and other parts of the head. Of these, cranial nerves designated 3, 4, and 6 send signals to the six eyeball muscles.
Engle pored over journals looking for case reports and families with similar conditions, and contacted clinicians around the world. Over several years she located more than 700 families affected by this newly described disorder or others related to it. Using DNA linkage and mutation analysis, Engle identified the genetic causes for a series of these disorders, and found that each perturbed development of one or more cranial nerves. These syndromes are now termed congenital cranial dysinnervation disorders (CCDDs). Among them: Duane syndrome, horizontal gaze palsy, Moebius syndrome, and congenital ptosis.
Engle and her colleagues found that CCDDs result from mutations in genes that encode transcription factors crucial to cranial motor neuron development and in genes for proteins that help growing nerve axons connect to the appropriate targets. The mutation in the toddler's family, for example, scrambles the gene for a particular kinesin, a motor molecule that shuttles nutritional and structural cargo through nerve cells. When it is defective, the nerves are starved of critical resources and fail to develop normally.
Engle's group is using mutant mice to reveal the details of the breakdown. “My colleagues and I are excited by the light these studies may shed on the normal development and targeting of cranial motor neurons, and why these neurons seem particularly vulnerable to specific gene mutations,” she said. She added that their findings may also reveal general principles guiding the development of more complex circuitry within the brain.
The CCDDs uncovered by Engle and her colleagues are rare forms of strabismus—defects in the coordinated movement and fixation of the eyes, often called “crossed eyes” or “lazy eye.” Thousands of patients with strabismus are seen each year at Boston Children's Hospital, where Engle heads a laboratory designated by the National Eye Institute as a center for strabismus diagnostics. Common forms of strabismus result from a combination of genetic and environmental influences, and Engle has begun a large study to identify genetic factors for these disorders.
Engle has kept up with many of her early patients. The toddler whose family helped chart the course of her research career is now a teenager. He had corrective surgery that helped but did not cure his condition. When his cousin graduated from high school this year, Engle joined the family to celebrate. Engle says she hopes her research will one day have a direct impact on her patients' lives. “One of my ultimate goals as a clinician-scientist,” she said, “is to move our research back to the bedside by finding better treatments for these early defects in brainstem motor neuron development.”