Overview 

What is gaucher’s disease?

Gaucher disease is a genetic disorder caused by a shortage of an important enzyme called glucocerebrosidase.¹ This enzyme helps break down a fatty substance known as glucocerebroside. When there isn’t enough of this enzyme, glucocerebroside builds up in different parts of the body, especially in cells that clean up waste (macrophages).² This buildup causes these cells to swell and stop working properly, leading to various health issues. Gaucher disease is the most common disorder of its kind, and it is inherited from parents. It affects approximately 1 in 40,000 to 60,000 people worldwide.³

What are the causes and the genetics involved in Gaucher disease?

Gaucher disease is caused by changes (mutations) in the GBA1 gene, which is responsible for the production of the glucocerebrosidase enzyme. There are over 300 known mutations of this gene.⁴ It is an autosomal recessive disease which means the child must inherit two defective copies of the gene (one from each parent), in order to develop the condition. Carriers, who have one defective copy, do not show symptoms but can pass the gene to their children.

How is gaucher’s disease diagnosed?

Diagnosing Gaucher’s disease involves a multifactorial approach and It is crucial for understanding the severity of the disease and planning for the appropriate treatment.

Clinical evaluation

• Patient history: Medical history is taken to identify symptoms suggestive of Gaucher disease, such as fatigue, bone pain, easy bruising, and internal organ enlargement (spleen and liver). Family history is also critical, especially given the hereditary nature of the disease
• Physical examination: The physician examines for signs like hepatosplenomegaly (enlarged liver and spleen), pallor (indicative of anaemia), and bone abnormalities

Laboratory tests

Laboratory tests are essential for measuring the activity of the deficient enzyme and identifying characteristic markers of the disease:

• Enzyme activity test: The gold standard for diagnosing Gaucher disease is measuring the activity of the enzyme glucocerebrosidase in blood leukocytes or cultured skin fibroblasts. Low or absent enzyme activity confirms the diagnosis. This test is very specific and sensitive (the test can correctly identify the positive and negative results)
• Biomarker Tests:
  • Chitotriosidase activity: Elevated levels of chitotriosidase enzyme are found in Gaucher disease patients. However, most of the general population has a genetic deficiency of this enzyme, so this test is not definitive on its own
  • Other biomarkers: Elevated levels of tartrate-resistant acid phosphatase (TRAP), CCL18, and glucosyl sphingosine (lyso-Gb1) can also indicate Gaucher disease

Genetic testing

Genetic testing is used to identify mutations in the GBA gene, which encodes the glucocerebrosidase enzyme:

• DNA analysis: Testing for common GBA1 gene mutations can confirm the diagnosis. The most commonly mutated genes are N370S and 84GG.⁵ Genetic testing helps in identifying carriers and providing genetic counselling for families

Imaging studies

Imaging studies help assess the extent of organ involvement and bone disease:

• Magnetic Resonance Imaging (MRI): It can identify the liver and spleen enlargement and the degree of bone marrow infiltration. It is particularly useful for detecting bone marrow involvement, which appears as a characteristic ‘bone-in-bone’ or ‘Erlenmeyer flask’ deformity
• Computed Tomography (CT): CT scans can also detect organ enlargement and bone abnormalities but involve radiation exposure
• Dual-Energy X-ray Absorptiometry (DEXA): This scan measures bone mineral density to assess the risk of osteoporosis and fractures in Gaucher disease patients

Additional diagnostic tools

• Bone Marrow Biopsy: Occasionally, a bone marrow biopsy may be performed to look for Gaucher cells, which are lipid-laden macrophages with a distinctive appearance
• Liver Function Tests: These tests may show elevated liver enzymes, indicating liver involvement
• Complete Blood Count (CBC): A CBC can reveal anaemia, thrombocytopenia (low platelet count), and leukopenia (low white blood cell count), which are common in Gaucher disease.

How is gaucher’s disease treated?

The primary treatments include enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and symptomatic treatments.

Enzyme replacement therapy (ERT)

Enzyme replacement therapy is the cornerstone of Gaucher disease treatment. This treatment replaces the defective enzyme with a recombinant enzyme.

• Imiglucerase (Cerezyme): This drug is the sought-after standard treatment for Gaucher’s disease
• Velaglucerase alfa (VPRIV): This is another recombinant glucocerebrosidase, produced in a human cell line, which is also administered intravenously every two weeks. Clinical trials have shown it to be effective and safe for long-term use

Benefits of ERT: ERT significantly reduces the size of the liver and spleen. Patients often see improvements in anaemia, thrombocytopenia, and leukopenia.

Challenges and considerations: ERT is expensive. Some patients may experience infusion-related reactions, such as fever, chills, or rash. The need for regular intravenous infusions can be burdensome for patients, impacting compliance and quality of life.

Substrate reduction therapy (SRT)

Substrate reduction therapy aims to reduce the production of glucocerebroside, thereby decreasing the substrate that accumulates in cells. SRT is particularly useful for patients who cannot tolerate ERT or prefer an oral medication. Two main SRT drugs are:

• Miglustat (Zavesca): This is an oral medication that inhibits glucosylceramide synthase, an enzyme involved in the production of glucocerebroside. It is used for adults with mild to moderate Gaucher disease
• Eliglustat (Cerdelga): This is a newer oral SRT that also inhibits glucosylceramide synthase. It is approved for use in patients who are CYP2D6 extensive or intermediate metabolizers, which accounts for the majority of patients

Benefits of SRT: The convenience of oral administration can improve patient compliance and quality of life. SRT has been shown to improve haematologic and visceral (internal organs) parameters, similar to ERT.

Challenges and considerations: Common side effects of SRT include diarrhoea, weight loss, tremor (shaking) with miglustat, and mild gastrointestinal symptoms with eliglustat. Patients on SRT require regular monitoring for efficacy and potential adverse effects.

Symptomatic treatment

Symptomatic treatments address specific symptoms and complications associated with Gaucher disease. These treatments are often used in conjunction with ERT or SRT:

• Analgesics: Pain management is crucial for patients experiencing bone pain. Drugs like NSAIDs are prescribed
• Bisphosphonates: These medications can help improve bone density and reduce the risk of fractures in patients with bone involvement
• Blood transfusions: They are administered in cases of severe anaemia or thrombocytopenia
• Splenectomy: Surgical removal of the spleen may be considered for patients with severe splenomegaly causing significant symptoms or complications, although it is less common due to the effectiveness of ERT and SRT.

Gene therapy

Gene therapy is an emerging treatment approach for Gaucher disease. The goal of gene therapy is to introduce a functional copy of the GBA gene into the patient’s cells, enabling them to produce functional glucocerebrosidase:

• Clinical Trials: Several clinical trials are ongoing to evaluate the safety and efficacy of gene therapy for Gaucher disease. Early results are promising, suggesting that gene therapy could provide a long-term or even permanent solution.

Benefits: Gene therapy offers the potential for a one-time treatment that could correct the underlying genetic defect. This treatment could permanently reduce the requirement of ERT or SRT treatments.

Challenges:  Ensuring safe and effective delivery of the gene to target cells is a significant challenge. Long-term safety and efficacy need to be established through ongoing research.

Hematopoietic stem cell transplantation (HSCT)

HSCT, also known as bone marrow transplantation (BMT) is used in severe cases:

• Procedure: The patient’s diseased bone marrow is replaced with healthy stem cells from a compatible donor. This procedure aims to establish a new, healthy hematopoietic system capable of producing functional glucocerebrosidase

Benefits: HSCT can potentially cure Gaucher disease by providing a permanent source of functional enzyme-producing cells.

Challenges: HSCT is associated with significant risks, including graft-versus-host disease (GVHD), infections, and other complications. Finding a suitable donor and managing the procedure’s complexity limits its use in severe cases.

Summary

Diagnosing Gaucher disease involves a combination of clinical evaluation, enzyme activity tests, genetic testing, and imaging studies to confirm the presence of the disorder and differentiate it from other conditions. Treatment primarily consists of enzyme replacement therapy, substrate reduction therapy, and supportive care measures. Emerging therapies, such as gene therapy, offer hope for more effective and long-term solutions. 

Early diagnosis and appropriate treatment are crucial in managing Gaucher disease and improving patient outcomes.