Patient centered guidelines for the laboratory diagnosis of Gaucher disease type 1

Abstract

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide.

Pediatric Gaucher Disease Presenting with Massive Splenomegaly and Hepatic Gaucheroma

“…CCL18 is a member of the C-C chemokine family, and like chitotriosidase, it accumulates in the alternatively activated macrophages present in Gaucher cells in GD. An increase in CCL18 can also be found in various lysosomal and non-lysosomal diseases, similar to chitotriosidase [7].…”

Revisiting the diagnosis of Gaucher disease in a family with multiple GBA1 variants

“…However, it was always noted that there is a range in enzyme activity, dependent on the laboratory and source of protein tested. The incorporation of measurement of glucosylsphingosine (lysoGL1, lysoGb1) levels can now aid in confirming the enzymatic analysis, as this lipid substrate is elevated in samples from patients with GD (Dardis et al, 2022; Revel‐Vilk et al, 2020).…”

“…If patients were genotyped previously with screens for a limited number of mutations, it may be advisable to repeat the genotyping with an analysis of the entire GBA1 gene, especially when there is a question regarding the diagnosis. Today, especially in the newborn period, assays for glucocerebrosidase activity are increasingly performed on dried blood spots, which are often stored and transported by mail, and may have compromised accuracy, requiring validation by careful GBA1 sequencing and glucosylsphingosine assays (Dardis et al, 2022) Furthermore, even patients with two identified mutations can potentially have both on the same allele (Balwani et al, 2011), so collecting samples from family members can be useful. Since variant T369M and E326K (p.E365K), a second non‐GD‐causing variant (Park et al, 2002), are frequently encountered in the general population, counselors will need to be informed regarding the implications of these alleles, which may mildly reduce glucocerebrosidase activity but do not cause GD, especially as they may be identified in newborn screening.…”

Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann–Pick disease types A, B and A/B)

“…Results can be influenced by anemia, leucopenia, and recent transfusions [ 15 ]. Pre-analytical conditions for sampling and storage conditions are also important since enzyme activities in DBS are highly sensitive to heat and humidity [ 50 , 51 ]. Regarding acid sphingomyelinase activity, contrary to most other lysosomal enzymes, the assay had so far been restricted to a very limited number of laboratories, due to its technical complexity.…”

“…Results can be influenced by anemia, leucopenia, and recent transfusions [15]. Pre-analytical conditions for sampling and storage conditions are also important since enzyme activities in DBS are highly sensitive to heat and humidity [50,51].…”