Deficient activity of the lysosomal enzyme b-glucocerebrosidase (GBA; EC 22.214.171.124), caused by mutations in the GBA gene, results in storage of glucocerebroside (or glucosylceramide; GC). GBA is activated by saposin C, which is derived from proteolytic cleavage of prosaposin. Build-up of undegraded GC occurs primarily in macrophages, resulting in characteristic “Gaucher-cells”: enlarged, sometimes multinucleated cells with a typical striated cytoplasm. The disorder has an autosomal recessive pattern of inheritance and is extremely rare.
The estimated birth prevalence reported for The Netherlands is 1.16 per 100.000, which is consistent with other reports of approximately 1 in 75.000. While the disorder is panethnic, the prevalence of type I disease in the Ashkenazi Jewish population is 1 in 850.
Gaucher disease (GD) is divided in three major clinical subtypes. GD type 1 (OMIM 230800), or chronic non-neuronopathic GD, is the most prevalent subtype encompassing approximately 94% of all GD cases.
Pathophysiology and phenotypes
Gaucher cells are primarily found in liver, spleen and bone marrow. In severe cases, infiltration of lymph nodes, lung, kidney and heart by Gaucher cells has been described.
How Gaucher cells induce pathology in different tissues is only partially understood. The sheer number of cells may create mass effects. Furthermore, since Gaucher cells are metabolically active, secreting several cytokines and proteins into the circulation, there has been speculation that inflammation may play an important role as well. While mature Gaucher cells resemble alternatively activated macrophages, smaller, surrounding cells have been identified as possessing a more classically activated pattern. This mixture of cells may display a range of pro- and anti-inflammatory effects on the surrounding tissue and beyond. A number of associated conditions in Gaucher disease have been ascribed to some of these factors: increased risk of (haematological) cancers; wasting; increased energy expenditure; insulin resistance; bone disease.
There is wide variability in disease severity, especially in non-neuronopathic or type 1 disease. This observation suggests that other genetic and environmental factors influence the phenotype.
(OMIM 230800) patients have variable degrees of cytopenia, hepatosplenomegaly and bone disease ranging from atypical bone pain to extremely painful bone crises or avascular necrosis. The term “non-neuronopathic” is not completely adequate as these patients have a higher incidence of peripheral neuropathy and Parkinson’s disease. Table one shows the most prominent features of GD1 and complications/management.
(OMIM 230900), or acute neuronopathic GD, has its onset at <1 year of age with progressive neurological features leading to early death while (OMIM 231000), or chronic neuronopathic disease, refers to all Gaucher disease patients with neurological disease manifestations who do not have the acute form. Type 3 patients can exhibit a wide range of mild to severe neurological symptoms (such as supranuclear horizontal gaze palsy, epilepsy, progressive ataxia, cognitive impairment, severe thoracic kyphosis of neurological origin), organomegaly and skeletal disease.
A distinct form of type 2 GD is the perinatal lethal form (collodion type GD, OMIM 608013) which, aside from hepatosplenomegaly and pancytopenia, is associated with microscopic skin changes. This form often presents as nonimmune hydrops fetalis.
In addition, a rare variant of (chronic) neuronopathic disease (OMIM 231005) has been described in Jenin Arab patients, characterised by the presence of valvular heart disease with cardiovascular calcifications, oculomotor apraxia and mild visceromegaly.
Atypical forms of Gaucher disease may result from Saposin C deficiency or prosaposin deficiency (OMIM 610539).
Although sophisticated disease-specific treatments are now available, supportive care is still of importance. Since the advent of ERT in the 1990s, splenectomies are rarely needed. However, in non-Western countries, ERT may not be affordable and patients may still need to undergo this procedure. Splenectomy usually results in immediate improvement in cytopenia and relief of abdominal discomfort. However, without disease specific treatment, patients are at risk of progressive bone and liver disease, including the associated complications.
Chronic symptoms in Gaucher disease include fatigue and wasting, although the latter is rarely seen in adults. Whether chronic fatigue in adults is directly caused by Gaucher disease is not entirely clear, as no direct relationship exists between disease severity and degree of disability because of fatigue. Lifestyle interventions to increase activity and fitness are sometimes helpful.
Bleeding has been a major problem related to thrombocytopenia, thrombocytopathy and decreased clotting factors. Coagulation studies, including PT and aPTT need to be performed before any surgical procedure and prepartum. Supplementation with coagulation factors or plasma may be indicated.
For those with chronic bone disease, specific physical therapy programs may be needed. For patients with severe skeletal disease, especially those with fractures and osteoporosis, bisphosphonates have been used. While they lead to an increase in bone density, the clinical relevance of this treatment is unclear. Also, new evidence points towards decreased osteoblast activity rather than increased bone loss, and prolonged bisphosphonate therapy may further impair bone remodeling.
Allogeneic bone marrow transplantation or HSCT has proven to be useful, especially in young type 3 patients, but is nowadays not frequently applied in Western countries.
Enzyme replacement therapy
The most important change in the treatment of Gaucher disease has been the development of highly effective enzyme replacement therapy (ERT). Recombinant GBA, slightly modified to enhance uptake in macrophages, has exerted dramatic effects. More than two decades of experience with Cerezyme (imiglucerase, Genzyme Corp. MA) has shown that spleen and liver size can shrink dramatically, with concomitant improvements in cytopenia and physical wellbeing. Effects of ERT in advanced cases of Gaucher disease are less robust. Those with extensive pre-treatment bone or liver disease may show a partial response to treatment, but remain at risk for complications.
Disease manifestations in mildly affected adults remain reversible for a long time and their disease is usually stable. These patients may not need any therapy.
ERT is also very effective in reducing the visceral and skeletal symptoms in chronic neuronopathic disease. However, there is no evidence that ERT has reversed, stabilized or slowed the progression of neurological involvement.
In the past years, two new enzyme preparations have been developed: velaglucerase (Vpriv, Shire HGT) licensed in the EU and the USA, and taliglucerase (Uplyso, Protalix/Pfizer) licensed in the USA. Studies have shown effectiveness on all key disease manifestations for all of these enzymes.
Safety has so far not been a major concern.
Substrate reduction therapy
An alternative to infusion therapy is the use of orally available substrate inhibitors. These small molecules act through inhibition of glucosylceramide synthase, the first committed step in the biosynthesis of complex glycosphingolipids. Miglustat (N-butyl deoxynojirimycin, Zavesca, Actelion) is licensed for patients with mild to moderate type 1 Gaucher disease, who are unsuitable to receive ERT. Miglustat has been shown to reduce liver and spleen size and improve haemoglobin and platelet counts. For patients with poor venous access, this therapeutic modality may offer an alternative to ERT. However, a recent study designed to switch patients with stable disease from ERT to miglustat has shown a high number of withdrawals because of side effects or progression of disease manifestations. Specifically, many patients experience gastrointestinal side effects, which limits the use of miglustat. Miglustat has been suggested to be of additional value to ERT for treatment of chronic neuronopathic patients, but this has not been proven.
A new substrate reduction therapy is eliglustat tartrate, a glucosylceramide analogue, reversibly inhibiting GCS. The effectiveness has been proven in clinical trials on all relevant disease parameters. As the molecule is metabolized by CYP2D6, certain medication needs to be avoided and individual variation in metabolizing capacity need to be checked. In high concentrations it may cause rhythm disturbances and use of eliglustat is not indicated for patients with cardiovascular disease. Currently, insufficient data are available that show superiority of eliglustat over ERT, especially on long-term complications and patients with active bone disease or polyneuropathy. However, it offers a new alternative for those patients that prefer an oral treatment. Eliglustat is now authorized in the USA and the EU (Cerdelga, Genzyme Corp, MA).
SPHINX is officially acknowledged as center of expertise for Gaucher disease. All Dutch patients with Gaucher disease will be referred to us after diagnosis for patient care and research.
The Amsterdam UMC participates in several research projects. More information on this can be found in the research section.