Adenosine triphosphate-binding cassette member A3 gene mutation in children from one family from Saudi Arabia.

Mutation in ABCA3, which is adenosine triphosphate-binding cassette member A3, a member of protein transporter family for phospholipids into the lamellar bodies during synthesis of surfactant, can cause lung disease related to surfactant dysfunction with autosomal recessive pattern. We reported three cases from same family with ABCA3 mutation, their gene, clinical course, and outcomes mentioning that one patient had successful lung transplantation, one started the process of the lung transplantation while the third one died during infancy. We concluded that the patients with ABCA3 gene mutations are increasing in numbers may be due to the availability of the genetic testing and high index of suspicion among physicians. Lung transplantation is the definitive treatment, but availability is limited in our region.

The pulmonary surfactant is a phospholipid and protein complex synthesized, stored, and secreted by alveolar Type II cells which function traditionally to decrease alveolar surface tension to keep the lungs open. Adenosine triphosphate-binding cassette member A3 (ABCA3) is member of proteins transporter family that has an important role in transporting phospholipids into the lamellar bodies during synthesis of surfactants.

Mutations in ABCA3 can cause lung disease related to surfactant dysfunction with autosomal recessive inheritance pattern.[12] In one study, they mentioned that p.Y1515X mutation was found in five unrelated individuals.[1] Here, we will present three cases from one related family with ABCA3 mutation (p.Y1515X), with details about the clinical pictures and progression of their illness.

Case Reports

Case 1

This was a full term baby girl born with a birth weight of 2605 g and Apgar scores of 9 at 1 min and 10 at 5 min, respectively. She was admitted to the Neonatal Intensive Care Unit (NICU) with respiratory distress and remained there for 4 months during which she required mechanical ventilation for 2 months. Computerized tomography (CT) of her chest at 2 weeks of age showed nonspecific diffuse ground glass opacities bilaterally, with no other lesions were detected [Figure 1].

Figure 1

Computerized tomography chest showed diffused ground opacities in both sides

Genetic testing was done, and the result was homozygous nonsense mutation in exon 29 of the ABCA3 gene. This mutation is defined as C.4545delC. Genetic study also was done for the parents and shows that parents are carrier for the respective gene. Parents are first-degree cousins. Her family history revealed that her brother had respiratory symptoms since birth and died at age of 42 days. There was limited information about the deceased brother except that he had postmortem lung biopsy that was consistent with surfactant deficiency.

The patient was discharged home at age of 5 months on home oxygen. She had frequent admissions due to respiratory distress secondary to intercurrent illnesses and bronchiolitis. There was regular follow-up in pulmonary clinic, the last clinic seen when her age was 2 years and 6 months, her weight was 10.5 kg, and oxygen saturation was 96% on 4 L/min nasal cannula. She presented with increasing cough with exercise; her chest X-ray showed increase in haziness. The family had discussed the option of lung transplant and started the process, but they were lost to follow-up.

Case 2

This girl was a 7-month-old female child when admitted at our institution through the emergency department as a case of respiratory distress with tachypnea, hypoxemia, and severe failure to thrive that was not explained by the confirmed gastroesophageal reflux disease (GERD).

She is a cousin for Case 1 from paternal side. She was born at term by spontaneous vaginal delivery following uneventful pregnancy. Birth weight 3.2 kg. At the age of 5 h, the patient developed respiratory distress with tachypnea and cyanosis required oxygen therapy via nasal cannula. At 10 days of age, the patient was admitted to hospital where she remained hospitalized for 50 days and diagnosed as a case of severe GERD by upper gastrointestinal contrast study. She was initiated on anti-reflux therapy without significant improvement. She was investigated thoroughly including bronchoscopy and bronchioalveolar lavage, which was followed by stormy course, complicated by respiratory syncytial virus-positive bronchiolitis and required mechanical ventilation for 10 days.

CT scan chest showed evidence of ground glass obesities involving both lungs and airspace disease features involving bilateral lower lobe. No pleural effusion or gross interstitial abnormality [Figure 2].

Figure 2

Computerized tomography scan chest showed evidence of ground glass opacities involving both lungs

The genetic result was homozygous nonsense mutation in exon 29 of the ABCA3 gene. This mutation is defined as C.4545delC. The last visit before lung transplant was on 2011, patient age was 1 year and 1 month, weight 6 kg, and height 69 cm. Her oxygen saturation was 100% on 0.5 L/min, and she showed some improvement developmentally and 2.3 kg in the last 4 months. The patient was on nasogastric tube feeding. She had a successful lung transplant in the United States at age of 1 year and 6 months and after transplantation no more follow-up in our institution.

Case 3

A full term girl was a cousin for Case 1 from paternal side and both parents were related. She had a birth weight of 2760 g and Apgar scores were 7 at 1 min and 9 at 5 min, respectively. She was admitted to the NICU at 3 h of age because of respiratory distress with initial diagnosis of transient tachypnea of newborn, with progressive deterioration and required mechanical ventilation. CT scan of the lung was done and showed ground glass opacities seen throughout both lungs with lobular septal thickening suggestive interstitial lung disease as shown in [Figure 3].

Figure 3

Computerized tomography scan of the lung showed ground glass opacities in both lungs with lobular septal thickening

Genetic testing showed homozygous for nonsense mutation in exon 29 of the ABCA3 gene. This mutation is defined as C.4545delC. Trail of one cycle of pulse steroids was given for 3 days showed no improvement in the patient's clinical condition. She had moderate GERD based on pH study and started anti-reflux medications. She received several courses of antibiotics for sepsis. The patient died at age of 6 months in the NICU.

Discussion

The first description of lung disease caused by ABCA3 gene in full-term infants with death in early infancy was in 2004.[2] Since then over 150 different mutations have been reported, and there are different phenotypic presentations and disease severity in relation to different gene mutations. Initial clinical presentation can be severe starting during the 1st year of life similar to that of surfactant protein-B deficiency, or the presentation can be later in infancy and childhood.[1]

Due to autosomal recessive inheritance, the prevalence of the disease can be more in cultures with consanguineous marriages such as in our reported cases. Majority of reported cases of the same gene mutation were from unrelated families from middle east except for two siblings.[1] All our cases are relatives from the same Arabian family, first-degree consanguineous marriages which has never been reported previously. The reported rate of consanguineous marriage in Saudi Arabia is (57.7%), the most frequent is first cousin marriage (28.4%), followed by distant relative marriage (15.2%), and second cousin marriage (14.6%).[3] To our knowledge, this homozygous mutation has not been identified in related individuals in the literature before.

The severity of the disease and clinical picture in our cases were different; Case 3 died at age of 6 months of age and never been off the ventilator while Case 1 lived beyond age of 2 years and Case 2 had limited admissions before the lung transplant. Overall our cases were less severe than cases in the literature which were deaths within first 3 months of life.[1] The severity of this specific mutation, in general, is progressive and usually fatal, and the only available management is supportive management. Lung transplantation is the other treatment option for severe cases but however it is still unavailable in Saudi Arabia which explains Case 2 receiving lung transplantation in the United States. Lung transplant in Saudi Arabia is still in its infancy and only limited in adult and old children cases[456] and we might have to wait for some time before the availability of pediatric lung transplantation program in the country.

Conclusion

Patients with ABCA3 gene mutation are increasing in numbers, likely related to the availability of clinical genetic testing and high index of suspicion among the physicians. Genetic testing may obviate the need for lung biopsy for diagnosis specifically in related cases. Lung transplantation is the only definitive treatment, but availability is limited in our region.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.