Última actualización:
1/29/2026
Años publicados: 2026
NORD gratefully acknowledges Ali Karimi, MD Candidate, University of South Florida Morsani College of Medicine , Katiana Garagozlo, MD, Assistant Professor, University of South Florida Morsani College of Medicine and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for their assistance in the preparation of this report.
Summary
ABCA3-related pulmonary surfactant metabolism dysfunction, also called ABCA3 deficiency, is a rare genetic disorder. It affects a substance in the lungs called surfactant, which helps the lungs stay open during breathing. When surfactant does not work properly, it can lead to serious breathing problems (respiratory distress), especially in newborns.
Most people with ABCA3 deficiency develop symptoms shortly after birth. However, in some individuals, symptoms may be milder at first and go unnoticed for years. In these cases, lung problems may slowly worsen over time and become noticeable during childhood, adolescence, or even adulthood. When symptoms appear later in life, the condition may look like interstitial lung disease (ILD), a group of disorders that cause scarring and stiffness in the lungs. 1,2
In newborns, some of the characteristic signs and symptoms include fast breathing (tachypnea), difficulty breathing (respiratory distress), shortness of breath (dyspnea), bluish color of the skin or lips (cyanosis), widening of the nostrils during breathing (nasal flaring), pulling in of the skin between the ribs (intercostal retractions) during breathing, and grunting sounds soon after birth.
In older children, adolescents, and adults, the presenting symptom could be long-term (chronic) cough, frequent lung (pulmonary) infections, shortness of breath during physical activity (exertional dyspnea), increased nail curvature (clubbing of nails), and not growing as expected for age or difficulty gaining weight (failure to thrive).1-5
ABCA3 deficiency is caused by disease-causing changes (pathogenic variants) in the ABCA3 gene. This gene provides instructions for making the ABCA3 protein, which is active in special cells in the lungs called alveolar type II cells. These cells are responsible for producing lung (pulmonary) surfactant. Lung (pulmonary) surfactant is a mixture of fats (lipids) and proteins that coat the tiny air sacs in the lungs called alveoli. Its job is to keep the alveoli from collapsing when a person breathes out (expiration), allowing oxygen to move in and out of the lungs efficiently. 2, 3, 6
Variants in the ABCA3 gene can lead to deficiency or dysfunction of the ABCA3 protein. This disrupts the production and function of lung surfactant. As a result, the air sacs in the lungs (alveoli) can collapse or fail to work properly, making it difficult for oxygen to move into the bloodstream and carbon dioxide to be removed during breathing (gas exchange during the respiratory cycle).2, 3, 6
There are currently no approved or effective treatments available to correct the underlying cause of ABCA3 deficiency.7,8 For newborns, treatment is mostly to support breathing, provide adequate oxygen, and closely monitor for stability, usually in the intensive care unit.7
Some medications, such as steroids, azithromycin, or hydroxychloroquine (either alone or in combination) has led to improvement of symptoms in some, but not all people treated.6-8
In severe cases, a lung transplant may be the only long-term treatment option. However, lung transplantation carries serious risks and lifelong side effects. In addition, not all individuals are eligible for transplant due to several factors such as lack of a matching lung donor, lack of access to specialists and advanced medical facilities, high medical costs and financial considerations, etc.8-10
Introduction
The connection between ABCA3 gene variants and life-threatening (fatal) lung surfactant deficiency in newborns was first described by Shulenin et al. in 2004.11 In 2005, Bullard et al. expanded the association from just fatal lung disease in newborns to long-term chronic lung disease in older children.12 In 2014, Epaud et al. reported the first case of an ABCA3 gene variant in an adult with lung disease.13
The following signs and symptoms have been described in people with ABCA3 deficiency:
Symptoms of respiratory failure include:
Symptoms are most often noticed between birth and early childhood, but in some people, they may go unnoticed until adolescence or adulthood.1,2 Individuals with more severe symptoms are usually identified shortly after birth, whereas those with mild symptoms may go undiagnosed for many years and are only diagnosed after symptoms gradually progress to a noticeable level.7
Those with variants of both copies (alleles) of the ABCA3 gene (biallelic variants) are more likely to present with severe newborn breathing difficulty (neonatal respiratory failure). Many pass away or require lung transplantation within the first 3 or 4 months of life.8,14
The outlook for ABCA3 deficiency varies widely and depends on the age when symptoms begin and the specific genetic variants involved.
In general, people whose symptoms begin later in life (later symptoms onset) generally have better survival and are less likely to need long-term supplemental oxygen. Overall, about two-thirds of affected people do not survive beyond the first year of life. Among those with changes in both copies (biallelic variants) of the ABCA3 gene that result in no working ABCA3 protein (null variants), about 15% survive past the first year.
Studies have shown that for people who live beyond infancy, outcomes differ. Some do not require supplemental oxygen, while others need it either continuously or intermittently (sometimes). Survival can extend into childhood, with one study showing that 82% of those who survived beyond the first year were alive at six years of age without a lung transplant.
Over time, lung function in long-term survivors tends to decline slowly. On average, studies have shown yearly decreases of:
Prognosis is strongly influenced by the type of ABCA3 genetic variant.¹⁵ Some variants cause severe lung disease in newborns, while others allow survival into childhood and are associated with childhood interstitial lung disease (chILD).⁶ Individuals who need little or no supplemental oxygen tend to live longer than those with greater oxygen needs.¹⁴
Among those with changes in both copies (biallelic variants) of the ABCA3 gene that allow limited production of functional protein (hypomorphic variants), about 27% survive to 12 years of age, and around 10% of individuals older than 16 years require supplemental oxygen.¹⁴
Milder forms of ABCA3 deficiency may not be diagnosed until adolescence or adulthood and are often identified as interstitial lung disease (ILD).8, 16, 17 Some people are initially misdiagnosed with asthma.¹⁷ In later-diagnosed cases, symptoms may include chronic cough, poor growth in childhood, or shortness of breath (dyspnea), especially with physical activity.14, 15 Most affected adults experience breathing difficulties, and about one-third have worsening symptoms over a ten-year period.¹⁷
The ABCA3 gene is active (expressed) in specialized lung cells called alveolar type II cells (pneumocytes), which produce lung surfactant. This gene provides instructions for making the ABCA3 protein, which is essential for the normal production, storage, and function of lung surfactant.³ Lung (pulmonary) surfactant is a substance made of fats (lipids) and proteins that coats the inside of the lung air sacs called alveoli. It reduces surface tension and helps keep the air sacs of the lungs (alveoli) open, preventing them from collapsing when a person breathes out (expiration).⁶ Without properly functioning surfactant, breathing becomes difficult, and oxygen cannot move efficiently into the bloodstream.
In addition to helping the lungs make surfactant to coat the inside of the alveoli, the ABCA3 protein helps move fats (lipids), such as cholesterol, within lung cells. This process is essential for forming lamellar bodies, which are small storage structures inside lung cells that hold surfactant until it is released into the tiny air sacs (alveoli).3
Changes (variants) in the ABCA3 gene can interfere with these normal transport processes inside the cell.⁹ Some variants prevent the ABCA3 protein from reaching the correct location inside the cell. These are known as type 1 variants. Other variants affect the protein’s ability to transport certain phosphorus-containing fats (called phospholipids), which are a key part of surfactant. These are referred to as type 2 variants.
How severe the disease is can depend on the specific type of genetic change (variant) involved. Some variants cause only small changes to the ABCA3 protein. For example, missense variants change just one building block of the protein, and in-frame insertions or deletions add or remove small pieces without disrupting how the rest of the protein is read. These types of variants may lead to mild symptoms, or in some cases, no noticeable symptoms at all. ⁸
Other variants have a much greater affect on the protein. Nonsense variants cause the protein to be cut short, and biallelic frameshift variants disrupt how the genetic instructions are read in both copies of the gene. These more disruptive variants are usually associated with more severe disease.⁹
ABCA3 gene variants can impair normal gas exchange in the lungs, leading to respiratory failure. This occurs when oxygen levels in the blood fall too low and carbon dioxide levels rise above normal. Variants may also cause phosphorus-containing fats (phospholipids) to accumulate within the alveoli. This buildup attracts immune cells, leading to inflammation and thickening of the alveolar walls, which further interferes with breathing. Over time, this process can result in pulmonary fibrosis, a chronic lung disorder in which healthy lung tissue is replaced by thick scar tissue made up of fibroblasts and structural proteins such as collagen.
Changes (variants) in the ABCA3 gene are also associated with lower levels or poor functioning of surfactant protein C. This protein helps keep surfactant working properly during breathing by stabilizing the fatty (lipid) layers that line the air sacs (alveoli) in the lungs. Because surfactant protein C repels water (is hydrophobic), it helps prevent the alveoli from collapsing as the lungs expand and contract. Loss of normal surfactant protein C function contributes to problems with how surfactant is made, processed, and recycled (also known as abnormal surfactant metabolism).²
In addition, the ABCA3 protein appears to protect lung cells from damage caused by excess cholesterol (cholesterol toxicity). When ABCA3 does not function normally, cholesterol can build up inside lung cells, which may further contribute to lung injury.⁸
Inheritance
Genetic conditions are determined by the combination of genes a person inherits from their parents. Each gene comes in two copies – one inherited from the mother and one from the father.
The inheritance pattern of ABCA3 deficiency is autosomal recessive. This means that a person must inherit a disease-cuasing variant in both copies of the ABCA3 gene in order to develop the condition. 1
A person who has one normal copy of the gene and one disease-causing variant is called a carrier. Carriers usually do not have symptoms. If both parents are carriers, with each pregnancy, there is a 1 in 4 (25%) chance of being affected, a 1 in 2 (50%) chance of being a carrier, and a 1 in 4 (25%) chance of having two normal copies of the gene and being neither a carrier nor affected.
If one parent is affected and the other parent has two normal copies of the gene, all children will be carriers but are not expected to have symptoms.18
Because ABCA3 deficiency is inherited in an autosomal recessive pattern, a family history of the condition may be absent.8 However, a family history if interstitial lung disease (ILD) has been reported in about one-quarter of affected individuals.17
ABCA3 deficiency is extremely rare, with an estimated prevalence of less than 1 in 1,000,000 (one million) people.1 Variants in the ABCA3 gene account for less than 1% of cases of familial pulmonary fibrosis.18
Even so, ABCA3 variants are the most common cause of inherited disorders of surfactant metabolism, responsible for approximately 30% to 40% of the cases. It is estimated that 1 in 33 people is a carrier of an ABCA3 gene variant (carries one copy). Based on this estimate, about 1 in 3,500 people would be expected to develop symptoms. However, far fewer individuals are actually diagnosed, suggesting that the condition may be underrecognized or underdiagnosed.19
Severe newborn breathing problems (respiratory distress) associated with ABCA3 gene variants have been observed in people from many different racial and ethnic backgrounds. At this time, ABCA3 gene variants are not known to be more common in any specific population. It is possible that certain populations may have a higher frequency of these variants, but this has not yet been identified, likely due to a lack of large enough sample size to do population studies.3
The median age when people affected with interstitial lung disease associated with ABCA3 variants are identified is about 31.5 years, and it seems to be more common in females.17
Surfactant deficiency or dysfunction should be considered in infants with breathing difficulties who fail to improve with conventional therapies, do not improve after the first week of life, or pass away due to lung disease early on.6,19,22 In children with genetic surfactant dysfunction, such as ABCA3 deficiency, laboratory test findings are often nonspecific and not very useful.
In adults, ABCA3 deficiency should be considered in those with interstitial lung disease (ILD) or pulmonary fibrosis before the age of 30, especially if there is also family history.18,19
Lung imaging can be useful in supporting the diagnosis. Typically, the use of a high-resolution chest computed tomography (HRCT) can demonstrate widespread changes affecting both lungs.2,6-8 Some of the other tests used to work-up surfactant dysfunction include airway bronchoscopy with bronchoalveolar lavage fluid analysis (a procedure doctors use to look inside the lungs and collect a small sample of fluid from the airways to look for signs of infection, inflammation, bleeding, abnormal cells or problems with lung surfactant). However, they are unlikely to provide a definite diagnosis. Genetic studies are the best and most specific way to get a definite diagnosis.6,8
If there is strong clinical suspicion for ABCA3 deficiency or another genetic condition and standard gene sequencing does not identify a variant, additional testing such as deletion/duplication analysis or chromosomal microarray should be considered. While chromosomal microarray testing can detect large duplications or deletions, it may miss smaller genetic changes or structural rearrangements. There are reported cases in which individuals with ABCA3 deficiency had negative genetic testing, suggesting that not all disease-causing variants are currently detectable. Whole genome sequencing, a genetic test that examines all the patient’s genes may help overcome some of these limitations.⁸
Testing of both biological parents and other family members is also recommended.17, 18
Clinical Testing and Work-Up
Children with suspected or confirmed ABCA3 deficiency should be regularly monitored for proper growth patterns. Comparing the child’s weight and height with the appropriate/expected range is a good way to check for failure to thrive (when a child is not growing or gaining weight at the expected rate).2 For those who are six years or older, lung function tests can be used to assess and monitor lung function over time.7 Those with concerning variants should undergo clinical screening and lung function tests every year along with chest imaging every 5 years.14,17 Currently ,there are no laboratory markers that can reliably track disease progression over time.14
There are currently no approved or specific proven effective therapies for ABCA3 deficiency or dysfunction.7,8 Treatment is mostly to support breathing with additional oxygen to keep levels within appropriate ranges and provide adequate nutrition. Those with severe symptoms may need to be in the intensive care unit (ICU) at the hospital for close monitoring and support.7
For those with severe symptoms, a lung transplant could be considered.7,15 Lung transplantation is currently the only definitive treatment option. However, it is associated with significant risks and side effects. Half of those who receive a transplant pass away within 5 years.9,10 Lung transplantation requires long-term suppression of the body’s immune system which carries both short-term and long-term risks such as infections, transplant rejection, and other complications. The procedure is costly, and it is not available at many medical centers. The supply of donor lungs is also limited, and many people who qualify for lung transplant pass away before a donor can be found. Due to the severity and variability of the condition, the decision whether to pursue a lung transplant can be very difficult.8
There are reports where treatment with steroids, azithromycin, or hydroxychloroquine (either alone or in combination) resulted in symptom improvement.6-8 In some cases, symptoms did not return after hydroxychloroquine was stopped, although the optimal duration of treatment is unknown.⁶ These therapies are nonspecific and do not benefit all individuals.⁹
For children who do not produce any significant amount of functional ABCA3 protein, it may be appropriate to consider comfort or palliative care, as the outcome can be very poor.8 Artificial surfactant may help with breathing in the short term; however, it is not a long-term solution because it is quickly broken down and cleared from the lungs and ongoing lung injury, inflammation and scarring can continue despite surfactant replacement.7,16
Those affected are more susceptible to infections and therefore it is important to stay up to date on all age-appropriate vaccinations and yearly flu shots.7
In laboratory experiments, cyclosporine (a medication that reduces the activity of the immune system) has been able to correct several ABCA3 variants. Given the poor outcome of infants with ABCA3, it may not be unreasonable to try cyclosporine experimentally. However, it is important to note that these experiments were not done on human or animal subjects and that the majority of ABCA3 variants will not respond to cyclosporine. Furthermore, cyclosporine is associated with significant side effects such as increased blood pressure (hypertension), kidney damage (nephrotoxicity), suppression of the body’s immune system, etc.9.10
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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