What is the treatment for Gaucher disease?

Gaucher Disease: Comprehensive Overview

Disease Pathophysiology

Gaucher disease is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme acid β-glucosidase (glucocerebrosidase), leading to accumulation of glucosylceramide (GL-1) primarily in macrophages of the reticuloendothelial system. 1 This accumulation creates characteristic "Gaucher cells" (foam cells) that infiltrate the liver, spleen, bone marrow, and other organs, causing the clinical manifestations of the disease. 1, 2

The disease results from mutations in the GBA1 gene, with over 70 different mutations identified. 3 In the Ashkenazi Jewish population, common mutations include N370S (86%), 84GG (5.6%), L444P (2.1%), and IVS21G>A (0.9%). 4 The incidence varies between 0.4 and 5.8 per 100,000 inhabitants in the general population, but reaches 1 in 450 births for type 1 disease in Ashkenazi Jewish individuals. 4, 2

Clinical Classification and Presentation

Type 1 Gaucher Disease (Non-Neuronopathic)

Type 1 represents approximately 90% of all Gaucher disease cases and is characterized by the absence of primary central nervous system involvement. 5 The clinical manifestations include:

• Hematologic abnormalities: Anemia and thrombocytopenia due to bone marrow infiltration and hypersplenism 3, 2
• Organomegaly: Hepatosplenomegaly, often massive splenomegaly 3, 2
• Skeletal involvement: Bone infarcts, bone crises, avascular necrosis, osteoporosis, and pathologic fractures 3, 6, 7
• Variable presentation: Ranges from asymptomatic to severe, potentially disabling disease 2, 5

Type 2 Gaucher Disease (Acute Neuronopathic)

Type 2 disease presents in infancy with severe, rapidly progressive neurological involvement leading to death typically within the first 2 years of life. 3, 5 Currently, no effective treatment exists for type 2 Gaucher disease, and only supportive care is recommended. 3

Type 3 Gaucher Disease (Chronic Neuronopathic)

Type 3 disease involves variable neurological manifestations including supranuclear gaze palsy, seizures, ataxia, and cognitive regression, with later onset than type 2. 4, 5

Diagnostic Algorithm

Initial Diagnostic Steps

The definitive diagnostic method is measurement of leukocyte acid β-glucosidase enzymatic activity, which will be low in affected individuals. 3, 7

1. Measure leukocyte GBA enzyme activity in patients with suggestive clinical features 3
2. If enzyme activity is low on initial testing, repeat the measurement 3
3. Proceed to GBA1 gene sequencing to identify biallelic pathogenic variants 3, 4
4. If only one mutation is identified, perform GBA deletion testing 3

Baseline Evaluation After Diagnosis Confirmation

After confirming the diagnosis and providing genetic counseling, the following evaluations must be performed 3:

• Complete blood count including hemoglobin and platelet levels 3, 7
• Liver enzymes and acid phosphatase 7
• Imaging for organomegaly: MRI or CT scans to assess spleen and liver volumes 7
• Skeletal assessment: T1- and T2-weighted MRI of entire femora and plain radiography of femora, spine, and symptomatic sites 7
• Neurological assessment for patients predicted to have neuronopathic disease or uncertain genotype-phenotype correlation 3
• Gaucher biomarkers: Measure chitotriosidase activity, tartrate-resistant acid phosphatase, lyso-Gb1 levels, and anti-GBA antibody levels before initiating treatment 3, 4

Treatment Recommendations

Type 1 Gaucher Disease

Treatment should be initiated in type 1 patients who have two or more disease manifestations. 3 The primary treatment modalities include:

Enzyme Replacement Therapy (ERT)

ERT with recombinant glucocerebrosidase is the mainstay of treatment and became the first successfully managed lipid storage disease. 6 This life-long intravenous therapy leads to significant improvement in general condition and quality of life when started early enough. 8

Substrate Reduction Therapy (SRT)

Eliglustat (CERDELGA) is indicated for long-term treatment of adult patients with type 1 Gaucher disease who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs). 1

• Dosing based on CYP2D6 metabolizer status (requires FDA-cleared genotype testing): 1

  • EMs and IMs: 84 mg twice daily
  • PMs: 84 mg once daily
  • Ultra-rapid metabolizers may not achieve adequate concentrations 1

• Mechanism: Eliglustat inhibits glucosylceramide synthase, reducing GL-1 production and alleviating accumulation in target organs 1

Type 3 Gaucher Disease

Type 3 patients should be started on treatment immediately upon diagnosis. 3 Only enzyme replacement therapy is indicated for type 3 disease. 2

Type 2 Gaucher Disease

Only supportive care is recommended for type 2 Gaucher disease due to lack of currently effective treatment. 3

Monitoring and Follow-Up

Untreated Patients

• Hematologic and biochemical parameters: Complete blood count, platelets, acid phosphatase, and liver enzymes every 12 months 7
• Visceral assessment: Every 12 to 24 months 7
• Skeletal assessment: Every 12 to 24 months 7

Treated Patients

• Hematologic and biochemical parameters: Every 3 months and at therapy changes 7
• Visceral and skeletal assessments: Every 12 months and at therapy changes 7
• Infants: Monitor at least quarterly to assess treatment response and development of additional manifestations requiring intervention 3

Associated Complications and Risks

Patients with type 1 Gaucher disease have increased risk of several serious conditions: 2

• Parkinson disease: Carriers of GBA1 mutations have significantly elevated risk 4, 2
• Hematologic malignancies: Particularly multiple myeloma 2
• Solid cancers: Increased risk of certain solid tumors 2

Critical Clinical Pitfalls

Gaucher disease often remains misdiagnosed or undiagnosed for extended periods due to its rarity and variable clinical presentations. 2, 5 The wide variability in symptoms leads to diagnostic delays, resulting in irreversible complications. 2

Early diagnosis and appropriate treatment are essential for reducing complications, improving quality of life, and avoiding inappropriate procedures such as splenectomy. 5, 7 Skeletal involvement can permanently disable patients if not monitored and treated appropriately. 7

Hematologists and oncologists must maintain high clinical suspicion for Gaucher disease in patients presenting with unexplained cytopenias, hepatosplenomegaly, or bone disease, particularly in Ashkenazi Jewish individuals. 5