What is Gaucher disease? Are there treatments?

F. Scott Furbish, Associate Director of Medical Affairs at Genzyme Corporation, gives this response:

Gaucher (pronounced Go-SHAY) disease is a rare genetic disorder affecting fewer than 10,000 people worldwide. It is caused by deficiency of the enzyme glucocerebrosidase, which breaks down a certain lipid, or fat, in the body's cells called glucocerebroside. Without this enzyme, the lipid builds up, causing the disease's symptoms. The type and severity of symptoms can vary widely among individuals with the disease. Symptoms include anemia, fatigue, and enlarged liver and spleen. Patients can also suffer from easy bleeding and bruising, and deterioration of bones, leading to frequent fractures.

Although the disease most often becomes apparent in childhood or early adulthood, some patients do not develop symptoms until later in life. Gaucher disease is a recessive disorder, which means that in order to develop the disease, an individual must inherit two defective copies of the gene, one from each parent. The disorder occurs across many racial and ethnic groups, but it is the most common genetic disorder among Jews of Eastern European descent. Within this Ashkenazi Jewish population, approximately one in 40 people have a genetic mutation for Gaucher disease, and about one in 400 develop the disease.

The only therapy for Type 1 Gaucher disease is Cerezyme* (imiglucerase for injection), a recombinant drug developed by Genzyme General of Cambridge, Mass. Cerezyme stops and reverses the symptoms of Gaucher disease, allowing patients to live normal, healthy lives. Cerezyme and its predecessor, Ceredase*, have been available for nearly 10 years. They have proved safe and effective in reversing the symptoms of Gaucher disease in nearly 3,000 patients in 55 countries over the course of nine years.

Genzyme is conducting research on potential next-generation treatments for Gaucher disease, including gene therapy. For Gaucher disease, gene therapy may be used to help patients' cells produce the required enzyme for years or perhaps a lifetime. Gaucher disease is one of approximately 40 lysosomal storage disorders caused by enzyme deficiencies. Genzyme has products in development for Fabry disease, MPS-I, Pompe disease and Neimann-Pick disease.

Additional information comes from Deborah Elstein at the Gaucher Clinic at the Shaare Zedek Medical Center in Jerusalem.

Gaucher disease was first described in a 32-year-old woman in 1882 by French medical student Philippe Gaucher, who actually assumed that the large splenic cells (which today bear his name) were a manifestation of a primary neoplasm of the spleen. More than a century later, we now know that Gaucher disease is the most prevalent lysosomal storage disorder, caused by an inherited enzymatic defect with consequent accumulation of undegraded glucocerebroside in monocyte-macrophage cells, the so-called Gaucher cells. Diagnosis of the disease is via assay of decreased glucocerebrosidase activity in peripheral blood samples, in conjunction with DNA mutation analysis. Nonetheless, neither quantity of residual activity nor specific genetic makeup (genotype) can accurately predict the type or degree of severity of the disease (phenotype), except in a broad sense.

Classically, three types of Gaucher disease have been described. Type I, which is marked by the absence of neurological involvement by virtue of the presence of the N370S (1226G) mutation on at least one allele, is especially prevalent among the Ashkenazi Jewish population. Within this group, the frequency of the disease is approximately one in 850 live births, although it is seen in other ethnic groups as well. There is tremendous heterogeneity in the severity of the clinical manifestations of type I disease. The vast majority of patients are totally asymptomatic or mildly asymptomatic, but some patients experience lifelong debilitating disease. Most of the symptoms are related to the often massive enlargement of the spleen and liver. Decreased platelet counts (thrombocytopenia) as well as low hemoglobin (anemia) and decreased white blood cell counts (leukopenia) result in easy bruisability and hence black-and-blue marks (ecchymoses); easy bleeding--for example, after dental interventions; fatigue; and a tendency to infections.

In children, growth retardation and delayed sexual maturation are not uncommon. The most debilitating, albeit most variable, symptom is bone involvement: pathological fractures after slight trauma; destruction of heads of the femur or humerus in the hip or shoulder joints (avascular necrosis), and compression fractures of the spine; and "bone crises" of pain, which although self-limiting and diminishing after puberty, may require even narcotics for pain reduction. The basic truism, however, is that there are no two patients with the same constellation of symptoms.

It may be postulated that the enormous heterogeneity in the clinical manifestations of Gaucher disease is attributable to the genotypic variability, this does not gainsay the fact that there is clinical variability even among siblings with the same genetic mutations and even between identical twins. Thus, it must be assumed that there are other genetic and/or nongenetic environmental factors (e.g., hormonal effects, viral infections) affecting the course of the disease, and indeed they may be the trigger for onset of signs and symptoms.

Types II and III are both relatively rare and panethnic, and are marked by involvement of the central nervous system. The minimal neurologic component common to both types is abnormal eye movements in the horizontal plane (oculomotor apraxia). Type II, the infantile or acute form of the disease, is characterized by the appearance of several neurologic features in addition to the severe spleen and liver manifestations. The onset of symptoms is usually during the first six months of life with progressive deterioration of neurologic function until death intervenes, often due to respiratory failure or infection, before the second year of life.

Type III, the juvenile or subacute form of the disease, is marked by a less aggressive acceleration of the neurologic and visceral aspects as seen in type II. Generally, the onset and course of both components is attenuated in type III so that the advent of symptoms is in mid-childhood and survival extends into mid-adulthood. Although cardiac involvement was considered relatively rare, a new variant of type III has been described in Arab, Spanish and Japanese children who are homozygous for a unique genetic mutation, D409H, and evince progressive calcification of aortic and/or mitral valves of the heart that is life-threatening.

Before the advent of enzyme replacement therapy in 1990, medical management was confined to symptomatic relief, and surgical interventions such as orthopedic operations and splenectomy. Enzyme therapy with placental-derived enzyme, alglucerase (Ceredase", Genzyme, Inc.), or the recombinant form, imiglucerase (Cerezyme", Genzyme Therapeutics, Inc., Cambridge, Mass.), has proved to be safe and effective in more than 2,500 patients worldwide. Reduction in organ volumes and improvement in hematological parameters have dramatically improved quality of life of treated patients. Consequently, today there are only very limited indications for splenectomy in Gaucher disease. The good clinical results have been axiomatic despite the wide range of dosages and frequencies employed.

However, therapy as recommended by the manufacturer is administered weekly or biweekly via intravenous infusions, must be continued for life, does not appreciably affect bone or lung disease, and is so expensive (approximately $400,000 per year per 70kg patient) that many patients in less wealthy countries are unable to receive treatment. Too, a serious side effect of life-threatening pulmonary hypertension has been reported in about 10 percent of treated patients in the largest clinic in the world for Gaucher disease in Jerusalem. Thus, the hope for the future is novel approaches to management and maintenance, such as a new oral drug based on substrate inhibition (OGT 918; Oxford GlycoSciences, Oxford, England); in the future, one can look to curative modalities such as gene therapy.