Gaucher disease
Gaucher disease is a lysosomal storage disease characterized by the accumulation of deposits of glucosylceramide (or glucocerebroside) in macrophage cells of the liver, spleen and bone marrow mononuclear system.
The incidence of Gaucher disease in the general population is about 1 in 60,000, but it becomes 1 per 1000 among Ashkenazi Jews.
Gaucher disease is transmitted in an autosomal recessive manner and it is caused by mutations in the GBA gene (1q21), leading to a defect in the activity of glucocerebrosidase (also known as glucosylceramidase or beta-glucosidase).
Clinical manifestations are highly variable. Classically, three main phenotypes are distinguished.
Type 1 is the chronic and non-neurological form, and represents 95% of cases. It is a heterogeneous disease characterized by the association of organomegaly (spleen, liver), bone (pain, bone infarcts, osteonecrosis) and cytopenia (thrombocytopenia, anemia and, more rarely, neutropenia). The activity of some biological markers including chitotriosidase enzyme, ACE (angiotensin converting enzyme), ferritin and tartratorresistente acid phosphatase (TRAP) are increased.
Type 2 is the acute neurological form, characterized by early onset (during the first year of life) brainstem dysfunction, rapid progression and associated organomegaly.
Type 3 is the subacute neurological form and is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia), associated with the manifestations of the disease type 1 and with onset in childhood or adolescence. Encephalopathy may be the first sign of the disorder or can occur later in the disease course.
It has also been described a lethal perinatal form manifested as a decrease or absence of fetal movements or anasarca.
Diagnosis can be confirmed by measuring the level of glucocerebrosidase activity in circulating leukocytes or skin fibroblasts.
Currently, there are two specific treatments available for Gaucher disease, but the substitute intravenous treatment with recombinant enzyme imiglucerase remains the treatment of choice indicated in patients with type 1 and type 3 disease.
Oral substrate reduction therapy using miglustat provides an alternative second-line treatment. It is important that patients with Gaucher disease receive treatment before the onset of sequels that do not respond to these therapies.
Symptoms
The clinical manifestations are highly variable and the disease is divided into three types:
- GD type 1: this is the most common form in Western populations, accounting for 95% of cases. It produces fatigue, liver and spleen enlargement, bone pain and cytopenias (mainly thrombocytopenia and anemia). It does not affect the nervous system.
- GD type 2 is a rare type of GD that severely affects the spinal cord in the first two years of life and has a poor prognosis.
- GD type 3 is the less severe neurological form that is rare in the United States and Europe, but is the most common worldwide. It is characterized by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia). It usually appears in childhood or adolescence. Patients can live into adulthood, some up to 50 years of age, with the help of treatment.
Genes analyzed
Bibliography
Grabowski GA, Horowitz M. Gaucher’s disease: molecular, genetic and enzymological aspects. Baillieres Clin Haematol. 1997 Dec 10(4):635–56.
Lesage S, Anheim M, Condroyer C, Pollak P, Durif F, Dupuits C, et al. Large-scale screening of the Gaucher’s disease-related glucocerebrosidase gene in Europeans with Parkinson’s disease. Hum Mol Genet. 2011 Jan ;20(1):202–10.
Zimran A, Gelbart T, Westwood B, Grabowski GA, Beutler E. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet. 1991 Oct;49(4):855–9.
