80 - Genetics and Physiology of Surfactant Protein Deficiencies

Abstract

Genetic surfactant dysfunction disorders are rare but are associated with significant morbidity and mortality. Surfactant protein B (SP-B) deficiency is an extremely rare but almost invariably fatal cause of neonatal respiratory failure in term infants and demonstrates an essential role for SP-B in normal lung metabolism. ABCA3 deficiency is likely the most common surfactant dysfunction disorder and may result in a clinical picture similar to that of SP-B deficiency or may result in interstitial lung disease presenting later in life; the specific ABCA3 variants may be helpful in predicting prognosis. SP-B deficiency and ABCA3 deficiency are autosomal recessive disorders with disease resulting from loss-of-function variants that result in a lack of functional protein. Variants in the gene encoding SP-C are associated with lung disease of variable severity and age of onset that may be sporadic or inherited in an autosomal dominant pattern. Lung disease due to pathogenic variants in SFTPC results from a gain of toxic function resulting in misfolded protein that is unstable, aggregates in the secretory pathway, or is abnormally routed in alveolar epithelial type II cells. Deletions of or pathogenic variants in NKX2-1 may result in lung disease of variable onset, severity, and nature, and are frequently associated with neurologic findings and/or hypothyroidism. The pathophysiology of the lung diseases due to these disorders remains incompletely understood. Environmental and genetic factors that modify the course of these diseases need to be identified, and more effective treatments need to be developed. Development of new model systems to study surfactant dysfunction disorders and gene editing offer promise to treat and perhaps even correct these devastating disorders.