Introduction
A rare genetic metabolic illness known as Gaucher disease occurs through a loss of the enzyme glucocerebrosidase. This causes dangerous concentrations of particular fats (lipids), primarily the glycolipid glucocerebroside, to build up throughout the body, especially in the bone marrow, spleen, and liver.1
Although the spleen, liver, and bones are the main organs of Gaucher disease, the cardiovascular system may also be severely affected. These cardiovascular consequences have increased the disease's morbidity and mortality. Enlarged heart, heart failure, and vascular repercussions need to be carefully managed.2
This article outlines these impacts to bring a better awareness of the disease and its complications.
Types of gaucher disease
Gaucher disease comes in three varieties.
Type 1 (non-neuronopathic)
- Adults with type I Gaucher disease are frequently observed
- Type I is distinguished from other types by the absence of neurological symptoms
- 70 to 100% of the patients have:3
- Bone disease
- Anaemia
- Thrombocytopenia
- Delayed puberty
- Delayed growth
- Enlarged liver
- Enlarged spleen
- Sometimes the lungs can also be impacted
Type 2 (acute neuronopathic)
- A rare disease type that usually appears in the first six months of life and strikes during infancy
- A patient with this type of Gaucher disease has a life expectancy of fewer than two years, making it the most severe type
- Patients with type II exhibit neurological symptoms in addition to spleen and liver enlargement
- This kind of Gaucher illness currently has no known cure because of the severe and irreversible brain damage it causes3
Type 3 (chronic neuronopathic)
- This juvenile type usually affects children and teenagers
- Affected patients can live into adulthood, despite the condition shortening their life expectancy
- However, type III Gaucher’s illness advances quickly, exhibiting neurological and visceral symptoms from the outset3
Causes
A deficiency in the enzyme glucocerebrosidase primarily causes Gaucher Disease. This deficiency is due to faulty mutations in the GBA gene. The conversion of glucocerebroside into glucose and ceramide requires this gene. When glucocerebrosidase is deficient, glucocerebroside accumulates in immune cells, forming "Gaucher cells" that disrupt normal organ functions.
An individual must inherit two defective copies of the gene, one from each parent, to acquire the disease, this type of inheritance is known as autosomal recessive. Over 300 distinct mutations have been found in the GBA gene, resulting in a range of illness presentations and severity.4
Impact on the heart
Significant heart symptoms that get worse with time are a possible side effect of Gaucher disease.
Here are some symptoms that frequently start in childhood:
- Swollen and hardened heart valves
- Enlarged liver
- Enlarged spleen
- Brittle bones
- Apraxia (difficulty coordinating eye movement)
- Opaque corneas
Cardiac anomalies in patients with Gaucher Disease include:
- Mitral insufficiency
- Mitral valve stenosis
- Involves the narrowing of the mitral valve, which separates the left atrium and left ventricle of the heart
- Instead of flowing effectively into the left ventricle, blood leaks backwards into the left atrium when the mitral valve does not seal adequately
- The heart has to work harder to pump blood backwards, which can cause symptoms such as exhaustion, palpitations, and shortness of breath
- Aortic stenosis
- Involves the narrowing of the aortic valve opening, which is located between the left ventricle and the aorta, the largest artery in the body
- This illness causes symptoms including exhaustion, shortness of breath, and chest pain, by limiting the quantity of blood that can leave the heart and reach the rest of the body
- Abnormal aortic arch
- The presence of calcium salt buildup (calcification) and thicker artery walls are indicative of an anomalous aortic arch
- The aortic arch may narrow significantly due to this calcification and thicken, making it more difficult for the heart to effectively pump blood through the aorta and to the rest of the body.2
Impact on blood vessels
Atherosclerosis, a disorder marked by the accumulation of fatty deposits in the arterial walls, is more common in patients with Gaucher disease. This buildup leads to the narrowing and hardening of the arteries, reducing blood flow. An elevated risk of atherosclerosis may play a role in the blockage of blood supply to the brain, which can cause an ischemic stroke.
Additionally, Gaucher disease is associated with pulmonary hypertension, a condition characterised by high blood pressure in the lungs’ arteries. If left untreated, this can result in right heart failure. Pulmonary hypertension may be due to various factors, including infiltration of Gaucher cells.4
Diagnosis of cardiovascular complications
Gaucher disease cardiovascular problems can be diagnosed using a variety of diagnostic methods and instruments. With echocardiography, clinicians may use:
- Ultrasonic waves produce comprehensive images of the organ to evaluate the anatomy and physiology of the heart
- High-resolution images from MRI and CT scans can identify early indicators of cardiovascular problems, allowing for prompt management
- Blood tests and biomarkers to quantify the concentrations of particular markers, such as lipid profiles
- Gaucher Disease-associated enzymes, that indicate inflammation and cardiovascular risk
To avoid serious consequences, custom treatment regimens, and improve patients' quality of life, frequent cardiovascular evaluations ought to be a crucial component of the care strategy for patients with Gaucher Disease. This guarantees that possible problems are found and dealt with quickly.6
Management and treatment strategies
Multiple techniques are employed in the management and treatment of cardiovascular problems associated with Gaucher disease.
- Recombinant glucocerebrosidase is infused intravenously as part of enzyme replacement therapy (ERT) to replace the defective enzyme. By lowering the risk of atherosclerosis and pulmonary hypertension, this medication can lessen the symptoms associated with cardiovascular disease
- By blocking glucosylceramide synthase, substrate reduction therapy (SRT) seeks to lower the synthesis of glucocerebroside, hence reducing the accumulation of glucocerebroside that worsens atherosclerosis and vascular inflammation
- Medication used to manage the symptoms of heart failure such as beta-blockers and ACE inhibitors, lower blood pressure, lessen heart workload, and stop additional cardiac damage are examples of symptomatic therapy
- Calcium channel blockers assist in lowering blood pressure by reducing blood vessel tension and enhancing the heart's pumping action
- Regular monitoring and alterations to one's lifestyle are also essential.7
Current research and future directions
The long-term cardiovascular outcomes in people with Gaucher disease are being studied in several ongoing trials. These investigations look at the role of glucocerebroside buildup in vascular inflammation and endothelial dysfunction to better understand the occurrence and evolution of heart and blood vessel problems in various forms of Gaucher disease.
To clarify the mechanisms of cardiovascular involvement and enable personalised medication, novel treatments and therapies including gene therapy, next-generation enzyme replacement therapies, and small molecule medicines are being investigated.8
Summary
- The rare illness known as Gaucher disease is brought on by a genetic mutation in the GBA 1 gene, which codes for the glucocerebrosidase enzyme
- The spleen, liver, and bone marrow accumulate glucosylceramide when this enzyme isn't working efficiently
- Neurological diseases, bone disease, and hepatic and/or splenic enlargement are the related symptoms
- Both genetic testing and the BGL blood test are used in the screening process for Gaucher disease
- Symptom management, substrate reduction therapy, and enzyme replacement therapy are available as forms of treatment
- Patients who actively participate in clinical trials will help discover more about the illness and help develop new therapies and screening techniques
References
- Hindo C, Pastores GM, Brady RO. Gaucher disease. [Internet]. rarediseases.org. National Organization for Rare Diseases, NORD [updated 3 March 2020; cited 24 June 2024]. Available from: https://rarediseases.org/rare-diseases/gaucher-disease/
- Naderian M, Khederlou H, Hosseinsabet A, Salarifar M. Extensive cardiovascular involvement in a young boy with Gaucher’s disease: a case report. Eur Heart J Case Rep. 2023 [cited 25 June 2024]; 7(9):ytad456. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519875/
- Massachusetts General Hospital. Gaucher disease: causes and symptoms. [Internet]. massgeneral.org. Massachusetts General Hospital [updated 25 January 2024; cited 27 June 2024]. Available from: https://www.massgeneral.org/children/gaucher-disease
- Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A review of gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci. 2017 [cited 27 June 2024]; 18(2):441. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343975/
- Committee on Diagnostic Error in Health Care, Board on Health Care Services, Institute of Medicine, The National Academies of Sciences, Engineering, and Medicine, Balogh EP, Miller BT, Ball JR. Improving Diagnosis in Health Care. Washington, D.C.: National Academies Press; 2015 [cited 25 June 2024]. Available from: http://www.nap.edu/catalog/21794
- Stone WL, Basit H, Mukkamalla SKR, Master SR. Gaucher disease. [Internet]. ncbi.nlm.nih.gov. StatPearls [Internet] [updated 12 November 2023; cited 27 June 2024]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK448080/
- Phizer. Gaucher Disease. [Internet]. phizer.com. Phizer [cited 27 June 2024]. Available from: https://www.pfizer.com/disease-and-conditions/gaucher-disease
- National Gaucher Foundation. Recently Published Research. [Internet]. gaucherdisease.org. National Gaucher Foundation [cited 27 June 2024]. Available from: https://www.gaucherdisease.org/research/recent-research/