A Novel Homozygous Mutation ABCA3gene: Presented as Sever Respiratory Distress Syndrome in a Term Neonate

Congenital surfactant deficiency is a rare condition diagnosed in newborns who present with respiratory distress at birth. We report a case of a term Omani neonate with fatal surfactant protein deficiency who was admitted to the Neonatal Intensive Care Unit (NICU)of the Royal Hospital with respiratory distress syndrome with persistent interstitial infiltrates on serial chest x-ray responsive to intermittent surfactant administration. He underwent a lung biopsy, and immunohistochemistry confirmed the diagnosis of congenital surfactant protein deficiency. However, despite aggressive treatment and supportive measures, his condition rapidly deteriorated, and he succumbed after two months of admission. This case report will highlight and review surfactant deficiency differential diagnoses, management, and complications.

Persistent Respiratory Distress in the Term Neonate: Genetic Surfactant Deficiency Diseases

: Respiratory distress is one of the most common clinical presentations in newborns requiring admission to a Neonatal Intensive Care Unit (NICU). Many of these infants develop respiratory distress secondary to surfactant deficiency, which causes an interstitial lung disease that can occur in both preterm and term infants. Pulmonary surfactant is a protein and lipid mixture made by type II alveolar cells, which reduces alveolar surface tension and prevents atelectasis. : The etiology of surfactant deficiency in preterm infants is pulmonary immaturity and inadequate production. Term infants may develop respiratory insufficiency secondary to inadequate surfactant, either from exposure to factors that delay surfactant synthesis (such as maternal diabetes) or from dysfunctional surfactant arising from a genetic mutation. : The genetics of surfactant deficiencies are very complex. Some mutations are lethal in the neonatal period, while others cause a wide range of illness severity from infancy to adulthood. Genes that have been implicated in surfactant deficiency include SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD (which encode for surfactant proteins A, B, C, and D, respectively); ABCA3 (crucial for surfactant packaging and secretion); and NKX2 (a transcription factor that regulates the expression of the surfactant proteins in lung tissue). : This article discusses the interplay between the genotypes and phenotypes of newborns with surfactant deficiency to assist clinicians in determining which patients warrant a genetic evaluation.

Surfactant Replacement Therapy for Respiratory Distress Syndrome in the Newborn: A Review

Respiratory failure secondary to surfactant deficiency is a major cause of morbidity and mortality in low birth weight premature infants. Surfactant therapy substantially reduces mortality and respiratory morbidity for this population. Exogenous surfactant therapy has become well established in newborn infants with respiratory distress. Many aspects of its use have been well evaluated in high-quality trials and systematic reviews. Secondary surfactant deficiency also contributes to acute respiratory morbidity in late-preterm and term neonates with meconium aspiration syndrome, pneumonia/ sepsis, and perhaps pulmonary hemorrhage; surfactant replacement may be beneficial for these infants. This article summarizes the evidence and gives recommendations for the use of surfactant therapy for respiratory distress syndrome (RDS) in newborn.Bangladesh J Child Health 2016; VOL 40 (1) :26-30

Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids

BackgroundThis study examines the biophysical and preclinical pulmonary activity of synthetic lung surfactants containing novel phospholipase-resistant phosphonolipids or synthetic glycerophospholipids combined with Super Mini-B (S-MB) DATK and/or SP-Css ion-lock 1 peptides that replicate the functional biophysics of surfactant proteins (SP)-B and SP-C. Phospholipase-resistant phosphonolipids used in synthetic surfactants are DEPN-8 and PG-1, molecular analogs of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), while glycerophospholipids used are active lipid components of native surfactant (DPPC:POPC:POPG 5:3:2 by weight). The objective of the work is to test whether these novel lipid/peptide synthetic surfactants have favorable preclinical activity (biophysical, pulmonary) for therapeutic use in reversing surfactant deficiency or dysfunction in lung disease or injury.MethodsSurface activity of synthetic lipid/peptide surfactants was assessedin vitroat 37 °C by measuring adsorption in a stirred subphase apparatus and dynamic surface tension lowering in pulsating and captive bubble surfactometers. Shear viscosity was measured as a function of shear rate on a Wells-Brookfield micro-viscometer.In vivopulmonary activity was determined by measuring lung function (arterial oxygenation, dynamic lung compliance) in ventilated rats and rabbits with surfactant deficiency/dysfunction induced by saline lavage to lower arterial PO2to <100 mmHg, consistent with clinical acute respiratory distress syndrome (ARDS).ResultsSynthetic surfactants containing 5:3:2 DPPC:POPC:POPG or 9:1 DEPN-8:PG-1 combined with 3% (by wt) of S-MB DATK, 3% SP-Css ion-lock 1, or 1.5% each of both peptides all adsorbed rapidly to low equilibrium surface tensions and also reduced surface tension to ≤1 mN/m under dynamic compression at 37 °C. However, dual-peptide surfactants containing 1.5% S-MB DATK + 1.5% SP-Css ion-lock 1 combined with 9:1 DEPN-8:PG-1 or 5:3:2 DPPC:POPC:POPG had the greatestin vivoactivity in improving arterial oxygenation and dynamic lung compliance in ventilated animals with ARDS. Saline dispersions of these dual-peptide synthetic surfactants were also found to have shear viscosities comparable to or below those of current animal-derived surfactant drugs, supporting their potential ease of deliverability by instillation in future clinical applications.DiscussionOur findings support the potential of dual-peptide synthetic lipid/peptide surfactants containing S-MB DATK + SP-Css ion-lock 1 for treating diseases of surfactant deficiency or dysfunction. Moreover, phospholipase-resistant dual-peptide surfactants containing DEPN-8/PG-1 may have particular applications in treating direct forms of ARDS where endogenous phospholipases are present in the lungs.

Activity and biophysical inhibition resistance of a novel synthetic lung surfactant containing Super-Mini-B DATK peptide

Background/objectives.This study examines the surface activity, resistance to biophysical inhibition, and pulmonary efficacy of a synthetic lung surfactant containing glycerophospholipids combined with Super Mini-B (S-MB) DATK, a novel and stable molecular mimic of lung surfactant protein (SP)-B. The objective of the work is to test whether S-MB DATK synthetic surfactant has favorable biophysical and physiological activity for future use in treating surfactant deficiency or dysfunction in lung disease or injury.Methods.The structure of S-MB DATK peptide was analyzed by homology modeling and by FTIR spectroscopy. Thein vitrosurface activity and inhibition resistance of synthetic S-MB DATK surfactant was assessed in the presence and absence of albumin, lysophosphatidylcholine (lyso-PC), and free fatty acids (palmitoleic and oleic acid). Adsorption and dynamic surface tension lowering were measured with a stirred subphase dish apparatus and a pulsating bubble surfactometer (20 cycles/min, 50% area compression, 37 °C).In vivopulmonary activity of S-MB DATK surfactant was measured in ventilated rabbits with surfactant deficiency/dysfunction induced by repeated lung lavages that resulted in arterial PO2values <100 mmHg.Results.S-MB DATK surfactant had very high surface activity in all assessments. The preparation adsorbed rapidly to surface pressures of 46–48 mN/m at 37 °C (low equilibrium surface tensions of 22–24 mN/m), and reduced surface tension to <1 mN/m under dynamic compression on the pulsating bubble surfactometer. S-MB DATK surfactant showed a significant ability to resist inhibition by serum albumin, C16:0 lyso-PC, and free fatty acids, but surfactant inhibition was mitigated by increasing surfactant concentration. S-MB DATK synthetic surfactant quickly improved arterial oxygenation and lung compliance after intratracheal instillation to ventilated rabbits with severe surfactant deficiency.Conclusions.S-MB DATK is an active mimic of native SP-B. Synthetic surfactants containing S-MB DATK (or related peptides) combined with lipids appear to have significant future potential for treating clinical states of surfactant deficiency or dysfunction, such as neonatal and acute respiratory distress syndromes.