INTRODUCING
Early diagnosis of Gaucher disease is essential in implementing the appropriate patient assessment and management plans as soon as possible.
Why test for glucosylsphingosine (lyso-Gb1)?
Mutations in the GBA1 gene lead to a reduction in the enzymatic activity of glucocerebrosidase, causing accumulation of glucosylceramide in lysosomes.1 Glucosylsphingosine (lyso-Gb1) is a metabolic precursor of glucosylceramide synthesis, suggesting that the rate of accumulation and degradation of glucosylsphingosine (lyso-Gb1) may contribute to disease manifestations in patients with Gaucher disease. Therefore, glucosylsphingosine (lyso-Gb1) is useful as a biomarker for Gaucher disease.2,3
What is the glucosylsphingosine (lyso-Gb1) test?
Determination of free glucosylsphingosine (lyso-Gb1) can be obtained from EDTA plasma samples in patients undergoing biochemical analysis and genetic testing for Gaucher disease.3,4 Levels of glucosylsphingosine (lyso-Gb1) in dried blood spots have also been useful to aid in diagnosing patients with Gaucher disease. One study found that patients with neuronopathic Gaucher disease Types 2 or 3, exhibited significantly higher levels of glucosylsphingosine (lyso-Gb1) than patients with non-neuronopathic Gaucher disease Type 1. In addition to being a biomarker of Gaucher disease, glucosylsphingosine (lyso-Gb1) may be useful for prenatal diagnosis of the disease and in dried blood spot screening programmes.5
In patients with Gaucher disease Type 1 (n=64), levels of glucosylsphingosine (lyso-Gb1) are markedly increased in the plasma (median [range] 230.7 [15.6‒1035.2] nM) compared with individuals without Gaucher disease (n=28; median [range] 1.3 [0.8‒2.7] nM).3 Plasma glucosylsphingosine (lyso-Gb1) levels have also shown correlation with chitotriosidase (Spearman coefficient, p=0.66) and CC chemokine ligand 18 (CCL18) (p=0.40), which are produced by Gaucher cells and secreted into the circulation.3,6,7
The levels of glucosylsphingosine (lyso-Gb1) in the spleen of patients with Gaucher disease Type 1 are reportedly 54‒728 ng/mg protein. In patients with Gaucher disease Types 2 and 3, glucosylsphingosine (lyso-Gb1) levels are reported as 133‒1200 ng/mg protein and 109‒1298 ng/mg, respectively. Splenic levels of glucosylsphingosine (lyso-Gb1) are below 1 ng/mg protein in individuals without Gaucher disease. Moreover, brain levels of glucosylsphingosine (lyso-Gb1) are 22‒51-times and 38‒694-times higher in patients with Gaucher disease Type 3 and Gaucher disease Type 2, respectively, than individuals without Gaucher disease. Conversely, brain levels of glucosylsphingosine (lyso-Gb1) in patients with Gaucher disease Type 1 are within the normal range (1 ng/mg protein) and comparable to individuals without Gaucher disease (range, 0.04‒1.2 ng/mg protein). These data suggest that elevated levels of glucosylsphingosine (lyso-Gb1) may contribute to the disease manifestations of Gaucher disease.2
Glucosylsphingosine (lyso-Gb1) as a biomarker for paediatric Gaucher disease
The clinical charts of 81 patients aged <18 years with Gaucher disease from the Shaare Zedeck Medical Center in Israel, over a 4-year period, were reviewed to evaluate glucosylsphingosine (lyso-Gb1) as a biomarker for Gaucher disease in children. Disease severity was based on genotype: 35 patients had mild Gaucher disease Type 1; 34 had severe Gaucher disease Type 1; and 12 had Gaucher disease Type 3.8
At the time of last visit, glucosylsphingosine (lyso-Gb1) levels were significantly lower in children with mild Gaucher disease Type 1 versus those with severe Gaucher disease Type 1 (p=0.009); levels were comparable between patients with Gaucher disease Type 3 (p=0.81). With regards to age, gender, haemoglobin levels, liver or spleen volumes and platelet count, there were no significant differences between children with mild and severe Gaucher disease Type 1 (p>0.05). However, patients with Gaucher disease Type 3 had significantly larger liver (p=0.007) and spleen (p=0.005) volumes than children with Gaucher disease Type 1.8
In all cohorts combined, glucosylsphingosine (lyso-Gb1) levels significantly correlated with platelet count (p<0.0001) and haemoglobin levels (p=0.003), but not with liver or spleen volumes. There was no association between levels of glucosylsphingosine (lyso-Gb1) and age or weight. These data highlight that glucosylsphingosine (lyso-Gb1) appears to be a useful biomarker for children with Gaucher disease and can be included during routine follow-up.8
Glucosylsphingosine (lyso-Gb1) as a biomarker for adult Gaucher disease
The sensitivity and specificity of glucosylsphingosine (lyso-Gb1) as a biomarker for Gaucher disease was evaluated in 148 healthy adults (54.7% male; median age, 29 years) and compared with 98 genetically diagnosed patients with Gaucher disease (52.2% male; median age, 29 years), 13 carriers of Gaucher disease (64.7% male; median age, 35 years), and 261 patients with other lysosomal storage diseases (44.8% male; median age, 38 years).4
The levels of glucosylsphingosine (lyso-Gb1) across the four cohorts are presented in Figure 1. Only patients with Gaucher disease had glucosylsphingosine (lyso-Gb1) levels above the normal range: determined as a cut-off value of 12 ng/mL. This effect was independent of gender, with both male and female patients with Gaucher disease demonstrating elevated levels of glucosylsphingosine (lyso-Gb1) compared with individuals without Gaucher disease, carriers of Gaucher disease or patients with other lysosomal storage diseases.4
Figure 1.
Glucosylsphingosine (lyso-Gb1) levels in patients with Gaucher disease compared with healthy individuals, carriers of Gaucher disease and patients with other lysosomal storage diseases. Reproduced with permission from Rolfs A et al. PLoS One 2013; 8: e79732.4
Of the DNA data available, 45 different GBA1 mutations (see genetic inheritance of Gaucher disease) were identified in 98 patients with Gaucher disease. The most prevalent mutations were N370S (c.1226A>G; p.Asp409Ser, 32.5%), L444P (c.1448T>C; p.Leu483Pro, 22.1%) and RecNcil (c.1448T>C; 1483G>C; 1497G>C, 8.0%) which comprised approximately two-thirds of all mutations. Patients with Gaucher disease with the L444P (c.1448T>C; p.Leu483Pro) mutation had higher glucosylsphingosine (lyso-Gb1) levels (median, 184.5 ng/mL) than those with the N370S (c.1226A>G; p.Asp409Ser) mutation (median, 143.1 ng/mL). Moreover, median levels of glucosylsphingosine (lyso-Gb1) were higher in patients who had homozygous mutations (N370S/N370S, 143.1 ng/mL; L444P/L444P, 184.5 ng/mL) compared with heterozygous mutations (N370S, 77.1 ng/mL; L444P: 107.0 ng/mL). The accuracy of glucosylsphingosine (lyso-Gb1) as a biomarker for Gaucher disease was found to be significantly better than either chitotriosidase (p=0.027) or CCL18 (p<0.001).4
C-ANPROM/INT//7567; Date of preparation: September 2020
DIFFERENTIAL DIAGNOSIS
What is the glucocerebrosidase activity test for Gaucher disease?
A diagnosis of Gaucher disease can be confirmed or excluded through assays to test for glucocerebrosidase enzyme activity, typically in leukocytes, skin fibroblasts or dried blood spots.
DIFFERENTIAL DIAGNOSIS
Can chitotriosidase be used as a biomarker for Gaucher disease?
Chitotriosidase activity is significantly elevated in patients with Gaucher disease Type 1 and can be a valuable biomarker during assessment and follow-up.
DIFFERENTIAL DIAGNOSIS
Can CC chemokine ligand 18 (CCL18) be a useful biomarker for Gaucher disease?
Plasma levels of CCL18 are significantly elevated in patients with Gaucher disease Type 1 and can be a useful biomarker for assessing disease severity and response to treatment.
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