Pulmonary Surfactant Metabolism Dysfunction: Congenital Alveolar Proteinosis - Respiratory insufficiency - Interstitial Lung Disease - Familial Pulmonary Fibrosis

Screening for surfactant associated gene mutations represents a major advance in the early and rapid diagnosis of several severe lung diseases like congenital alveolar proteinosis (CAP), respiratory distress syndrome (RDS), desquamative interstitial pneumonitis (DIP) and familial interstitial lung disease (ILS) in full term newborn and infants.

In the last two decades mutations in a number of genes have been found to be the cause of lung surfactant metabolism dysfunction ^1-5. Depending on clinical symptoms, ethnic background, age and laboratory findings, these genes can be screened for mutations to confirm or exclude the clinical diagnosis. Detection of surfactant-related gene mutations is relevant for family counseling and enables prenatal mutation screening.

SMDP1: Surfactant protein B deficiency  OMIM 265120

In SP-B-related surfactant deficiency, full term newborn develop fatal respiratory failure and pulmonary alveolar proteinosis. Patients can survive with ventilation for 1-2 months and are not or only transiently responsive to surfactant replacement therapy.

Affected children are homozygous or compound heterozygous for mutations in the SP-B gene SFTPB on chromosome 2p12-p11.2 leading to the absence of mature SP-B and incompletely processed proSP-C in the lung ⁴. SP-B deficiency has an incidence of 1 per million live births ⁶. The most frequent mutation is the 121ins2 mutation in exon 4 ¹.

The polymorphism Ile¹³¹Thr in exon 4 was proposed to be a risk factor for idiopathic pulmonary fibrosis⁷ and, associated with the SP-A-2 allele 6A² and SP-A1 allele 1A⁰, for neonatal RDS ⁸. Deletion variants in intron 4 have been associated with bronchopulmonary dysplasia (BPD) in premature infants ⁹.

SFTPB has 10 protein coding-exons. When suspecting SP-B deficiency, we amplify and sequence the most frequently mutated exons from the genomic DNA of the patient. We provide results of the mutation screening within 48 hours after receipt of the sample.
The remaining protein-coding exons and the regulatory region of SP-B as well as intron 4 deletion variants can also be analyzed.

SMDP2: Surfactant protein C deficiency OMIM610913

SP-C-related lung diseases have a variable clinical course and age of onset: from acute presentation at birth to the development of a chronic lung disease as infants or adults. Patients can develop progressive respiratory insufficiency, interstitial lung disease, alveolar proteinosis, interstitial pneumonitis or pulmonary fibrosis ^{3, 10, 11}.

SP-C-related disorders are inherited in an autosomal dominant mode. Sporadic de novo mutations account for approximately 55% of mutations ⁴. Patients are heterozygous for mutations in the SP-C gene SFTPC on chromosome 8p21 resulting in aberrantly processed proSP-C and the absence of mature SP-C. The most common mutation is the Ile⁷³Thr mutation in exon 3. Allelic polymorphisms in exon 4 and 5 were associated with the risk of RDS in premature newborn ¹².

Tiered mutation screening involves all 5 protein-coding exons and the regulatory region of the gene.

SMDP3: ABCA3 deficiency OMIM610921

Mutations in the ATP-binding cassette transporter A3 gene ABCA3  on chromosome 16p13.3 can either lead to progressive fatal lung disease in full term newborn or result in chronic respiratory insufficiency in infancy and childhood ^2,13,14.

Loss-of-function mutations have been found in such cases of fatal neonatal respiratory failure that could not be explained by mutations in SP-B or SP-C ².

Clinical signs are much like those in SP-B deficient patients, small dense lamellar bodies are characteristic of ABCA3 deficiency ^13,15. ABCA3 deficient patents generally do not survive the first three months of age.

Some patients survive the neonatal period and present with chronic respiratory insufficiency in infancy or childhood. ABCA3 mutations resulting in an impaired function rather than a complete loss of function have been detected in these patients. They can survive with or without lung transplantation¹⁵.

Mutations in ABCA3 are inherited in an autosomal recessive mode. Patients have homozygous or compound heterozygous mutations leading to ABCA3 deficiency or impairment which results in disturbance of surfactant phospholipids transport in the lung and surfactant homeostasis ¹⁶. The most common ABCA3 mutation in older children with chronic interstitial lung disease is the Glu²⁹²Val mutation in exon 9 ^14,17. E²⁹²V was also associated with the risk of RDS in newborns ¹⁸.

ABCA3 has 30 protein-coding exons. A tiered approach is offered for mutation screening: Exon 5, 14, 21, 23, 24, 30, 31, followed by a stepwise screening of the remaining 23 exons of the gene in case of neonatal respiratory failure. Exon 9 followed by stepwise screening of the remaining 29 coding exons of the gene in case of chronic lung disease in older patients.

  ¹⁾ Nogee et al. (1994) J. Clin. Invest. 93:1860-1863. A mutation in the surfactantprotein B gene responsible for fatal neonatal respiratory disease in multiple kindreds.

  ²⁾ Shulenin et al. (2004) N. Engl. J. Med 350: 1296-1303. ABCA3 mutations in newborns with fatal Surfactant deficiency.

  ³⁾ Nogee et al. (2001) N. Engl. J. Med. 344: 573-579. A mutation in the surfactant protein C gene associated familial interstitial lung disease.

  ⁴⁾ Hamvas et al. (2007) Neonatology 91:311-317 Genetic disorders of Surfactant proteins.

  ⁵⁾ Wert et al. (2009) Pediatr. Dev. Pathol. 12: 253-274 Genetic disorders of surfactant dysfunction.

  ⁶⁾ Cole et al. (2000) Pediatrics 105:538-541. Population-based estimates of surfactant protein B    

     deficiency.
   ⁷⁾ Selman et al. (2003) Hum. Genet. 113:542-550 Surfactant protein A and B genetic variants  predispose to idiopathic pulmonary fibrosis.

  ⁸⁾ Haataja et al. (2000) Hum. Mol. Genet. 9:2751-2760 Surfactant proteins A and B as interactive  genetic determinants of neonatal respiratory distress syndrome.

  ⁹⁾ Rova et al. (2004) Hum. Mol. Genet. 13:1095-1104 Data mining and multiparameter analysis of  lung surfactant protein genes in bronchopulmonary dysplasia.

 ¹⁰⁾ Tredano et al. (2004) Am. J. Med. Genet. 126A:18-26 Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease.

¹¹⁾ van Moorsel et al. (2010) Am. J. Respir. Crit. Care Med. 182:1419-1425 Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort.

¹²⁾ Lahti et al. (2004) Eur. J. Hum. Genet. 12:312-320 Surfactant protein C gene variation in the Finnish population - association with perinatal respiratory disease.

¹³⁾ Bullard et al. (2006) Semin. Perinatol. 30:327-334 ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease.

¹⁴⁾ Nogee, LM (2006) Curr. Opin. Pediatr. 18:287-292 Genetics of pediatric interstitial lung disease.

¹⁵⁾ Doan et al. (2008) Thorax 63:366-373 Clinical, radiological and pathological features of ABCA3 mutations in children.

¹⁶⁾ Brasch et al. (2006) Am. J. Respir. Crit. Care Med. 174:571-580 Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency.

¹⁷⁾ Bullard et al. (2005) Am. J. Respir. Crit. Care Med. 172:1026-1031 ABCA3 mutations associated with pediatric interstitial lung disease.

¹⁸⁾ Garmany et al. (2008) Pediatr. Res. 63:645-649 Population and disease-based prevalence of the common mutations associated with surfactant deficiency.