What is Gaucher's disease?

From the Guidelines

Gaucher's disease type 1 should be treated with enzyme replacement therapy (ERT) as the first-line treatment, specifically with imiglucerase (Cerezyme), due to its proven efficacy and safety in managing major peripheral symptoms and bone abnormalities 1. The treatment of Gaucher's disease type 1 primarily focuses on managing the symptoms and preventing further complications.

• ERT is the reference treatment and has been shown to be effective in restoring GBA activity in patients with GD type 1, with numerous studies documenting its safety and efficacy concerning major peripheral symptoms within the first year of treatment 1.
• Approximately 15% of treated patients develop IgG antibodies against the recombinant enzyme, but in most cases, these antibodies disappear when ERT is continued with the same dosage, and only a few patients develop therapy-limiting inhibitory antibodies 1.
• Substrate reduction therapy (SRT) with N-butyl-deoxynojirimycin (Miglustat; Zavesca) is an alternative option, but it is currently only recommended as second-line therapy for adult patients with GD type 1 who either show severe side effects on ERT or refuse to receive ERT at all and have mild to moderate disease 1.
• The profile of adverse effects on SRT comprises mild to moderate diarrhea, initial weight loss, (sensory) peripheral neuropathy, transient tremor, and possibly cognitive impairment, which may limit its use as a first-line treatment 1.
• Management of Gaucher's disease requires a multidisciplinary approach with regular monitoring of organ function, blood counts, and bone health, as well as genetic counseling for affected families due to the hereditary nature of the condition.

From the FDA Drug Label

Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow ELELYSO, an enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.

Gaucher's Disease is a genetic disorder caused by a deficiency of the enzyme glucocerebrosidase. The main clinical features of Gaucher's disease are:

• Accumulation of Gaucher cells in the liver, spleen, and bone marrow
• Organomegaly due to the accumulation of Gaucher cells
• Anemia and thrombocytopenia due to the presence of Gaucher cells in the bone marrow and spleen The treatment for Gaucher's disease is enzyme replacement therapy, which involves the use of recombinant analogs of human lysosomal glucocerebrosidase, such as taliglucerase alfa and velaglucerase alfa, to catalyze the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside 2 3.

From the Research

Gaucher Disease Overview

• Gaucher disease is a rare autosomal recessive genetic disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leading to the accumulation of its substrate glucosylceramide in macrophages 4, 5, 6.
• The incidence of Gaucher disease varies between 0.4 and 5.8/100,000 inhabitants in the general population, with a higher incidence in Ashkenazi Jews 5, 6.
• The disease is characterized by extreme heterogeneity, with symptoms including anemia, thrombocytopenia, splenomegaly, hepatomegaly, and bone involvement 5, 6.

Clinical Presentation and Diagnosis

• Type 1 Gaucher disease is the most frequent form, accounting for 90% of cases in Europe and the USA, and is characterized by effects on the viscera 6.
• Type 2 and type 3 Gaucher disease are associated with neurological impairment, with type 2 being more severe 5, 6.
• Diagnosis is confirmed by demonstrating a deficiency of acid glucocerebrosidase activity in leukocytes and identifying biallelic pathogenic variants in the GBA1 gene 5, 6.

Treatment Options

• Enzyme replacement therapy (ERT) is the preferred treatment for Gaucher disease, with several products available, including imiglucerase, velaglucerase alfa, and taliglucerase alfa 4, 7, 8.
• Substrate reduction therapy (SRT) is an alternative treatment option, with miglustat and eliglustat being used to inhibit glucosylceramide biosynthesis 6, 7.
• ERT has been shown to improve quality of life and prognosis, with SRT being considered for patients who do not tolerate or cannot receive ERT 4, 7.

Treatment Efficacy and Safety

• Studies have shown that different recombinant glucocerebrosidases are bio-similar and non-inferior in safety and efficacy for surrogate biological response parameters 4.
• ERT given at 30 to 45 units/kg body weight every two to four weeks was generally as effective as the 60 unit/kg dose for assessed clinical outcomes 4.
• Serious adverse events were reported, but nearly all were deemed unrelated to treatment 4.