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Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Gaucher Disease (GD)

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
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Background

Gaucher disease (GD) is the most common lipid-storage disorder, with variable symptoms ranging from no outward symptoms to severe disability. The most common symptoms of Gaucher disease are enlargement of the liver and spleen, anemia, reduced platelets (resulting in easy bruising and long clotting times), bone pain and osteoporosis. There are three clinical forms of Gaucher disease, which are distinguished by the occurrence and form of neurological involvement. Type 1 GD does not have any neurological symptoms. Type 2 GD is characterized by severe neurological symptoms, and is usually fatal during the first three years of life. Type 3 GD also shows neurological symptoms, but they appear later in childhood and progress more slowly than the symptoms of Type 2 GD.

Gaucher disease is an autosomal recessive disorder caused by mutations in the acid b-glucosidase (GBA) gene, located on chromosome 1 (1p21 p23). Although GD has been reported in individuals of various ethnic backgrounds, it occurs most often in people of Ashkenazi Jewish ancestry. Over 100 different mutations in this gene have been identified in affected patients; however four mutations in the GBA gene account for over 90% of the mutations seen in Ashkenazi Jewish individuals affected with Gaucher disease [84G>GG, IVS2(+1)G>A, N370S and L444P]. These four mutations account for 50-60% of disease-causing alleles seen in the non-Jewish population. Non-Jewish individuals with Gaucher disease tend to be compound heterozygotes with one common mutation and one 'rare' mutation of which four are tested for in this panel [D55bp, V394L, D409H and R496H].

To be affected with GD, an individual must have two mutations in the GBA gene (one inherited from each parent); these may or may not be identical mutations. Any person with one copy of the defective GBA gene is a Gaucher disease carrier. Carriers do not have, and will not develop, Gaucher disease. However, if two carriers wish to have children, there is a one in four chance (25%) that their baby will be born with the disease. There is a three in four chance (75%) that their baby will not have Gaucher disease.

An accurate biochemical test is available for the diagnosis of Gaucher disease consisting of the analysis of b-glucosidase activity in plasma, leucocytes or cultured cells. This test should be considered before molecular analysis is undertaken. Molecular identification of the mutation in individuals with a confirmed diagnosis can be used for carrier testing and prenatal diagnosis in the family. The biochemical test is not reliable for identifying carriers.

Who should be tested

  • individuals with low b-glucosidase enzyme activity, to identify the underlying GBA mutation
  • individuals with a family history of Gaucher disease and their spouses, to determine the carrier status of unaffected individuals
  • pregnancies at risk due to a family history of Gaucher disease

Testing Methodology

Direct Mutation Analysis: Samples are analyzed for eight mutations in the GBA gene: 84G>GG, IVS2(+1)G>A, N370S, L444P, D55bp, V394L, D409H, R496H.

The nomenclature used for reporting the eight mutations in the GBA gene uses common internationally recognized nomenclature and does not meet standardized guidelines.

Test Sensitivity: Detection rates vary significantly between ethnic groups. Four mutations account for over 90% of the mutations seen in Ashkenazi Jewish individuals affected with Gaucher disease, and approximately 50-60% of disease-causing alleles in the non-Jewish population [84G>GG, IVS2(+1)G>A, N370S, L444P]. Non-Jewish individuals with Gaucher disease tend to be compound heterozygotes with one common mutation and one ‘rare’ mutation of which four are tested for in this panel [D55bp, V394L, D409H and R496H].

Potential Outcomes & Interpretation of Test Results

Reason
for referral

GBA Gene Mutations
allele 1 / allele 2

Explanation

carrier testing

none detected / none detected

  • This individual is unlikely to be a carrier of Gaucher disease.

carrier testing

mutation detected / none detected

  • This individual is a carrier of Gaucher disease, and may transmit a mutation to offspring.

diagnosis

none detected / none detected

  • This result does not support a diagnosis of Gaucher disease.

diagnosis

mutation detected / none detected

  • This result is unable to confirm a diagnosis of Gaucher disease.

diagnosis

mutation detected / mutation detected

  • This result confirms a diagnosis of Gaucher disease

Cautions:

  • Current molecular testing will not detect all possible mutations in this gene. A negative result does not rule out the possibility that the individual has a rare GD mutation not included in the assay.
  • We strongly recommend that biochemical analysis be done on these patients as it can be a useful complement to molecular testing.
  • It is often helpful to first identify the mutation(s) in an affected family member or in the parent of the affected family member. If the familial mutation can be identified in this way, the molecular test is conducted only for the familial mutation.
  • The identification of mutations cannot conclusively differentiate between Gaucher disease type I, II and III. The clinical course or severity of symptoms cannot be predicted by molecular analysis.
  • Test results should be interpreted in the context of clinical findings, family history, ethnicity and other laboratory data.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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