Developing abnormal antibodies specific to glucosylsphingosine — a fat that builds up in cells of Gaucher disease patients — may be the cause of monoclonal gammopathy, and explain why patients with type 1 disease are at high risk of multiple myeloma, a small study shows.
A test in two patients also indicates that substrate reduction therapy (SRT), including Cerdelga (eliglustat), may help to prevent or lessen gammopathy in these people.
The report with these findings “Glucosylsphingosine but not Saposin C, is the target antigen in Gaucher disease-associated gammopathy” was published in the journal Molecular Genetics and Metabolism.
Gaucher disease is caused by mutations in a gene called GBA, which provides instructions to make the beta-glucocerebrosidase enzyme. Deficiency in this enzyme results in toxic quantities of a fat (lipid) called glucocerebroside (GlcCer) and its derivative glucosylsphingosine (GlcSph), especially within the bone marrow, spleen, and liver.
Both GlcCer and GlcSph are highly inflammatory lipids that can alter the function of certain blood cells.
Patients with type 1 Gaucher (GD1) — the most common type of the disease, and one that normally does not involve neurologic symptoms — have a markedly high risk of blood cancer, particularly multiple myeloma.
The likelihood of this cancer developing in GD1 patients is estimated to be almost 37 times higher than the general population.
Many type 1 patients also have polyclonal or monoclonal gammopathy of unknown significance (MGUS) — a condition where an abnormal antibody, known as M protein, is produced in the blood. In some, monoclonal gammopathy can progress to multiple myeloma.
The reasons for the increased risk of monoclonal gammopathy in type 1 Gaucher disease are still enigmatic. What induces uncontrolled proliferation of antibody-producing cells (B-cells) and the mechanisms underlying progression to multiple myeloma also remain poorly understood.
Previously, scientists identified GlcSph as an important mediator of B-cell activation and production of abnormal antibodies. In fact, research suggested that GlcSph is the target for those unusual antibodies in the blood of patients with monoclonal gammopathy.
Yet other studies point to a different factor — a lipid-binding protein called saposin C (SapC) — as the molecule targeted by those antibodies.
To clarify this, a team led by researchers at Yale University conducted a blood screening for anti-GlcSph or anti-SapC antibodies in 16 patients with GD1 who also had monoclonal gammopathy, ages 37 to 90, as well as in eight GD1 patients without gammopathy and eight healthy subjects.
While anti-SapC reactivity was present in people in all these groups, anti-GlcSph antibodies were exclusively found in patients with monoclonal gammopathy; it was not present in those without gammopathy or in healthy controls. These results were confirmed using multiple approaches.
Researchers then conducted a small test in two patients, to see if substrate reduction therapy with Cerdelga could lessen gammopathy. (Of note, Cerdelga is marketed by Sanofi Genzyme, which funds the National Gaucher Disease Treatment Center at Yale School of Medicine.)
In both patients (one switched from long-term enzyme replacement therapy), Cerdelga significantly lowered the levels of GlcSph, which was accompanied by decreased levels of abnormal antibodies.
“Together, our data show that GlcSph but not SapC is the antigenic target in GD1-associated [monoclonal gammopathy] and that therapy aimed at reducing the levels of [GlcSph] resulted in reduction of clonal immunoglobulin [antibody] in vivo,” the scientists wrote.
Larger studies are needed to clarify the diversity and natural history of monoclonal gammopathy, and to confirm if treatments that lower GlcSph levels are able to prevent the condition or slow its transition to multiple myeloma, the team said.
