In this issue of Thorax, Doan et al1 report the clinical and pathological findings from nine paediatric patients with severe acute and chronic lung disease caused by mutations in the ATP-binding cassette A3 protein (ABCA3), a lamellar body-associated transport protein expressed selectively in type II epithelial cells in the alveoli (see page 366). Previous reports regarding the mutations in ABCA3 were derived primarily from the analysis of term infants presenting with severe respiratory failure in the neonatal period.2 3 In the study by Doan et al, five of nine infants had respiratory symptoms at birth but only one died during the neonatal period. The others presented with chronic respiratory signs and symptoms at 3 months to 4 years of age, indicating the marked variability in age and severity of presentation of this genetic disease. These infants generally fail to thrive. Clinical, radiographic and pulmonary function testing were consistent with diffuse alveolar disease. Hypoxaemia and pulmonary function studies indicated severe restrictive lung disease. Lung pathology was commonly termed endogenous lipid pneumonia, pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis. The variability seen in the clinical presentation and pathological findings are perhaps related to age and treatments, as well as to the mutations inherited by each of the infants. Only one of the infants has died from the disorder. Three have received lung transplants and the others have had severe but relatively stable interstitial lung disease, clearly distinguishing this group of patients with ABCA3 gene-related lung disease from newborn infants presenting with fatal respiratory distress following birth.

ABCA3-related lung disease, like those caused by mutations in surfactant protein B (SFTPB) and surfactant protein C (SFTPC), demonstrate the critical importance of alveolar type II cell homeostasis in the pathogenesis of alveolar and interstitial lung disease.2^–7 Each of these genes is expressed selectively in type II alveolar epithelial cells, the site of surfactant synthesis. Proteins encoded by each gene regulate distinct aspects of the surfactant system, and each mediates distinct intracellular and extracellular activities related to surfactant function and/or lipid homeostasis. Together, these genetic defects in the surfactant system provide strong support for the concept that disruption of alveolar epithelial cell function causes chronic cell injury or cell death resulting in disturbed surfactant protein and lipid homeostasis, thus providing a paradigm for understanding the pathogenesis of acute and chronic lung diseases that have previously been considered idiopathic. It will be of interest to identify new genes within the pathways regulating alveolar type II cell function and surfactant homeostasis as a cause of other genetic disorders. Likewise, these genes represent potential proteins whose functions and expression may be altered secondarily by other inflammatory processes leading to acute and chronic lung disease.

ABCA3 is expressed selectively—but not specifically—in type II epithelial cells in the lung where it is detected at high levels in limiting membranes of lamellar bodies. Marked disruption of the morphology of lamellar bodies was observed by ultrastructural studies of tissue from patients with ABCA3-related lung disease. Likewise, decreased surfactant lipid content and abnormal intracellular and extracellular structure of lung lipids were associated with the disorder, as described herein and previously, and all consistent with the proposed role of ABCA3 in lipid transport.1 2 8^–10 Numerous distinct mutations in ABCA3 (a large and complex gene/protein) have been identified and associated with severe lung disease. Since no common mutations have been identified to date, the genetic diagnosis of ABCA3 is relatively difficult to make with certainty unless known mutations are identified. The present report provides strong clinical, radiographic and pathological correlates of ABCA3 deficiency that should be helpful in considering the diagnosis of this disorder. A definitive diagnosis will be helpful in the clinical management, genetic counselling and prenatal diagnosis of ABCA3-related disease. The diversity of age and clinical presentation of the lung disease associated with mutations in the ABCA3 gene suggest that environmental factors and other inherited genes may strongly influence the disease.

The study of surfactant homeostasis has provided ongoing insights into the important role of surfactant proteins and lipids that are required for lung function after birth. ABCA3 joins a number of other genes—including solute carrier 34, a phosphate transporter recently associated with pulmonary microlithiasis,11 SFTPB and SFTPC6 7—as genes encoding proteins critical for type II alveolar cell function related to surfactant homeostasis. While these disorders are generally rare genetic causes of alveolar and interstitial lung disease, together they strongly support the critical role of type II alveolar epithelial cell homeostasis that provides the basis for the pathogenesis of lung diseases in neonates, infants and, more rarely, in older individuals. Together, advances in understanding the role of the surfactant system in the pathogenesis of acute and chronic lung disease has rendered the term “idiopathic” pulmonary fibrosis or idiopathic interstitial lung disease as obsolete for at least a few of these inherited disorders.