Alpha-Synuclein mRNA Level Found Dependent on L444P Variant in Carriers and Gaucher Disease Patients on Enzyme Replacement Therapy.

Gaucher disease (GD) is the most frequent sphingolipidosis, caused by biallelic pathogenic variants in the GBA1 gene encoding for ß-glucocerebrosidase (GCase, E.C. 3.2.1.45). The condition is characterized by hepatosplenomegaly, hematological abnormalities, and bone disease in both non-neuronopathic type 1 (GD1) and neuronopathic type 3 (GD3). Interestingly, GBA1 variants were found to be one of the most important risk factors for the development of Parkinson's disease (PD) in GD1 patients. We performed a comprehensive study regarding the two most disease-specific biomarkers, glucosylsphingosine (Lyso-Gb1) and α-synuclein for GD and PD, respectively. A total of 65 patients with GD treated with ERT (47 GD1 patients and 18 GD3 patients), 19 GBA1 pathogenic variant carriers (including 10 L444P carriers), and 16 healthy subjects were involved in the study. Lyso-Gb1 was assessed by dried blood spot testing. The level of α-synuclein as an mRNA transcript, total, and oligomer protein concentration were measured with real-time PCR and ELISA, respectively. α-synuclein mRNA level was found significantly elevated in GD3 patients and L444P carriers. GD1 patients, along with GBA1 carriers of an unknown or unconfirmed variant, as well as healthy controls, have the same low level of α-synuclein mRNA. There was no correlation found between the level of α-synuclein mRNA and age in GD patients treated with ERT, whereas there was a positive correlation in L444P carriers.

Plasma chitotriosidase activity versus plasma glucosylsphingosine in wide spectrum of Gaucher disease phenotypes - A statistical insight.

Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate. In this paper we focused entirely on statistical analysis, performing a thorough search of possible relations, dependencies and differences in the levels of these two biomarkers in a cohort of 64 Polish GD patients. We found that the treatment of GD with enzyme replacement therapy (ERT) changes the distribution of the disease biomarkers; their levels follow a normal distribution only in untreated patients. The variable "disease biomarker level" was found dependent of the binary variable "treated with ERT or not". It was found independent of the following variables: "disease type", "splenectomized or not", and "heterozygous for 24-bp duplication for CHIT1 variant" or "CHIT1 wild type". An almost perfect linear correlation (coefficient of determination R2 = 0.99) between the chitotriosidase activity and GlcSph level was revealed in splenectomized patients.