ACD is a rare and lethal developmental anomaly of the pulmonary vasculature. It is generally described as the failure of formation of the normal air-blood diffusion barrier in the newborn lung. ACD is usually associated with misalignment or displacement of the pulmonary veins. The disease presents very early in infancy, usually after a few hours of normal breathing (""""""""honeymoon period""""""""). Infants become critically ill very rapidly in the first days of life with severe hypoxemia and pulmonary hypertension. There is no cure for ACD. The disease is uniformly lethal. Standard therapies include mechanical ventilation, high concentrations of inspired oxygen, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO) support. These therapies may prolong life by days to weeks, but they have led to no long-term survival. The purpose of this application is to map and clone the putative gene(s) responsible for ACD. We have established a close working relationship with the ACD Association, the only parent support organization, and have already collected 29 families, each with one or more infant with ACD in preparation for positional mapping and eventually cloning the ACD gene(s). Clinical records and pathological samples from affected individuals and DNA from affected and unaffected individuals were obtained. Our review of the pre- and postmortem records of affected individuals allows us to define better both the natural history of this condition and the associated anomalies with the ACD phenotype. Our collection of families corroborates the possible recessive nature of this condition and provides additional data for genetic and prenatal counseling. Analysis of the various associated anomalies allows us to formulate a hypothesis regarding possible candidate genes and/or signaling pathways. Finally, the material collected allows for positional mapping of the putative ACD gene as a first step towards understanding this condition. Support is requested to defray the costs of DNA preparation from peripheral blood samples and lung biopsies/autopsies, of positional mapping of the putative ACD gone(s), and of completing collection and analysis of the patient records. Cloning an ACD """"""""gene"""""""" has implications for counseling, for prenatal testing, and for understanding the molecular pathophysiology of ACD and other organ malformation that are associated with this condition.
| Sen, Partha; Thakur, Nivedita; Stockton, David W et al. (2004) Expanding the phenotype of alveolar capillary dysplasia (ACD). J Pediatr 145:646-51 |
