Original ArticleFatal Familial Lung Disease Caused by ABCA3 Deficiency without Identified ABCA3 Mutations
Section snippets
Case Histories
Two female siblings died >10 years apart from severe neonatal respiratory failure with similar presentations and courses. Both parents are of Asian descent, and no history of consanguinity was reported. Figure 1 illustrates the 2-generation pedigree for this family. The first affected child (II.1) was born at term via vaginal delivery with a birth weight of 2850 g to a healthy mother. No meconium was noted at birth. Respiratory distress and hypoxemia were noted later, on day-of-life (DOL) 1.
Methods
All members of the family described here were enrolled in an institutional review board-approved protocol focused on identifying genetic causes of lung disease in children. The parents provided informed, written consent for their own participation and that of their children.
Results
With H&E staining and light microscopy of lung tissue samples from both affected infants, proteinaceous material filling the alveolar airspaces was shown. Absent staining for ABCA3 protein was demonstrated with immunohistochemical staining. ABCA3 was easily detected in a non-diseased, human, pediatric, control lung at 1:500 without the use of antigen retrieval (data not shown). Normal staining was seen for proSP-B (not shown), proSP-C, and mature SP-B (Figure 3). Examination with EM of alveolar
Discussion
The clinical picture with the lung histopathology, immunohistochemistry, and EM findings suggest that surfactant dysfunction was the cause of fatal lung disease in these 2 infants from the same family. However, no mutations in the 3 genes known to cause surfactant dysfunction (ABCA3, SFTPB, or SFTPC) were identified. The immunostaining patterns and finding that the affected infants were discordant for their SFTPB alleles further exclude SP-B deficiency as the basis for their lung disease. The
References (33)
- et al.
Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3
J Biol Chem
(2002) - et al.
ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells
FEBS Lett
(2001) - et al.
Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles
Biochem Biophys Res Commun
(2004) - et al.
ABCA3 as a lipid transporter in pulmonary surfactant biogenesis
J Biol Chem
(2007) - et al.
Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation
Mod Pathol
(2007) - et al.
ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn
J Pediatr
(2007) - et al.
ABCA3 mutation and pulmonary hypertension: a link with alveolar capillary dysplasia?
J Pediatr
(2008) - et al.
Usual interstitial pneumonia in an adolescent with ABCA3 mutations
Chest
(2008) - et al.
A common mutation in the surfactant protein C gene associated with lung disease
J Pediatr
(2005) - et al.
Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease
Chest
(2005)
Expression of ABCA3 in developing lung and other tissues
J Histochem Cytochem
ABCA3 gene mutations in newborns with fatal surfactant deficiency
N Engl J Med
Surfactant composition and function in patients with ABCA3 mutations
Pediatr Res
ABCA3 mutations associated with pediatric interstitial lung disease
Am J Respir Crit Care Med
Ultrastructure of lamellar bodies in congenital surfactant deficiency
Ultrastruct Pathol
Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency
Am J Respir Crit Care Med
Cited by (25)
Genetics and Physiology of Surfactant Protein Deficiencies
2017, Fetal and Neonatal Physiology, 2-Volume SetNovel ABCA3 mutations as a cause of respiratory distress in a term newborn
2014, GeneCitation Excerpt :Genetic testing for mutations in ABCA3 may obviate the need for lung biopsy in some patients. Approximately 150 mutations in ABCA3 have been reported to date (Gower et al., 2010; Park et al., 2010; Shulenin et al., 2004; Whitsett et al., 2010). In this report, we present a newborn that developed immediate respiratory distress and was discovered to be a compound heterozygote for two novel ABCA3 gene mutations.
Surfactant dysfunction
2011, Paediatric Respiratory ReviewsCitation Excerpt :In a child whose condition is rapidly deteriorating this may be inadequate. The sensitivity of this mode of testing is not known, but is not 100%.55 Mutations outside of translated regions that affect gene expression will not be detected and complete or partial gene deletions, duplications or rearrangements will not be detected by current PCR based approaches unless specific methods to detect such variants are employed.
Surfactant protein disorders in childhood interstitial lung disease
2021, European Journal of PediatricsGenetic disorders of surfactant proteins
2021, Pediatriya - Zhurnal im G.N. Speranskogo
Supported by The Hartwell Foundation and Arricale Family Foundation (W.G.), The Eudowood Foundation and National Institutes of Health HL54703 (L.N.), and National Institutes of Health HL085610 (J.W., S.W.). None of the funding entities were involved in the study design or the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit for publication. The authors declare no conflicts of interest.