NORD gratefully acknowledges Anthony K. Shum, MD, Department of Medicine, Division of Pulmonary and Critical Care, University of California San Francisco, and the COPA Syndrome Foundation, for assistance in the preparation of this report.
COPA syndrome is a rare, genetic autoimmune disorder that can affect multiple systems of the body, especially the lungs, kidneys, and joints. Symptoms usually appear in childhood during the first or second decade of life. The signs and symptoms, and the severity of the disorder can be very different in one person when compared to another. This is true even for members of the same family. COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. The disorder is caused by variations (mutations) in the COPA gene and occurs spontaneously as a new variation, or is inherited in an autosomal dominant pattern.
COPA syndrome has been described as having features of both autoimmune disorders and autoinflammatory disorders. An autoimmune disorder is one in which the body’s adaptive immune system, which protects the body from infectious or other foreign substances, mistakenly attacks healthy tissue instead. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or factors (e.g. environmental factors) influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Individuals and parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Lung disease associated with COPA syndrome can be classified as interstitial lung disease (ILD), which is a general term for disorders that cause progressive scarring of the lungs. Lung disease may occur before the development of joint disease. General symptoms associated with lung disease include a chronic or persistent cough, shortness of breath, and abnormal, rapid breathing (tachypnea). Affected individuals may also develop inflammation of the air passages of the lungs (bronchitis) and lung cysts. Chronic wheezing and chest pain can also occur. There can be a slow, gradual decline in lung function.
About half of individuals with COPA syndrome experience bleeding from the alveoli (alveolar hemorrhaging). The lungs contain millions of tiny air sacs called alveoli. When a person breathes in air, oxygen travels to the lungs and into the alveoli. It passes through the walls of the alveoli into tiny blood vessels called capillaries and then into the bloodstream to be carried throughout the body. Alveolar hemorrhaging is a severe complication that can cause coughing up of blood (hemoptysis) and low levels of circulating red blood cells (anemia). Anemia can cause fatigue, lightheadedness, pale skin color, dizziness, rapid heartbeat, and shortness of breath. Alveolar hemorrhaging is a potentially life-threatening complication that can lead to blood through the lungs (diffuse pulmonary infiltrates) and a rapid inability to breathe (acute respiratory failure).
Many affected individuals will develop inflammation of the joints (arthritis). Affected joints have included large joints such as the shoulders and knees, and smaller joints like those found in the fingers. Affected individuals experience pain, swelling, and stiffness of the affected joints. Joint pain can potentially be severe and debilitating. Symptoms may be worse upon waking. Children can also experience severe arthritis. Arthritis can sometimes develop before symptoms of lung disease.
Affected individuals may also develop inflammation of the kidneys (nephritis). Progressive damage to the kidneys can lead to blood in the urine (hematuria), abnormal levels of protein in the urine (proteinuria), and decreased urine output. Eventually, swelling due to fluid accumulation (edema) and reduced kidney function develop. Some individuals develop scarring (fibrosis) of the kidneys.
Other conditions have been reported to occur in a few individuals with COPA syndrome include inflammation of the spinal cord and optic nerve (neuromyelitis optica) and the degeneration of the bone near where the long bone of the leg meets the hip (avascular necrosis). However, it is not known whether these are potential complications of the disorder, or coincidental findings.
COPA is caused by a variation in the coatomer protein complex subunit alpha (COPA) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The COPA gene creates (encodes) a protein complex that is involved in the trafficking of other proteins from the Golgi complex to the endoplasmic reticulum. The Golgi complex (or apparatus) is a structure found in most cells that changes, sorts, packages and transports proteins. The endoplasmic reticulum is an extensive membrane network of a cell where proteins are processed. The exact manner that disease-causing variations in the COPA gene contribute to or cause the specific signs and symptoms of COPA syndrome is not fully understood.
COPA syndrome is an immune-mediated disorder, which means that the characteristic inflammation results from abnormal functioning (dysregulation) of the immune system and the presence of specific autoantibodies. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Autoantibodies are ones that mistakenly attack healthy tissue. Affected individuals often develop anti-neutrophil cytoplasmic antibodies and anti-nuclear antibodies. Some individuals may be positive for rheumatoid factor. The exact role these autoantibodies play in the development of COPA syndrome is not fully understood.
COPA syndrome can be inherited from a parent or it can occur as a new (sporadic or de novo) variation, which means that the gene change has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
COPA syndrome is described as having incomplete or reduced penetrance and variable expressivity. These are genetic terms. Incomplete penetrance means that some individuals who inherit the gene for a dominant disorder will not be affected by the disorder. Variable expressivity in a dominant disorder means that widely varying signs and symptoms can occur among affected individuals.
Initial reports have shown more females being affected than males. Larger groups of patients will need to be identified to confirm whether women are affected more often than men. Less than 100 families have been identified with this disorder in the medical literature, but the exact number of people who have this disorder is unknown. The low number of people identified with this disorder is because COPA syndrome was only first defined as a disorder in 2015, and genetic testing has only recently become available. In general, rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COPA syndrome is likely underrecognized and underdiagnosed.
A diagnosis of COPA syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Molecular genetic testing can confirm a diagnosis. Two findings that are suggestive of COPA syndrome are diffuse alveolar hemorrhaging and follicular bronchiolitis. Follicular bronchiolitis is when there is an overgrowth (hyperplasia) of lymphoid tissue within the small airways (bronchioles) of the lungs causing inflammation of those airways. Lymphoid tissue is the tissue in the body that produces white blood cells and antibodies.
Clinical Testing and Workup
Molecular genetic testing can detect variations in the COPA gene known to cause the disorder. Doctors will take a blood sample of individuals suspected of having COPA syndrome and the sample will undergo targeted sequencing of the region of the COPA gene that is known to cause the disease to assess for the presence of variations known to cause the disease.
Additional tests may be run before or after molecular genetic testing to determine the extent of the disease or to rule out other conditions. Such tests can include plain chest x-rays (radiographs) or a specialized imaging technique such as computerized tomography (CT) scanning of the lungs. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. Affected individuals have distinctive changes in lung tissue that can be detected on x-rays. For example, a CT scan can show areas of haziness that resembles ground glass (ground glass opacity) or small bumps (nodules) in the lungs.
Pulmonary function tests may be administered to determine how effectively or ineffectively the lungs are working. This can include having an individual breathe into a machine called a spirometer to measure how much air they can breathe out or take in, and can reveal reduced airflow and reduced air volume. Doctors may measure a person’s forced vital capacity, which is the amount of air that can be forcibly blown out after taking a deep breath. A similar test called forced expiratory volume may also be recommended. This test measures how much air a person can breathe out during a forced breath.
Another test called a plethysmography measures the total among of air people can hold in their lungs, which is called total lung capacity. During this exam, patients will sit or stand in an airtight chamber that is similar to a phone booth. The nostrils will be clipped shut and the patient will be asked to breathe into a mouthpiece.
A sample of lung tissue taken via a surgical lung biopsy (sometimes called a video-assisted thoracoscopic surgery (VATS) lung biopsy) and studied under a microscope can reveal characteristic changes in the lung that indicate COPA syndrome. During this procedure, a small needle is passed through the skin to the lungs to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Follicular bronchiolitis can be confirmed through a lung biopsy.
A bronchoscopy exam might be needed during the workup to evaluate for alveolar hemorrhaging or other diseases that might be present, such as a lung infection. During a bronchoscopy, a physician inserts a bronchoscope through the mouth and down an affected individual’s throat and obtains a sample of tissue to be analyzed (biopsy). A bronchoscopy exam may also be used to allow doctors to see into the airways and air passages of the lungs.
Blood tests can reveal the presence of autoantibodies including anti-neutrophil cytoplasmic antibody and anti-nuclear antibody. Some individuals may be positive for rheumatoid factor.
The treatment of COPA syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating lung disorders (pulmonologists), physicians who specialize in diagnosing and treating kidney disorders (nephrologists), physicians who specialize in diagnosing and treating inflammation of the bones and joints (rheumatologists), physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.
Genetic counseling is recommended for affected individuals and their families.
Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on COPA syndrome.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with COPA syndrome.
There is no cure for COPA syndrome, but affected individuals can be treated with drugs that suppress the immune system (immunosuppressive drugs). COPA syndrome involves abnormal functioning (dysregulation) of the immune system. By suppressing the activity of the immune system, doctors can reduce the damage to the healthy organ systems (e.g. the lungs) affected by the disorder. Some affected individuals may also receive low doses of systemic corticosteroids, which are drugs that reduce inflammation in the body. Individuals will respond to these medications differently.
During periods of time when symptoms are worse, called exacerbations, stronger immunosuppressive drugs may be tried. Sometimes, high doses of systemic corticosteroids. Long-term use of high doses of systemic corticosteroids is often associated with significant side effects. Most patients have the drug dosage slowly reduced (tapered) after the exacerbation has passed.
Some affected individuals have required supplemental oxygen at a young age. Supplemental oxygen, or oxygen therapy, is required when the lungs cannot take in enough oxygen to deliver oxygen to the bloodstream. Supplemental oxygen can help with symptoms like shortness of breath or fatigue.
In severe disease, an endotracheal intubation may be necessary. This involves inserting a thin tube into the mouth or nostrils, down the windpipe (trachea), and into the lungs. This allows air to pass freely to the lungs.
Several patients have received or are awaiting a lung transplant for progressive, severe lung disease. At least one patient has received a kidney transplant.
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:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Tsui JL, Estrada OA, Deng Z, et al. Analysis of pulmonary features and treatment approaches in the COPA syndrome. ERJ Open Res. 2018;4:00017-2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019741/
Taveira-DaSilve AM, Markello TC, Kleiner DE, et al. Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features. J Med Genet. 2018;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/30385646
Volpi S, Tsui J, Mariani M, et al. Type I interferon pathway activation in COPA syndrome. Clin Immunol. 2018;187:33-36. https://www.ncbi.nlm.nih.gov/pubmed/29030294
Brennan M, McDougall C, Walsh J, Crow YJ, Davidson J. COPA syndrome – a new condition to consider when features of polyarthritis and interstitial lung diseases are present. Rheumatology. 2017;56:Issue supple_6. https://academic.oup.com/rheumatology/article/56/suppl_6/kex356.059/4331610
Vece TJ, Watkin LB, Nicholas S, et al. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. J Clin Immunol. 2016;36:377-387. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4842120/
de Jesus AA, Goldbach-Manksy R. Newly recognized Mendelian disorders with rheumatic manifestations. Curr Opin Rheumatol. 2015;27:511-519. https://www.ncbi.nlm.nih.gov/pubmed/26196376
Watkin LB, Jessen B, Wiszniewski W, et al. COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat Genet. 2015;47:654-660. https://www.ncbi.nlm.nih.gov/pubmed/25894502
Park MS. Diffuse alveolar hemorrhage. Tuberc Respir Dis (Seoul). 2013;74:151-162. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3651925/
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:616414; Last Update:08/21/2015. Available at: https://omim.org/entry/616414 Accessed November 27, 2018.
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