Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Revel‐Vilk, Shoshana; Fuller, Maria; Zimran, Ari

doi:10.3390/ijms21197159

Cited by 71 publications

(83 citation statements)

References 132 publications

(478 reference statements)

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“…All analysed plasma samples were below the reference cut-off value for normal lyso-Gb1 level (Table A.3). The extremely low lyso-Gb1 levels are in line with the data previously reported on healthy controls [ 6 , 27 ].…”

Section: Resultssupporting

confidence: 92%

“…Although four out of five patients were on enzyme replacement therapy (ERT) at the time of sample donation, lyso-Gb1 levels were above the assay-specific thresholds in all study subjects ( Table 2 ) which is line with the data in the literature [ 27 ]. Some variation was observed between the results obtained from the plasma and DBS samples with DBS samples showing 1.2–2.2 times higher lyso-Gb1 concentrations compared with frozen plasma samples ( Table 2 ).…”

Section: Resultssupporting

confidence: 86%

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The Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS): Evaluation of a prototype in Finnish Gaucher disease patients and feasibility of screening retrospective electronic health record data for the recognition of potential undiagnosed patients in Finland

Savolainen

Karlsson

Rohkimainen

et al. 2021

Molecular Genetics and Metabolism Reports

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Background Gaucher disease (GD) is a rare inherited multiorgan disorder, yet a diagnosis can be significantly delayed due to a broad spectrum of symptoms and lack of disease awareness. Recently, the prototype of a GD point-scoring system (PSS) was established by the Gaucher Earlier Diagnosis Consensus (GED-C) initiative, and more recently, validated in Gaucher patients in UK. In our study, the original GED-C PSS was tested in Finnish GD patients. Furthermore, the feasibility of point scoring large electronic health record (EHR) data set by data mining to identify potential undiagnosed GD cases was evaluated. Methods This biobank study was conducted in collaboration with two Finnish biobanks. Five previously diagnosed Finnish GD patients and ~ 170,000 adult biobank subjects were included in the study. The original PSS was locally adjusted due to data availability issues and applied to the Finnish EHR data representing special health care recordings. Results All GD patients had high levels of the biomarker lyso-Gb1 and deleterious GBA mutations. One patient was a compound heterozygote with a novel variant, potentially pathogenic mutation. Finnish EHR data allowed the retrospective assessment of 27–30 of the 32 original GED-C signs/co-variables. Total point scores of GD patients were high but variable, 6–18.5 points per patient (based on the available data on 28–29 signs/co-variables per patient). All GD patients had been recorded with anaemia while only three patients had a record of splenomegaly. 0.72% of biobank subjects were assigned at least 6 points but none of these potential “GD suspects” had a point score as high as 18.5. Splenomegaly had been recorded for 0.25% of biobank subjects and was associated with variable point score distribution and co-occurring ICD-10 diagnoses. Discussion This study provides an indicative GED-C PSS score range for confirmed GD patients, also representing potential mild cases, and demonstrates the feasibility of scoring Finnish EHR data by data mining in order to screen for undiagnosed GD patients. Further prioritisation of the “GD suspects” with more developed algorithms and data-mining approaches is needed. Funding This study was funded by Shire (now part of Takeda).

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 86%

The Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS): Evaluation of a prototype in Finnish Gaucher disease patients and feasibility of screening retrospective electronic health record data for the recognition of potential undiagnosed patients in Finland

Savolainen

Karlsson

Rohkimainen

et al. 2021

Molecular Genetics and Metabolism Reports

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“…Moreover, an in vitro inhibitory GD model demonstrated that PBMC differentiated into osteoclasts with higher rate support the finding that GD patients with active bone disease formed more osteoclasts [32]. Thus, altered RANKL/RANK/OPG triad plays an integral role in GD bone pathology [2,20] In the present study, RANKL was elevated in 51% of the patients with GD. However, elevated plasma RANKL only correlates with osteopenia, but not osteoporosis, suggesting that the acceleration of osteoclast differentiation occurs before the onset of osteoporosis.…”

Section: K E L I G a N D 1supporting

confidence: 84%

“…We think that this finding is relevant to understanding the pattern of events that occur in GD bones. Because the significant correlation was verified between TRAP5b and Lyso-Gb1 and correlations between lyso-Gb1, CHITO or CCL18 were observed in several clinical studies [20], we postulate that Lyso-Gb1 is the primary contributor to TRAP5b activation, not CHITO or CCL18. A possible mechanism underlying activation expression of TRAP5 in osteoclasts is Gb1 accumulation in bone marrow cells, including monocytes/macrophages precursors cells and osteoclasts.…”

Section: K E L I G a N D 1mentioning

confidence: 64%

“…and Lyso-Gb1 induce expression of pro-inflammatory cytokines in macrophages, including TNFα, Il-6, and monocyte chemoattractant protein 1 (MCP-1) [20], we suggest that inflammatory cytokines contribute to RANKL/OPG imbalance and thus promote osteoclastic bone resorption. The bone pain that also correlates with bone density abnormalities suggests the contribution of a systemic inflammatory response to GD-related bone disease [39].…”

Section: K E L I G a N D 1mentioning

confidence: 79%

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TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

Ivanova

Dao

Noll

et al. 2021

Preprint

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Bone involvement occurs in 75% of patients with Gaucher disease (GD), and comprises structural changes, debilitating pain, and bone density abnormalities. Osteoporosis is a silent manifestation of GD until a pathologic fracture occurs. Thus early diagnosis is crucial for identifying high-risk patients to prevent irreversible complications. Thirty-one patients with GD were assessed prospectively to identify predictive markers associated with bone density abnormalities, osteopenia (OSN), and osteoporosis (OSR). Subjects were categorized into three cohorts based on T- or Z- scores of bone mineral density (BMD): In GD cohort with no bone complication (Z-score≥-0.9; T-scores≥-1), the OSN group (-1.8 ≥ Z-score ≥ -1; -2.5 ≥ T-score ≥ -1) and OSR group (Z-score ≤ -1.9; T-scores ≤ -2.5). Serum levels of TRAP5b, RANKL, OPG, and RANK were quantified by enzyme-linked immunosorbent assays. TRAP5b was increased in GD and showed a positive correlation with GD biomarkers, including plasma glucosylsphingosine (Lyso-Gb1), macrophage activation markers CCL18 and chitotriosidase. The highest levels of TRAP5b was measured in patients with osteoporosis. The elevation of RANKL and RANKL/OPG ratio correlated with osteopenia in GD. Elevation of TRAP5b, RANKL, and RANKL/OPG indicate osteoclast activation in GD. TRAP5b is a potential bone biomarker for GD with the ability to predict the progression of bone density abnormalities.

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Use of Ambroxol as Therapy for Gaucher Disease

et al. 2023

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ImportanceAmbroxol was identified as an enhancer of stability and residual activity of several misfolded glucocerebrosidase variants in 2009.ObjectivesTo assess hematologic and visceral outcomes, biomarker changes, and safety of ambroxol therapy for patients with Gaucher disease (GD) without disease-specific treatment.Design, Setting, and ParticipantsPatients with GD who could not afford enzyme replacement therapy were enrolled and received oral ambroxol from May 6, 2015, to November 9, 2022, at Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China. Thirty-two patients with GD (29 with GD type 1, 2 with GD type 3, and 1 with GD intermediate types 2-3) were enrolled. Of those, 28 patients were followed up for longer than 6 months; 4 were excluded due to loss of follow-up. Data analyses were performed from May 2015 to November 2022.InterventionAn escalating dose of oral ambroxol (mean [SD] dose, 12.7 [3.9] mg/kg/d).Main Outcomes and MeasuresPatients with GD receiving ambroxol were followed up in a genetic metabolism center. Biomarkers of chitotriosidase activity and glucosylsphingosine level, liver and spleen volumes, and hematologic parameters were measured at baseline and various time points throughout the ambroxol treatment.ResultsA total of 28 patients (mean [SD] age, 16.9 [15.3] years; 15 male patients [53.6%]) received ambroxol for a mean (SD) duration of 2.6 (1.7) years. Two patients with severe symptoms at baseline experienced deterioration of hematologic parameters and biomarkers and were deemed nonresponders; clinical response was observed in the other 26 patients. After 2.6 years of ambroxol treatment, the mean (SD) hemoglobin concentration improved from 10.4 (1.7) to 11.9 (1.7) g/dL (mean [SD], 1.6 [1.7] g/dL; 95% CI, 0.8-2.3 g/dL; P &lt; .001), and the mean (SD) platelet count improved from 69 (25) to 78 (30) × 103/µL (mean [SD], 9 [22] × 103/µL; 95% CI, −2 to 19 × 103/µL; P = .09). The mean (SD) spleen volume decreased from 17.47 (7.18) to 12.31 (4.71) multiples of normal (MN) (mean [SD], −5.16 [5.44] MN; 95% CI, −10.19 to −0.13; P = .04), and the mean (SD) liver volume decreased from 1.90 (0.44) to 1.50 (0.53) MN (mean [SD], −0.39 [0.42] MN; 95% CI, −0.75 to −0.04; P = .03). Biomarker median percentage changes from baseline were −43.1% for chitotriosidase activity (from 14 598 [range, 3849-29 628] to 8312 [range, 1831-16 842] nmol/mL/h; z = −3.413; P = .001) and −34.1% for glucosylsphingosine level (from 251.3 [range, 73.6-944.2] to 165.7 [range, 21.3-764.8] ng/mL; z = −2.756; P = .006). Patients were divided into subgroups according to age when initiating treatment; those who received treatment at a younger age (mean [SD] age, 6.3 [2.7] years) experienced more rapid improvements: hemoglobin concentration increased by 16.5% (from 10.3 [1.5] to 12.0 [1.5] g/dL; mean [SD] change, 1.6 [1.6] g/dL; 95% CI, 0.7-2.5 g/dL; P = .002), and platelet count increased by 12.0% (from 75 [24] to 84 [33] × 103/µL; mean [SD] change, 9 [26] × 103/µL; 95% CI, −5 to 24 × 103/µL; P = .17); whereas chitotriosidase activity decreased by 64.0% (from 15 710 [range, 4092-28 422] to 5658 [range, 1146-16 843] nmol/mL/h; z = −2.803; P = .005), and glucosylsphingosine level decreased by 47.3% (from 248.5 [range, 122.8-674.9] to 131.0 [range, 41.1-448.5] ng/mL; z = −2.385; P = .02). Three of the 28 patients experienced mild and transient adverse events.Conclusions and RelevanceIn this case series of ambroxol repurposing among patients with GD, long-term treatment with ambroxol was safe and associated with patient improvement. Improvements in hematologic parameters, visceral volumes, and plasma biomarkers were larger among patients with relatively mild symptoms of GD and patients who received initial treatment at younger ages.

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Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

Cited by 71 publications

References 132 publications

The Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS): Evaluation of a prototype in Finnish Gaucher disease patients and feasibility of screening retrospective electronic health record data for the recognition of potential undiagnosed patients in Finland

The Gaucher earlier diagnosis consensus point-scoring system (GED-C PSS): Evaluation of a prototype in Finnish Gaucher disease patients and feasibility of screening retrospective electronic health record data for the recognition of potential undiagnosed patients in Finland

TRAP5b and RANKL/OPG Predict Bone Pathology in Patients with Gaucher disease

Use of Ambroxol as Therapy for Gaucher Disease

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