Interstitial lung disease in two brothers with novel compound heterozygous ABCA3 mutations

Abstract

Mutations in genes critical for surfactant metabolism, including surfactant protein C (SP-C) and ABCA3, are well-recognized causes of interstitial lung disease. Recessive mutations in ABCA3 were first attributed to fatal respiratory failure in full-term neonates, but they are also increasingly being recognized as a cause of respiratory disorders with less severe phenotypes in older children and also adults. Here, we report a 20-month-old boy with interstitial lung disease caused by two distinct ABCA3 mutations. Initial treatment with methylprednisolone was unsuccessful, but the additional administration of hydroxychloroquine was effective. The family history revealed that the patient's older brother had died of idiopathic interstitial lung disease at 6 months of age, suggesting a genetic etiology of the disease. Sequence analyses of SP-C and ABCA3 genes were performed using DNA samples from the patient himself, his parents, and his brother. These analyses revealed novel compound heterozygous mutations in the coding exons of ABCA3 in both the patient and his brother: c.2741A > G, of paternal origin, and c.3715_3716insGGGGGG, of maternal origin. Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.

The biology of the ABCA3 lipid transporter in lung health and disease

“…Many of these mutations are clustered within the first and forth luminal loops as well as in the cytosolic domains, particularly within or adjacent to the second nucleotide-binding domain (NBD2). As previously stated, the presence of a combination of Type I (trafficking) and Type II (lipid pump) variants as compound heterozygous mutations appears to increase the disease severity in children as evidenced by the parents of these children having only one of the mutations and being asymptomatic without apparent respiratory disease (Kitazawa et al, 2013; Wambach et al, 2014; Flamein et al, 2012; Goncalves et al, 2014; Kitazawa and Kure, 2015). While ABCA3 -associated lung disease is believed to be inherited in an autosomal recessive manner requiring mutations on both alleles, monoallelic ABCA3 mutations in infants with surfactant deficiency and in children and adults with IPF/DPLD are also common (Shulenin et al, 2004; Agrawal et al, 2012; Peca et al, 2015; Wambach et al, 2012; Naderi et al, 2014).…”

Variants of the ABCA3 gene might contribute to susceptibility to interstitial lung diseases in the Chinese population

“…Recently, the ABCA3 mutations were also identified in young adults with ILD 28 and even in adults with IPF and emphysema 29 . However, there are no data showing whether the deficiency of ABCA3 is prevalent in ILD development in the Chinese population.…”

Interstitial Lung Disease in Childhood: Clinical and Genetic Aspects

“…In neonates and young children, the clinical course may not always allow live genetic testing on time; however, efforts should be made to gather samples maybe at autopsy, especially if a family history of sudden respiratory distress of siblings is present. 87 In such cases, ethical considerations should be taken into account for sample collection. More knowledge about genetic features causing ILDs is further required; but in order to complete it, the sharing of information will be important.…”