The ELANE gene is a specific segment of our genetic code that holds instructions for producing a particular protein. This gene is located on chromosome 19. It plays a role in the body’s immune system, which is our natural defense against infections. The information within this gene’s sequence directly impacts the production of a protein involved in how our body responds to foreign invaders.
Normal Function of the ELANE Gene
The ELANE gene provides instructions for making a protein called neutrophil elastase. This protein is found inside neutrophils, which are a type of white blood cell. Neutrophils are immune cells that act as a first line of defense against microorganisms, including bacteria and fungi.
Neutrophil elastase plays a role in the body’s immune response to infection and inflammation. When the body encounters an infection, neutrophils release neutrophil elastase to help break down bacteria and cellular debris. The enzyme is typically processed and packaged into granules within neutrophils, where it remains active but is normally prevented from damaging the cell itself by protective mechanisms.
Conditions Linked to ELANE Gene Mutations
Mutations in the ELANE gene are primarily linked to two distinct types of neutropenia: severe congenital neutropenia (SCN) and cyclic neutropenia (CN). Both conditions involve abnormally low levels of neutrophils, which makes affected individuals more susceptible to recurrent infections.
Severe Congenital Neutropenia (SCN)
In severe congenital neutropenia, various ELANE gene mutations have been identified. These mutations often cause the neutrophil elastase protein to misfold. This misfolded protein then accumulates within neutrophils in the bone marrow, leading to damage and premature death of these developing infection-fighting cells. This premature cell death results in a chronic and severe deficiency of neutrophils from infancy.
Individuals with SCN typically experience frequent and severe infections starting in infancy. These can include bacterial infections affecting the skin, mouth, throat, sinuses, lungs, and liver. Fevers and inflammation of the gums are also common. In some cases, omphalitis, or inflammation of the umbilical cord stump, may be an early sign.
About 40% of affected individuals may also develop osteopenia or osteoporosis, conditions characterized by decreased bone density. Roughly 20% of SCN patients are at an increased risk of developing myelodysplastic syndrome or acute myeloid leukemia, which are types of blood cancers, usually during adolescence.
Cyclic Neutropenia (CN)
Cyclic neutropenia is associated with various ELANE gene mutations. These mutations alter neutrophil elastase, leading to an abnormal protein. However, neutrophils producing this altered elastase have a shorter lifespan than normal neutrophils. This shortened lifespan causes a periodic shortage of neutrophils.
The hallmark of cyclic neutropenia is the cyclical nature of its symptoms, which typically recur every 21 days, lasting for about three to five days. During these periods of low neutrophil counts, individuals may experience fevers, fatigue, sore throats, mouth sores, gum disease, and infections of the upper respiratory tract, digestive system, and skin. Between these cycles, affected individuals are generally healthy, and symptoms often improve in adulthood. Unlike SCN, cyclic neutropenia is not associated with an increased risk of developing leukemia.
Diagnosing and Managing ELANE-Related Neutropenias
Diagnosis of ELANE-related neutropenias involves a combination of clinical observations and specific laboratory tests. This often begins with a physical examination and a review of a person’s symptoms, especially recurring infections or cyclical fevers. Blood tests, particularly a complete blood count (CBC), are then performed to measure the absolute neutrophil count (ANC). A consistently low ANC, typically below 500/µL, is a primary indicator of neutropenia. For cyclic neutropenia, serial blood counts over several weeks are often needed to confirm the regular fluctuations in neutrophil levels.
Bone marrow examination may also be conducted to assess neutrophil development within the bone marrow, looking for signs like maturation arrest in SCN. The most definitive diagnostic step is genetic testing for ELANE gene mutations. This testing can identify the specific genetic changes responsible for the condition, confirming the diagnosis. For individuals with well-documented cyclic neutropenia and a family history, the mutation detection rate can be as high as 100%, while for congenital neutropenia, it ranges from 38% to 80%.
Management of ELANE-related neutropenias primarily focuses on preventing and treating infections. The main treatment for both SCN and CN is granulocyte colony-stimulating factor (G-CSF). This medication stimulates the bone marrow to produce more neutrophils, thereby increasing their numbers in the blood and reducing the frequency and severity of infections. G-CSF is typically administered through daily or alternate-day injections, with doses varying depending on the specific condition and individual response. For instance, individuals with SCN often require higher doses of G-CSF compared to those with CN.
Antibiotics are also used to treat existing infections. In severe cases of SCN that do not respond to G-CSF or if there is a progression to leukemia, hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplantation, may be considered as a curative option. However, HSCT carries its own risks and complications. Genetic counseling is an important aspect of managing ELANE-related neutropenias for affected individuals and their families. This counseling helps families understand the autosomal dominant inheritance pattern of ELANE mutations, assess the risk for future children, and discuss family planning options.