1. Glucosylsphingosine (lyso-Gb1) plays a central role in the diagnosis and proper assessment of disease severity in Gaucher patients

Glucosylsphingosine (lyso-Gb1) plays a central role in the diagnosis and proper assessment of disease severity in Gaucher patients

Prof. Arndt Rolfs, MD 1, 2 Anne Katrin Giese, MD 2, 3 Susanne Zielke 2 Claudia Cozma, MD 1
1 CENTOGENE AG 2 University of Rostock 3 Massachusetts General Hospital
September 22, 2017

These findings were presented at the 13th International Congress Inborn Errors of Metabolism (ICIEM 2017).


Introduction:

Gaucher disease (GD) is an autosomal recessive, rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophagemonocyte system.

Materials and methods:

We have developed and systematically validated a high-throughput workflow for the simple testing of GD patients: beta-glucocerebrosidase enzymatic activity, glycosylsphingosine (lyso-Gb1) quantification in DBS followed by GBA gene sequencing from the sample blood sample. We report data from over 940 Gaucher individuals. Determination of lyso-Gb1 using LC/MRM-MS was investigated in three GBA cohorts comprising of: (A) 247 homozygotes GBA cases; (B) 308 compound heterozygotes GBA patients and (C) 305 Gaucher carriers. Lyso-Gb1 has a sensitivity and specificity of 100% for the primary diagnosis of GD. The clinical severity of the mutations and their location could be correlated with the lyso-Gb1 in the homozygous cases, e.g. c.1295G>T is correlated with mild lyso-Gb1 values while c.1060G>A and c.518C>A with extremely high lyso-Gb1 values ( > 600 ng/mL). The most common GBA mutations arec.1226A>G (34 %) and c.1448T>C (25.5 %). c.1448T>C is a severe mutation correlating to a massive increase of lyso-Gb1 up to 2,850 ng/mL. Lyso-Gb1 for c.1226A>G can vary from very mild to moderate.

Summary:

Lyso-Gb1 concentrations in blood can be used for the easy, early and highly specific diagnosis of GD patients.