Genetic Testing for Gaucher Disease: Indications and Procedures
Genetic testing for Gaucher disease should be performed in individuals with clinical manifestations suggestive of the disease, those with a family history, and in Ashkenazi Jewish individuals as part of carrier screening, with diagnosis confirmed through a combination of enzyme activity testing and GBA gene analysis. 1
Clinical Indications for Testing
- Testing should be considered in patients presenting with hepatosplenomegaly, thrombocytopenia, anemia, bone involvement, and/or pulmonary involvement, which are the primary phenotypic consequences of type 1 Gaucher disease 1
- Individuals with neurological manifestations such as seizures, bulbar palsy, hypertonia, and supranuclear gaze palsy may have type 2 or 3 Gaucher disease and should undergo testing 1
- Ashkenazi Jewish individuals have a higher incidence (1 in 450 births for type 1) and should be offered carrier screening, particularly before pregnancy 1
- Patients with unexplained splenomegaly and cytopenias (especially thrombocytopenia with relative preservation of hemoglobin and white cell counts) should be evaluated for Gaucher disease 2
- Laboratory abnormalities that should prompt consideration of Gaucher disease include elevated serum ACE levels, low HDL cholesterol, and raised ferritin 2
Diagnostic Algorithm
Step 1: Initial Biochemical Testing
- Measure leukocyte acid β-glucosidase (GBA1) enzymatic activity 1, 3
- Low enzyme activity is the hallmark of Gaucher disease 1
- If enzyme activity is low, proceed to genetic testing and further evaluations at a metabolic center 1
Step 2: Genetic Testing
- Perform GBA1 gene sequencing to identify biallelic pathogenic variants 1, 3
- The GBA1 gene is located on chromosome 1q21, 16kb upstream from a highly homologous pseudogene, making genetic testing technically challenging 3
- Common mutations in Ashkenazi Jewish individuals include N370S (86%), 84GG (5.6%), L444P (2.1%), and IVS21G>A (0.9%) 1
- If only one mutation is identified, deletion/duplication testing may be necessary 1, 3
Step 3: Biomarker Analysis
- Biomarker testing can help establish diagnosis, evaluate therapeutic response, and monitor treatment compliance 1
- Lyso-Gb1 levels directly reflect sphingolipid turnover and are specific to Gaucher disease 1
- Other biomarkers include tartrate-resistant acid phosphatase, chitotriosidase activity, angiotensin-converting enzyme, and C-C motif ligand 18/pulmonary-activated-related chemokine 1
- These biomarkers reflect macrophage activation and lipid storage but are less specific than lyso-Gb1 1
Phenotype Determination and Treatment Planning
- After diagnosis confirmation, determine the disease type (1,2, or 3) based on clinical presentation and genetic findings 1
- Type 1: Limited neurological involvement, variable age of onset 1
- Type 2: Rapidly progressive with severe neurological manifestations, often fatal in early childhood 1
- Type 3: Chronic neuropathic form with variable neurological involvement 1
- FDA-approved enzyme replacement therapies (imiglucerase, velaglucerase alfa, taliglucerase alfa) are available for types 1 and 3 4, 5, 4
- Treatment should be initiated for type 3 patients immediately and for type 1 patients if they have anemia, thrombocytopenia, bone disease, hepatomegaly, or splenomegaly 1, 4
Common Pitfalls and Caveats
- Diagnostic delays are common (median 2 years, range 0.5-26 years), with 19% of patients experiencing delays of 5 or more years 2
- The GBA1 gene has a highly homologous pseudogene that can complicate genetic testing, requiring specialized laboratory techniques 3
- Approximately 75% of patients are diagnosed by hematologists, often following bone marrow biopsy findings 2
- Carriers of GBA1 mutations have an increased risk of developing Parkinson's disease, which should be considered in genetic counseling 1, 6
- The presence of Gaucher cells in bone marrow is suggestive but not diagnostic; enzyme activity testing is required for confirmation 2