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

Georgios Mitsiakos,Paraskevi Karagianni,Dimitra Gialamprinou,Ioannis Tsanakas,Vasiliki Soubasi,Dimitra Gialamprinou,Paraskevi Karagianni,Christos Tsakalidis,Christos Tsakalidis,Ilias Chatziioannidis,Ilias Chatziioannidis,Vasiliki Soubasi,Ioannis Papoulidis,Ioannis Papoulidis

doi:10.3390/medicina55070389

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.

Highlights

Genetic disorders of surfactant metabolism underlie a group of rare diseases with a wide range of clinical manifestations from lethal respiratory distress syndrome (RDS) in term newborns to chronic interstitial lung disease (ILD) in children and adults [1,2]
According to international best practice, the detection of an identical adenosine triphosphate-binding cassette transporter A3 (ABCA3) bi-allelic gene mutation in another patient with lethal RDS and surfactant deficiency is required to confirm the correlation between the genotype and the relevant clinical syndrome
More than 200 ABCA3 mutations have been reported to date with around three-quarters of patients presented as compound heterozygotes [14]

Summary

Introduction

Genetic disorders of surfactant metabolism underlie a group of rare diseases with a wide range of clinical manifestations from lethal respiratory distress syndrome (RDS) in term newborns to chronic interstitial lung disease (ILD) in children and adults [1,2]. Mono-allelic mutations represent a partially impaired ABCA3 transporting function, which is usually presented with mild clinical course [8]. They might act as disease modifiers in lung diseases, such as RDS of prematurity or are associated with mutations in other surfactant-related genes [6,7,8,9,10,11]. We define our differential diagnostic approaches and the application outcomes of the therapeutic strategies

Case Report

Variance oxygenation early

Results

Discussion and Conclusions