Research: Molecular Genetics of Familial Laryngeal Paralysis

Our laboratory performs research on the molecular genetics of laryngeal paralysis, which is currently supported by a five-year NIDCD grant. Laryngeal paralysis is a frequent cause of congenital stridor and airway obstruction. Persistent hoarseness, dysphagia and recurrent pneumonias are complications that may develop because of laryngeal immobility. Significant airway obstruction is a potentially life-threatening condition, often requiring a tracheostomy to provide adequate airway support. Laryngeal paralysis can be further differentiated according to whether the primary defect is in laryngeal abduction (glottic opening) or laryngeal adduction (glottic closure). Some common causes of laryngeal paralysis are birth trauma, neurologic abnormalities and iatrogenic injury, but the majority of described cases have an unknown cause. Recently, families with different forms of hereditary laryngeal paralysis have been described. These families provide an opportunity for understanding the genetic basis and mechanisms underlying laryngeal paralysis.

To briefly summarize the known syndromes of laryngeal dysfunction, Plott syndrome is an X-linked recessive form of congenital laryngeal abductor paralysis associated with mental retardation. In contrast, Gerhardt syndrome exhibits autosomal dominant or X-linked inheritance without associated mental retardation, although subtle central neurologic abnormalities can be demonstrated in some kindreds. Other neurologic syndromes, such as Charcot-Marie-Tooth Disease type IIC, feature laryngeal paralysis in addition to diaphragmatic and extremity weakness.

Previous studies of familial laryngeal paralysis have concluded that the most likely anatomic site affected is the nucleus ambiguous, because the neurons for the larynx reside in this area. Genetic abnormalities that affect the development of this central nucleus may also affect other portions of the brain and brainstem that develop concurrently. However, vocal fold paralysis can result from any aberration on the path from motor neuron to laryngeal musculature. Therefore other possibilities, such as neuropathies or myopathies, should also be considered as theoretical disease mechanisms.

The question of affectation status for this disease is complex in nature; no objective measurements like audiograms or biochemical assays exist to conclusively confirm the presence or absence of vocal fold movement. The determination of vocal fold paralysis is primarily subjective, and depends on the experience and skill of the physician examining the patient. Studies on laryngeal EMG and congenital vocal fold paralysis have been performed with the hopes of objectively diagnosing vocal fold paralysis with conflicting results. Although laryngeal EMG has a great deal of potential as an objective tool, its role has not been clearly established in the management of congenital vocal fold paralysis.

Our study of the molecular genetics of familial laryngeal paralysis is focused on the identification of genetic mutations that may be responsible for this disorder. This will shed light on the genetic pathways that not only underlie this particular disease, but are also crucial for normal laryngeal innervation and development. Genetic linkage analysis led to the localization of one form of familial laryngeal paralysis to chromosome 6q16-21. This finding constituted the first report of a genetic locus for any form of laryngeal disease or dysfunction. Our current research is now focused on candidate gene screening in this region by direct DNA sequencing to ultimately identify the mutation responsible for this disorder. We have identified other families with similar hereditary laryngeal paralysis syndromes, and we are using similar methods to analyze these families.