Classification and aetiology
Gaucher disease is one of at least 50 inherited lysosomal storage disorders (LSDs) that have a collective incidence of one per 7000 to 8000 live births.1 Each lysosomal storage disorder is caused by a genetic defect in a specific lysosomal enzyme, receptor target, activator protein, membrane protein, or transporter that causes lysosomal accumulation of specific substrates.
The genetic defect in Gaucher disease is mutation of the GBA gene encoding acid β-glucosidase (glucocerebrosidase), a lysosomal enzyme involved in the degradation of glycosphingolipids. Individuals with Gaucher disease have insufficient acid β-glucosidase activity, resulting in accumulation of the major substrate, glucosylceramide, in lysosomes.2
Glucosylceramide storage in Gaucher disease primarily occurs in cells of monocyte/macrophage lineage. Clinical manifestations occur wherever these cells migrate; in the bone marrow, skeleton, liver, spleen, and lungs.3 The disease can appear at any age and is always chronic and progressive. The severity and rate of progression varies widely among patients.
Clinical manifestations of Gaucher disease
Figure adapted from Grabowski GA. J Pediatr 2004; 144(5 Suppl): S15-9
The majority of patients* are affected by a form of Gaucher disease referred to as type 1, or non-neuronopathic.4,5 In these patients, disease progression causes debilitating symptoms and complications that reduce quality of life. Progressive deformity of the skeleton, enlargement of the liver/spleen, and painful complications of skeletal disease are causes of significant disability.6 Patients also have an increased risk of developing life-threatening conditions such as pulmonary hypertension or multiple myeloma.7,8 As a population, the life expectancy at birth may be reduced by up to 9 years compared with the general population.9
Around 5 percent of Gaucher patients are affected by severe, or neuronopathic, forms of Gaucher disease that involve the central nervous system and cause neurodegenerative disease.4,10 The most severe and rarest form, type 2, typically presents in infancy and leads to death by the age of 2 years. A third subtype, type 3, usually presents in childhood or adolescence and progresses more slowly.5 Patients with Gaucher disease type 3 have survived between 5 and 50 years.4
The subtype classification of Gaucher disease serves practical purposes but does not accurately reflect the disease presentation in clinical settings. As with most LSDs, Gaucher disease can be considered a continuum of clinical presentations with overlap between subtypes.11 This can make recognition and diagnosis of Gaucher disease challenging.
Gaucher disease is one of the most common LSDs with an incidence of 1 in 40,000 to 1 in 50,000.2 Gaucher disease is pan-ethnic but occurs with a higher incidence among individuals of Ashkenazi Jewish descent (1 in 800) due to the high frequency of carriers in this population.2 Males and females are affected equally.12
*In North American, European and other “European-derived” Caucasian populations.
The GBA gene encoding acid β-glucosidase is inherited in an autosomal recessive fashion. Hence an individual must carry two mutant alleles, one from each parent, for the disease to manifest.
Gaucher disease is named after the French dermatologist, Phillipe Charles Ernest Gaucher, who in his 1882 MD thesis first described the phenotype today classified as type 1 (non-neuropathic) Gaucher disease.