A New ABCA3 Gene Mutation c.3445G>A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome

Abstract

Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM: 601615) gene constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome (RDS) and interstitial lung disease (ILD) in children. Interstitial lung disease in children and especially in infants, in contrast to adults, is more likely to appear as a result of developmental deficits or is characterized by genetic aberrations of pulmonary surfactant homeostasis not responding to exogenous surfactant administration. The underlying ABCA3 gene mutations are commonly thought, regarding null mutations, to determine the clinical course of the disease while there exist mutation types, especially missense variants, whose effects on surfactant proteins are difficult to predict. In addition, clinical and radiological signs overlap with those of surfactant proteins B and C mutations making diagnosis challenging. We demonstrate a case of a one-term newborn male with lethal respiratory failure caused by homozygous missense ABCA3 gene mutation c.3445G>A (p.Asp1149Asn), which, to our knowledge, was not previously reported as a causative agent of newborn lethal RDS. Therapeutic strategies for patients with ABCA3 gene mutations are not sufficiently evidence-based. Therefore, the description of the clinical course and treatment of the disease in terms of a likely correlation between genotype and phenotype is crucial for the development of the optimal clinical approach for affected individuals.

Fatal Respiratory Failure in a Term Newborn Due to Non-previously Described Compound Heterozygous ABCA3 Mutations

“…Finally, a lung biopsy should be considered in these patients, as it can be of great value in establishing a diagnosis. 23,24 Lung tissue morphology shows suggestive findings such as alveolar septal thickening, alveolar type II cell hyperplasia, and alveolar proteinosis, but does not indicate specific gene defects. In contrast, electron microscopy showed small lamellar dense bodies in all patients in whom it was performed in 2 recent cohort studies.…”

Hydroxychloroquine, a successful treatment for lung disease in ABCA3 deficiency gene mutation: a case report

“…Therapeutic protocols with Hydroxychloroquine (HCQ), Corticosteroids and Macrolides in combination are suggested for patients with interstitial lung disease by SP-C deficiency and empirically used in patients with ABCB3 gene mutations [ 16 ].…”

“…Duration of therapy is not clear in literature and there were reported cases of cure with no recurrences after withdrawal of HCQ in surfactant dysfunction deficiency cases [ 7 , 16 , 21 ].…”

Whole exome sequencing identifies a novel variant in ABCA3 in an individual with fatal congenital surfactant protein deficiency

“…(https://www3.cmbi.umcn.nl/hope/ progress/5e9f34796f82a694596d3fa1/). Mitsiakos et al 9 reported a case with a missense variant located in exon 23 of the ABCA3 gene affecting intracellular interactions with total (surfactant) deficiency and fatal early onset. Our patients missense variant located in exon 24 resulted in the substitution of a neutral leucine residue for a non-polar hydrophobic proline residue at position 1226 (p.Leu1226Pro) which can affect intracellular interactions.…”