Gaucher disease is a rare inherited disorder, in which people do not have enough of an enzyme called acid beta-glucosidase, which normally breaks down a fatty waste product called glucosylceramide. Without the enzyme, glucosylceramide builds up in the body, typically in the liver, spleen and bone marrow, which produces the symptoms of the disease: anaemia (low red blood cell counts), tiredness, easy bruising and a tendency to bleed, an enlarged spleen and liver, and bone pain and breaks.
Gaucher disease (GD) is a lysosomal storage disorder encompassing three main forms (types 1, 2 and 3), a fetal form and a variant with cardiac involvement (Gaucher disease - ophthalmoplegia - cardiovascular calcification or Gaucher-like disease).
Frequency
The frequency is approximately 1/100,000. The annual incidence of GD in the general population is about 1/60,000, but it can reach up to 1/1,000 in Ashkenazi Jewish populations.
Symptoms
The clinical manifestations of this disease are highly variable.
- Type 1 (90% of cases) is the chronic and non-neurological form associated with organomegaly (spleen, liver), bone anomalies (pain, osteonecrosis, pathological fractures) and cytopenia.
- Type 2, the acute neurological form, is characterized by early onset, rapidly progressing brainstem dysfunction, associated with organomegaly and leading to death before the age of 2.
- Type 3, the subacute neurological form, affects children or adolescents and is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia) with the systemic manifestations seen in type 1. The fetal form manifests with a decrease or absence of fetal movements or anasarca. Gaucher-like disease presents with progressive calcification of the aorta and the aortic and/ or mitral valves as its main feature.
Genetics
GD is due to mutations in the GBA gene (1q21) that codes for a lysosomal enzyme, glucocerebrosidase, or in very rare cases the PSAP gene that codes for its activator protein (saposin C). The deficiency in glucocerebrosidase leads to the accumulation of glucosylceramidase (or beta-glucocerebrosidase) deposits in the cells of the reticuloendothelial system of the liver, the spleen and the bone marrow (Gaucher cells).
Transmission is autosomal recessive.
Diagnosis
Formal diagnosis of the disease is determined by the measurement of glucocerebrosidase levels in circulating leukocytes. Genotyping confirms the diagnosis.
Differential diagnoses include other lysosomal storage disorders. The presence of Gaucher-like cells can be found in certain hematologic diseases (lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukemia; see these terms).
Treatments
There are two available treatments for GD type 1 and 3: enzyme substitution therapy (using imiglucerase or velaglucerase) and substrate reduction therapy (miglustat). These treatments are ineffective for GD type 2.
Prognosis
The prognosis is good in GD type 1.
In type 2, death usually occurs before the age of 2. Without specific treatment,
GD type 3 progresses to death within a few years.