Description of the condition

Gaucher disease is the most common lysosomal storage disorder. It is inherited as an autosomal recessive trait and characterised by the accumulation of glucocerebroside in the lysosomes due to a deficiency of the enzyme glucocerebrosidase (lysosomal acid β‐glucosidase) (Beutler 2001). The glucocerebrosidase gene (GBA) has been mapped to chromosome one, band q21. More than 200 disease‐causing mutations have been documented (Jmoudiak 2005).

The incidence of Gaucher disease in the general population is less than 1 in 30,000 to 40,000. It is more prevalent in people of Eastern European (Ashkenazi) Jewish descent with a prevalence of 1 in 1000 and a carrier frequency of 1 in 14 people (Mehta 2006). Classically three types of Gaucher disease have been identified based on the presence or absence of primary central nervous system involvement and the severity of the disease (Beutler 2001).

Description of the intervention

The treatment of Gaucher disease before the 1990s was essentially symptomatic. The advent of enzyme replacement therapy (ERT) has revolutionised the treatment approach to this disorder. Human placental β‐glucocerebrosidase was modified to expose variable numbers of mannose residues, so that it can be targeted to the macrophages (Danuta 1995). This is the preferred form of treatment for symptomatic individuals with type 1 disease. Treatment results in significant regression of disease in these individuals and has very few side effects (Morales 1996). The main drawbacks of ERT are that weekly infusions of the enzyme are required, and the treatment is very expensive. The cost of therapy for a child weighing 50 kg (at a dose of 130 units per kg per month) is approximately USD 300,000 per year for the medication alone (Beutler 2005). Moreover, the enzyme does not cross the blood brain barrier so it cannot be effective in types 2 and 3 diseases to improve neurological symptoms (Erikson 1993; Zimran 1995).

Since the pathophysiology of Gaucher disease is due to accumulation of lipid laden macrophages, bone marrow transplantation was thought of as a logical treatment for the disease. The first allogeneic bone marrow transplantation was done in the 1980s. The individual died due to sepsis but had shown regression of disease manifestations (Rappeport 1984). Since then many people have undergone hematopoietic stem cell transplantation (HSCT) (August 1984; Chan 1994; Hobbs 1987; Ringden 1988; Ringden 1995; Svennerholm 1991; Tsai 1992). Initially the HSCT was performed using donor bone marrow from siblings with an identical tissue type. With major improvements in the various areas of transplantation, the choice of donor cells has now expanded to include peripheral blood stem cells (PBSC) mobilised into the blood of the donor using granulocyte colony stimulating factor (G‐CSF), marrow from matched or mismatched family members or unrelated donors and cord blood from siblings and unrelated babies. There is also increasing use of haploidentical tissue from parents.

How the intervention might work

The outcomes of HSCT are affected by numerous aspects of the transplant such as donor enzyme level, degree and persistence of donor chimerism, and post‐transplant complications (Peters 2003; Steward 2005). Benefit of transplantation varies between organ systems. Hematological and physical improvement is rapid and sustained. Reticuloendothelial organs, such as the liver and spleen regress within a few months (Peters 2003) and there is evidence that most of the skeletal changes seen in Gaucher disease regress (Starer 1987). The evidence on the beneficial effect of bone marrow transplantation on the regression of the neurological disease in people with types 2 and 3 is conflicting (Ringden 1988; Svennerholm 1991; Tsai 1992). The response is slow and the effectiveness appears to depend on the age of the individual, severity of the disease and its progression at the time of treatment.

Newer modes of Intervention

Besides ERT and HSCT there are a few other promising treatments. A recently introduced therapy is substrate reduction therapy (SRT). Miglustat (Zavesca, N‐butyl deoxynojirimycin, OGT 918) has been licensed for the treatment of Gaucher disease in those who are not able to receive ERT. This compound inhibits glucosylceramide synthase, preventing new synthesis of glucosylceramide. The clinical trials show it is effective in most people with mild and stable disease, but is less well‐tolerated. The drug crosses the blood brain barrier, and its effectiveness in the treatment of the types 2 and 3 Gaucher disease is under investigation. A new generation of therapeutic recombinant enzymes is under development which has an in‐frame fusion to HIV‐1 trans‐activator protein transduction domain (TAT). The TAT modification improves the delivery of the enzyme to cells without mannose ‐specific endocytic receptors on the plasma membrane. Another option is the use of more specific small molecules that inhibit substrate synthesis (substrate deprivation), or act as chaperones to increase the activity of the enzyme (enzyme enhancement therapy). Various gene transfer methods are also in different trial phases (Schmitz 2007).

Why it is important to do this review

HSCT is a less expensive procedure that offers the potential of permanent cure when compared to other conservative measures now in use (ERT, SRT). However, the procedure is associated with a mortality ranging from less than 5% to more than 10% depending on the availability of human leucocyte antigen (HLA)‐matched sibling and the source of the stem cells (Kumar 2007). The mortality is expected to be higher in the severely compromised individuals with Gaucher disease. The choice between HSCT and conservative measures to treat people with Gaucher disease depends on the assessment of the long‐term benefits of HSCT over the significant mortality and morbidity associated with the procedure. Another issue to be resolved in this area is whether HSCT can correct metabolic abnormalities of the central nervous system in individuals with type 2 and 3 Gaucher disease. This is an updated version of a previously published review (Somaraju 2008b; Somaraju 2010; Somaraju 2012).