Surfactant metabolism dysfunction

Surfactant metabolism dysfunction describes a group of dysfunctions caused by different mutations in surfactant related genes. Severe deficiency of pulmonary surfactant due to disturbed metabolism of any of these proteins can lead to some form of interstitial lung disease in newborns and adults. These conditions share similar pathophysiology and overlapping phenotypes because surfactant gene products interactively communicate and control one another. Pathology manifestation in full-term infant resembles characteristics of newborn with Respiratory Distress Syndrome. Imaging of epithelial type II cells with SP-B deficiency shows immature lamellar bodies without tightly packed membranes, but rather with loose and unorganized membranes. The ratio of phospholipid-protein also decreases with abnormal phospholipids. In addition, surfactant collected from SP-B deficiency epithelial type II cells is not as effective in lowering surface tension and creating film as normal surfactant. The mutations result in a loss of or reduced function of the ABCA3 protein, and are inherited in an autosomal recessive manner . There are more than 150 different mutations throughout ABCA3 gene with various allelic heterogeneity, making it the biggest class of genetic cause of surfactant dysfunction. Like SP-B deficiency, ABCA3 mutations are inherited in autosomal recessive trait. Mutations of ABCA3 consist of missense, nonsense, frameshift, splice-cite, insertion or deletion. These mutations are classified into two types of ABCA3 mutations, those that preclude normal trafficking of ABCA3 from ER to lamellar membrane, and those that affect ATP-binding ability of ABCA3 needed for phospholipid transportation. Due to its roles in lamellar body biogenesis and maturation of surfactant proteins, epithelial type II cells with altered ABCA3 exhibit premature lamellar bodies and damaged maturation of SP-B/SP-C. Surfactant samples from patients with ABCA3 deficiency do not lower surface tension as effectively. Affected surface tension ability results from incomplete formation of lamellar bodies, due to lack of lipid influx by ABCA3. Immunostaining of SP-B in ABCA3 patients show decreased level of mature SP-B and impaired process of proSP-B to SP-B, thus, confirming why ABCA3 dysfunction leads to severe surfactant metabolism dysfunction. ==Diagnosis==

Types Non-invasive genetic testing can be used to infer possible interstitial lung disorders caused by surfactant metabolism dysfunction. Although these sequencing tests can take up to several weeks, which may not be so useful in case of acute respiratory problems in newborns. Overlapping phenotypes of surfactant metabolism dysfunction and other interstitial lung diseases make it hard to propose definitive diagnosis for surfactant disorders. Overall testings, family history, external factors, and clinical presentations should all be considered to diagnose surfactant metabolism dysfunction. Testing for surfactant metabolism dysfunction should be considered for newborns with diffuse lung disease or hypoxemia, especially in families with history of neonatal lung diseases or ILD in adults. Neonatal and adult onset lung diseases with unfound causes should also be tested early for surfactant dysfunction. ABCA3 and SP-B dysfunctions manifest in newborns and progress aggressively within the first few months of life, thus, testing for ABCA3 and SP-B disorders should preclude those for SP-C, especially when infants are showing symptoms of ILD or diffuse lung disease. Distinctions between SP-B and ABCA3 are ABCA3 tends to occur in families with neonatal lung disease history, and SP-B testing almost unneeded in older children. Late on-set conditions with inheritance in dominant fashion should infer SP-C dysfunction. Antibodies against proSP-B, proSP-C, SP-B, SP-C, and ABCA3 have been thoroughly developed, which makes detection for these proteins highly accessible and accurate. Immuno staining of each of these types of surfactant dysfunction differs in absence and presence of specific proteins and propeptides, thus immunohistochemisty can help decipher which type of deficiency is being dealt with. In addition, hypothyroidism can cause damaged production of NKX2.1 proteins, which can lead to insufficient transcription of multiple surfactant proteins. ==Treatment==

Neonates with surfactant metabolism dysfunctions, especially those with SP-B disorder, only have lung transplantation as one possible choice of treatment. Children with lung transplant due to surfactant metabolism dysfunction perform on similar level to those with transplant for due to other reasons. Some less severe cases of ABCA3 dysfunctions manifest in late childhood or adult hood are due to missense mutations that result in semi-sufficient levels of active surfactant, while SP-C clinical presentation varies greatly depending on level of penetration of the mutated alleles. ==See also==