A review of the physiological mechanisms, clinical manifestations, and available treatments of Gaucher disease (GD) has been published.
The study, ”A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments,” appeared in the International Journal of Molecular Sciences. The research team was led by Jerome Stirnemann, MD, PhD, from the Department of Internal Medicine, Geneva University Hospital in Switzerland.
The incidence of GD is approximately 1 in 40,000 to 1 in 60,000 births in the general population, increasing to 1 in 800 in Ashkenazi Jews.
Physiological mechanisms
Gaucher disease is a rare, autosomal and recessive genetic disease caused by mutations in the GBA1 gene, which in turn leads to the decrease of the activity of the enzyme glucocerebrosidase (GCase). Gaucher cells are typically the result of the transformation of macrophages (a type of white blood cell) induced by the accumulation of glucosylceramide, which in normal circumstances is degraded by GCase.
GCase is found in lysosomes, a cellular organelle that contains degradative enzymes. Abnormal transport and delivery of GCase could also lead to impaired enzymatic activity in GD.
Alternative pathways for the formation of Gaucher cells have been proposed, including their origin from a sub-population of macrophages with anti-inflammatory, immunomodulatory and tissue repair properties. Increased amounts of molecules involved in immune response, such as cytokines and chemokines, are observed in the plasma of Gaucher patients.
Clinical presentations
Of note, the same GCase mutations can lead to clinical presentations that vary from life-threatening to almost asymptomatic, which highlights the phenotypic heterogeneity of GD.
The main cause of cytopenia (a reduction in the number of blood cells), splenomegaly (enlargement of the spleen), hepatomegaly (enlargement of the liver), and bone lesions associated with GD is considered to be Gaucher cells’ infiltration of the bone marrow, spleen, and liver.
Type 1 Gaucher disease, which affects the majority of patients (90% in Europe and the U.S., but less in other regions), is characterized by effects on the viscera, with onset at approximately age 20. GD1 can limit quality of life and is associated with significant morbidity, but is rarely life-threatening. Conversely, types 2 (the least common) and 3 are also associated with neurological impairment, either severe in type 2 (leading to possible growth disorders and lung lesions) or variable in type 3.
Regarding the association with other diseases, the substance that accumulates in GD influences the formation of Lewy bodies in Parkinson’s disease, which in turn may have an inhibitory effect on GCase activity.
Patients with type 1 GD – as well as carriers of the GBA1 mutation – are predisposed to develop Parkinson’s, often at an earlier age than usual. GCase deficiency may also be related to increased risk of certain types of cancer, including myeloma, lymphoma, melanoma, and pancreatic cancer.
A diagnosis of Gaucher disase usually occurs years after the onset of initial symptoms. It can be confirmed by demonstrating deficient GCase activity (approximately 10-15% of the normal value). Furthermore, identification of mutations in the GBA1 gene may be of prognostic value in some cases. Prenatal diagnosis of GD can be performed by genetic analysis or by measuring GCase activity.
Gaucher disease treatments
Disease-specific treatment consists of intravenous enzyme replacement therapy (ERT) using one of the currently available molecules – Cerezyme (imiglucerase), VPRIV (velaglucerase), or Elelyso (taliglucerase). Orally administered inhibitors of the synthesis of glucosylceramide (called substrate reduction therapy) – Zavesca (miglustat) or Cerdelga (eliglustat) – can also be used. Treatment should be accompanied by clinical, biological and radiological evaluations of Gaucher patients.
Importantly, “available treatments make it possible to reduce cytopenias and organomegalies and to significantly decrease bone manifestations, considerably improving a patient’s quality of life.” Nevertheless, associated complications such as bone disease, Parkinson’s disease, or cancer may lead to unfavorable outcomes. In addition, ERT may be ineffective in Gaucher type 3, whereas prognosis for GD-2 is nearly always fatal.
“The therapeutic advances of recent years, including the development of new enzymes and a new substrate inhibitor, represent significant progress, but research efforts must be maintained,” the authors concluded. “Patients with GD, including asymptomatic patients, must be monitored regularly to detect any complications in the disease’s progression.”
