Gaucher Disease

Gaucher disease (GD, ORPHA355) is a rare genetic disorder, with an incidence between 1/40000-1/60000 births, it grows in some ethnic groups, such as among Ashkenazi Jews it is 1: 800. Gaucher disease is characterized by a wide broad clinical spectrum, and it is classified in three main phenotypes. Type 1 GD, affecting 95% of patients, is a chronic non-neurological form, with a heterogeneous phenotype characterized by organomegaly (spleen, liver), orthopedic complications (pain, bone infarcts, osteonecrosis) and blood disorders such as cytopenia (thrombocytopenia, anemia, and, rarely, neutropenia). Type 2 GD is an acute neurological form characterized by organomegaly and early-onset brain stem dysfunction, within the first year of life with rapid progression. Type 3 GD is a subacute neurological form with onset in childhood or adolescence, characterized by the same symptoms of type 1 GD besides by progressive encephalopathy (oculomotor apraxia, epilepsy and ataxia).

GD is an autosomal recessive disorder, caused by mutations in GBA1 (1q21) gene, which encodes for glucocerebrosidase (GCase), or beta acid glucosidase. Glucocerebrosidase hydrolyzes glucosylceramide (GlcCer) into recyclable glucose and ceramide. The impaired functioning of beta acid glucosidase causes glucocerebroside storage in lysosomes of macrophages, inducing their transformation into Gaucher cells. These cells are typically enlarged, mainly infiltrate bone marrow, spleen, and liver, causing functional alterations of these organs. Since GD is an autosomal recessive disorder, in order to manifest the disease, affected patients have both allelic copies with one causative mutation in homozygosis or with 2 different pathogenic variants, one in paternal allele and the other in maternal one, in compound heterozygosis. Rarely, Gaucher disease can be caused by glucocerebrosidase activator deficiency, saposin C.

In GD, as well as others rare metabolic disorders, diagnostic delays and misdiagnosis are reported. A right and early diagnosis is a determining factor for starting the specific treatment of the disease. The main tool for GD diagnosis is GCase enzymatic activity analysis on DBS (Dried Blood Spot) or leucocytes. Genetic analysis is necessary to confirm GD diagnosis, for prognosis and genetic counseling. Furthermore, the determination of uncatalyzed substrate provides a diagnostic confirm and it is useful for monitoring therapy.

Nowadays, there are two therapeutic approaches for GD: enzyme replacement therapy (ERT) and substrate reduction therapy. The first uses a recombinant beta acid glucosidase, the second one is an oral therapy which balances the synthesis/degradation ratio of glucosylceramide, representing a valid therapeutic option for GD patients.