ABCA3 deficiency is a rare inherited disorder that primarily affects the lungs, leading to severe breathing problems. The condition arises from mutations in the ABCA3 gene, which provides instructions for making the ABCA3 protein, an important transporter in the respiratory system. This protein is concentrated in the specialized cells lining the air sacs of the lungs. When the ABCA3 protein is defective or absent, it disrupts the lung’s ability to produce and manage the substance necessary for normal breathing. This malfunction results in a spectrum of pulmonary conditions, often appearing as life-threatening respiratory failure in newborns or as a progressive lung disease in older children and adults.
How ABCA3 Manages Lung Surfactant
The ABCA3 protein is located within the Type II alveolar cells, which are responsible for producing and secreting lung surfactant. Surfactant is a complex mixture of lipids, primarily phospholipids, and proteins that coats the inner surface of the alveoli, the tiny air sacs where gas exchange occurs. This coating lowers the surface tension at the air-liquid interface within the alveoli.
Lowering surface tension keeps the air sacs from collapsing entirely when a person exhales, making it easier to inflate the lungs with the next breath. The ABCA3 protein resides in the membrane of cellular structures called lamellar bodies, which are the storage and processing units for surfactant components. Within these bodies, ABCA3 acts as a transporter, moving specific lipids, like phosphatidylcholine, from the cell’s cytoplasm into the lamellar body.
This transport function is necessary for assembling a complete and functional surfactant mixture before it is released into the alveolar space. A malfunction in ABCA3 means that the lamellar bodies are often abnormally formed, and the surfactant they release is deficient in crucial lipids, particularly phosphatidylcholine. Consequently, the resulting poorly functioning surfactant fails to adequately reduce surface tension, leading to the collapse of the alveoli and severe difficulty breathing.
The ABCA3 Gene and Inheritance
The ABCA3 gene contains the genetic blueprint for the ABCA3 protein and is located on chromosome 16. ABCA3 deficiency is caused by mutations in this single gene. The condition typically follows an autosomal recessive inheritance pattern, meaning a person must inherit two copies of the defective ABCA3 gene, one from each parent, to develop the disease.
An individual who inherits only one mutated copy of the gene is considered an asymptomatic carrier and does not exhibit symptoms of the disorder. If both parents are carriers, there is a one-in-four chance with each pregnancy that their child will inherit two defective copies and be affected. More than 100 different mutations have been identified in the ABCA3 gene, ranging from missense mutations that result in a partially functional protein to mutations that lead to a complete loss of protein function.
The specific combination of mutations an individual inherits correlates with the severity and timing of the disease’s onset. Mutations that eliminate protein function often result in the most severe, neonatal form of the disease. Conversely, mutations that allow for some residual protein activity may lead to milder, later-onset symptoms.
Lung Diseases Caused by ABCA3 Malfunction
The failure of the ABCA3 protein to correctly process and transport lipids results in two primary clinical presentations depending on the severity of the mutation. The most severe manifestation is Neonatal Respiratory Distress Syndrome (RDS), which typically affects full-term infants shortly after birth. These newborns experience profound respiratory failure because their lungs lack sufficient functional surfactant to keep the air sacs open.
Affected infants often require immediate and intensive respiratory support, and the condition can be fatal without intervention. The lack of a properly assembled surfactant layer causes the tiny air sacs to stick together, making breathing extremely difficult.
The second, less acute presentation is Chronic Interstitial Lung Disease (ILD), which is seen in older children and sometimes adults. In chronic ILD, the malfunctioning surfactant causes inflammation, scarring, and progressive damage to the lung tissue. This progressive damage can lead to various histopathological patterns, including chronic pneumonitis of infancy or non-specific interstitial pneumonia. Symptoms may include a persistent cough, rapid breathing, and difficulty gaining weight, reflecting the gradual destruction and stiffening of the lung tissue.
Identifying and Managing ABCA3 Related Disorders
Genetic testing is the definitive method for diagnosing ABCA3 deficiency, involving the sequencing of the ABCA3 gene to identify two disease-causing mutations. Genetic analysis is non-invasive and provides a precise molecular diagnosis. Lung biopsy, which reveals the characteristic abnormal lamellar bodies, was historically used but is now reserved for cases where genetic testing is inconclusive.
Management for acute neonatal respiratory failure focuses on supportive care, including mechanical ventilation and supplemental oxygen to maintain adequate breathing. While artificial surfactant can be administered to newborns, it is often less effective than in typical RDS cases because the underlying machinery for utilizing it remains defective.
For chronic ILD, treatment often involves a combination of anti-inflammatory and immunomodulatory medications. Medical therapies may include oral or pulse-dose corticosteroids, azithromycin, and hydroxychloroquine, which aim to reduce inflammation and slow the progression of lung damage. In cases where the disease progresses despite medical management, lung transplantation remains the only life-saving option. The specific treatment approach is highly individualized, depending on the patient’s age and the severity of their specific gene mutations.