Gaucher Disease Diagnosis Using Lyso-Gb1 on Dry Blood Spot Samples: Time to Change the Paradigm?

Abstract

For years, the gold standard for diagnosing Gaucher disease (GD) has been detecting reduced β-glucocerebrosidase (GCase) activity in peripheral blood cells combined with GBA1 mutation analysis. The use of dried blood spot (DBS) specimens offers many advantages, including easy collection, the need for a small amount of blood, and simpler transportation. However, DBS has limitations for measuring GCase activity. In this paper, we recount our cross-sectional study and publish seven years of experience using DBS samples and levels of the deacylated form of glucocerebroside, glucosylsphingosine (lyso-Gb1), for GD diagnosis. Of 444 screened subjects, 99 (22.3%) were diagnosed with GD at a median (range) age of 21 (1–78) years. Lyso-Gb levels for genetically confirmed GD patients vs. subjects negative to GD diagnosis were 252 (9–1340) ng/mL and 5.4 (1.5–16) ng/mL, respectively. Patients diagnosed with GD1 and mild GBA1 variants had lower median (range) lyso-Gb1, 194 (9–1050), compared to GD1 and severe GBA1 variants, 447 (38–1340) ng/mL, and neuronopathic GD, 325 (116–1270) ng/mL (p = 0.001). Subjects with heterozygous GBA1 variants (carrier) had higher lyso-Gb1 levels, 5.8 (2.5–15.3) ng/mL, compared to wild-type GBA1, 4.9 (1.5–16), ng/mL (p = 0.001). Lyso-Gb1 levels, median (range), were 5 (2.7–10.7) in heterozygous GBA1 carriers with Parkinson’s disease (PD), similar to lyso-Gb1 levels in subjects without PD. We call for a paradigm change for the diagnosis of GD based on lyso-Gb1 measurements and confirmatory GBA1 mutation analyses in DBS. Lyso-Gb1 levels could not be used to differentiate between heterozygous GBA1 carriers and wild type.

Glucosylsphingosine (Lyso-Gb1) as a reliable biomarker in Gaucher disease: a narrative review

“…More recently, a simple and accurate method to determine lyso-Gb1 measurements in DBS samples was established as a useful tool for the screening and diagnosis of GD [ 76 ], while a separate study showed that lyso-Gb1 measured in DBS samples alongside whole-gene sequencing reliably diagnosed GD, although lyso-Gb1 levels did not differentiate between heterozygous GBA1 carriers and wild type [ 77 ]. Nonetheless, Dinur and colleagues proposed a paradigm change for screening patients suspected to have GD based on an analysis of lyso-Gb1 measurements and GBA1 mutation analyses in DBS [ 77 ].…”

Real-Life Experience with Oral Eliglustat in Patients with Gaucher Disease Previously Treated with Enzyme Replacement Therapy

“…Efficacy parameters included changes in platelet count, plasma levels of hemoglobin, glucosylsphingosine (lyso-Gb1), HDL cholesterol and ferritin, liver and spleen volumes, and bone density (T score of lumbar spine measures by density dual-energy X-ray absorptiometry (DEX)). All efficacy parameters were analyzed locally, whereas lyso-Gb1 was performed at Centogene (Rostock, Germany) as previously reported [ 9 ]. IRB approval was obtained for this retrospective audit.…”

Newborn Screening in Gaucher Disease: A Bright and Complicated Future

“…In mass spectrometric approaches, the marker for GD is the decrease in glucocerebrosidase enzymatic activity [31]. While there are promising studies of using glucosylsphingosine (Lyso-GL1) as a biomarker for individual Gaucher screening [40], it has yet to be tested in a large population-based screen, and further investigation is warranted, especially focusing on its inclusion in larger LSD screening panels. In tandem mass spectrometry (MS/MS), the enzymatic reaction is first performed in the "pre-MS/MS" step before injection into the mass spectrometer to detect enzymatic products.…”