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ABCA3 deficiency
This condition primarily affects infants and young children, causing significant breathing difficulties due to impaired lung function. It is a severe lung disorder that requires specialised medical care to manage its respiratory effects.
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Overview
ABCA3 deficiency is a rare, inherited lung disorder that can cause severe breathing problems, particularly shortly after birth or in early childhood [PMID:33671846]. It is caused by genetic changes in the ABCA3 gene, which is essential for healthy lung function. The condition affects the production and function of pulmonary surfactant, a vital substance lining the air sacs (alveoli) in the lungs. Surfactant reduces surface tension, preventing these air sacs from collapsing and allowing for proper oxygen exchange. When surfactant is deficient or faulty, the lungs struggle to function effectively, leading to respiratory distress.
While often presenting in newborns with acute respiratory failure, ABCA3 deficiency can also manifest later in infancy or childhood with chronic lung disease [PMID:30138622]. The severity of the condition can vary, but it often leads to significant challenges for affected individuals and their families. Management typically focuses on respiratory support and symptom control.
Symptoms & clinical features
The symptoms of ABCA3 deficiency usually appear shortly after birth, within the first few hours or days of life. Newborns may experience severe respiratory distress, characterised by rapid breathing, grunting, flaring nostrils, and a bluish tinge to the skin (cyanosis) due to low oxygen levels [PMID:30138622]. These symptoms indicate difficulty in breathing and the lungs' inability to supply enough oxygen to the body.
In some cases, the condition may present later in infancy or childhood, leading to ongoing (chronic) lung disease. Symptoms can include persistent shortness of breath, wheezing, frequent lung infections, and a need for supplemental oxygen. Children with chronic ABCA3 deficiency may also experience failure to thrive, meaning they do not grow or gain weight as expected, due to the increased energy demands of breathing and poor oxygenation.
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Affected organs
ABCA3 deficiency primarily affects the lungs. Specifically, it impacts the alveolar type II cells within the lungs, which are responsible for producing and storing pulmonary surfactant [PMID:24076705]. These cells contain specialised structures called lamellar bodies, where ABCA3 protein is crucial for transporting components needed to make functional surfactant.
Risks & severity
ABCA3 deficiency can range in severity, from life-threatening respiratory failure in newborns to chronic lung disease in older children [PMID:33671846]. The most severe forms typically occur in infancy and can lead to acute respiratory distress syndrome, often requiring extensive medical support, including mechanical ventilation. The lifetime risks associated with ABCA3 deficiency are significant, particularly for those with early-onset severe disease. Prognosis depends heavily on the extent of lung damage and the response to supportive treatment.
Individuals who survive the neonatal period may develop chronic interstitial lung disease, where the tissue and space around the air sacs become inflamed and scarred, leading to ongoing breathing difficulties and a potential need for long-term respiratory support. The condition is rare, and its exact prevalence is not well established.
Genetic causes
ABCA3 deficiency is caused by pathogenic variants in the ABCA3 gene (ATP-binding cassette subfamily A member 3). This gene provides instructions for making a protein that acts as a transporter, moving phospholipids into specific compartments within lung cells. These compartments, called lamellar bodies, are where pulmonary surfactant is assembled and stored. Surfactant is a complex mixture of lipids and proteins that helps keep the tiny air sacs (alveoli) in the lungs open, preventing them from collapsing when we exhale.
When there are pathogenic changes in the ABCA3 gene, the ABCA3 protein may not be produced correctly, or it may not function properly. This disruption means that phospholipids cannot be efficiently transported into the lamellar bodies, impairing the production of healthy surfactant. As a result, the lungs lack sufficient functional surfactant, making it difficult for the air sacs to stay open, leading to breathing problems.
- ABCA3 ATP binding cassette subfamily A member 3The ABCA3 gene encodes a protein vital for lung surfactant production, which is crucial for normal breathing and preventing alveolar collapse.
Inheritance pattern
ABCA3 deficiency follows an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the ABCA3 gene - one from each parent - to develop the condition. If a person inherits only one altered copy of the ABCA3 gene, they are considered a carrier. Carriers typically do not show symptoms of the condition themselves but can pass the altered gene copy on to their children.
When both parents are carriers of a pathogenic ABCA3 variant, there is a 25% chance (1 in 4) with each pregnancy for their child to inherit two altered gene copies and develop ABCA3 deficiency. There is also a 50% chance (2 in 4) for the child to be a carrier like their parents, and a 25% chance (1 in 4) for the child to inherit two normal gene copies and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of ABCA3 deficiency often begins with clinical suspicion in newborns or infants presenting with unexplained severe respiratory distress or chronic lung disease. Imaging studies, such as chest X-rays or CT scans, may show characteristic abnormalities in the lungs. However, a definitive diagnosis is typically confirmed through genetic testing. Genetic testing for ABCA3 deficiency involves analysing the ABCA3 gene to identify pathogenic variants.
Referrals for genetic testing within the NHS Genomic Medicine Service (GMS) are usually made by paediatricians, respiratory specialists, or clinical geneticists, especially when clinical features strongly suggest an underlying genetic lung condition. The relevant NHS National Genomic Test Directory R-code for this condition is R283, "Paediatric interstitial lung disease". Genetic counselling is an integral part of the diagnostic process, providing families with information about the condition, inheritance patterns, and the implications of genetic test results.
Management & lifestyle
Management of ABCA3 deficiency is primarily supportive and aims to manage respiratory symptoms and complications. In newborns with severe respiratory failure, intensive care including mechanical ventilation, oxygen therapy, and sometimes extracorporeal membrane oxygenation (ECMO) may be necessary. There is no specific cure for ABCA3 deficiency, so treatment focuses on improving lung function and preventing further damage.
For ongoing lung disease, management may include supplemental oxygen, medications to reduce inflammation, and antibiotics to treat lung infections. Regular monitoring of lung function and overall health is crucial. Patients and their families are often supported by a multidisciplinary team, which may include paediatricians, respiratory specialists, clinical geneticists, and genetic counsellors, to help navigate the complexities of the condition and access appropriate care within the NHS. Genetic counsellors can also provide support and information regarding the implications of a genetic diagnosis for family planning.
UK care pathway
Within the UK, individuals suspected of having ABCA3 deficiency will typically be referred through the NHS Genomic Medicine Service. This pathway involves specialist clinicians, such as paediatric respiratory consultants or clinical geneticists, who can request appropriate genetic testing. Genetic tests are carried out according to the NHS National Genomic Test Directory, using specific R-codes like R283 for 'Paediatric interstitial lung disease', to confirm a diagnosis. Following diagnosis, individuals and their families will have access to genetic counselling services to discuss the condition, its inheritance, and implications for other family members.
Frequently asked questions
Is ABCA3 deficiency always severe?
The severity of ABCA3 deficiency can vary. While many infants experience severe, life-threatening respiratory failure shortly after birth, some individuals may have a less severe presentation, leading to chronic lung disease later in infancy or childhood. The specific genetic variant involved can influence the clinical picture.
Can ABCA3 deficiency be detected before birth?
Due to its autosomal recessive inheritance, if both parents are known carriers of ABCA3 variants, prenatal genetic testing can be considered during pregnancy. This involves analysing foetal DNA from amniocentesis or chorionic villus sampling to determine if the baby has inherited two altered copies of the gene.
What support is available for families affected by ABCA3 deficiency?
Families in the UK can access support through the NHS Genomic Medicine Service, including clinical geneticists and genetic counsellors who provide information and guidance. Support groups and charities focused on rare lung diseases or genetic conditions may also offer a community for sharing experiences and resources.
Are there any treatments that cure ABCA3 deficiency?
Currently, there is no cure for ABCA3 deficiency. Treatment focuses on supportive care to manage respiratory symptoms, improve lung function, and prevent complications. This may include oxygen therapy, mechanical ventilation, and medications to help with lung health.
How common is ABCA3 deficiency?
ABCA3 deficiency is considered a rare condition, meaning it affects a very small number of people. Exact prevalence figures are not widely established due to its rarity and often severe, early-onset nature.
References
- Wambach JA, Casey AM, Fishman MP. Genotype-phenotype correlations for infants and children with ABCA3 deficiency. American journal of respiratory and critical care medicine. 2014. PMID: 24871971
- Cooney AL, Wambach JA, Sinn PL. Gene Therapy Potential for Genetic Disorders of Surfactant Dysfunction. Frontiers in genome editing. 2021. PMID: 35098209
- Yang X, Forstner M, Rapp CK. ABCA3 Deficiency-Variant-Specific Response to Hydroxychloroquine. International journal of molecular sciences. 2023. PMID: 37175887
- Wambach JA, Nogee LM, Cole FS. First Steps toward Personalized Therapies for ABCA3 Deficiency. American journal of respiratory cell and molecular biology. 2022. PMID: 35077664
- Fleury M, Delestrain C, Hadchouel A. Phenotype-Genotype Correlations in ABCA3 Patients-The RespiRare Cohort. Pediatric pulmonology. 2025. PMID: 41090249
- Cooney AL, Lamer S, Yang P. Lentiviral-mediated gene complementation rescues pathogenic ABCA3 variants. bioRxiv : the preprint server for biology. 2025. PMID: 40909633
- Xu KK, Wegner DJ, Geurts LC. Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency. Pediatric pulmonology. 2022. PMID: 35170262
- Bullard JE, Wert SE, Nogee LM. ABCA3 deficiency: neonatal respiratory failure and interstitial lung disease. Seminars in perinatology. 2006. PMID: 17142158