Gaucher disease

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is characterized by deficiency of the enzyme glucocerebrosidase. This enzyme is responsible for degradation of glucocerebroside (GlcCer) and glucosylsphingosine (GluSph). As a consequence, accumulation of these substrates in lysosomes leads to specific manifestations of the disease, which traditionally has been divided into three types (1,2,3).Although each type of the disease has special manifestations and prognosis, there is a continuum of clinical findings from an asymptomatic to prenatal lethal forms. Differentiating between these types of the disease is challenging due to mutations that are common in 2 types or multiple mutations that can complicate genotype/ phenotype correlation. Albeit, it is essential to know the type of the disease in order to understanding clinical outcomes and response to therapy.Non-neuronopathic GD (GD type 1), the mildest form of the disorder, can present at any age. Symptomatic patients of this group suffer from hepatosplenomegaly, anemia, thrombocytopenia, fatigue, bone pain, osteoporosis, growth retardation and delayed puberty. Pulmonary or renal involvement is possible in this type. In contrary to conventional definitions of GD type 1, recently some mild neuropathies have been recognized such as Parkinson s disease or minimally symptomatic peripheral neuropathies and small fiber neuropathies. A variable spectrum of visceral manifestations of GD1 and neurological involvement would be expectable in Chronic neuronopathic GD (GD type 3). Its onset is more common in childhood. The third type of the disease has the worst prognosis. Early initiation of severe neurological impairment (between 3-6 months) accompanied by visceral involvement is the difference of this form from the others. Perinatal- lethal and cardiovascular subtypes of the disease that are the other phenotypes of GD are very rare.Although the presence of gaucher cells in bone marrow is helpful for diagnosis, measuring the GCase activity in totalocytes, mononuclear cells or cultured fibroblast is more accurate. Detection of GBA1 mutation in patients with low activity of the enzyme confirm the diagnosis.The level of some biomarkers such as chitotriosidase, CCL18, ACE, TRAP, ferritin, lysozymes, MGUS and Lyso-GL1 reflect the disease severity. Also, they are useful for evaluating the treatment outcomes. Glucosylsphingosine (lyso-GL1) appears to be the most specific, sensitive and predictive biomarker of GD symptoms.Enzyme replacement therapy in symptomatic patients with GD type 1 and 3 is the mainstay of the treatment and improves the quality of life and prevents long term complications. Substrate reduction therapy (Miglustat, Eliglostat) is an alternative therapy in some patients. Bone marrow transplantation is no longer used due to low benefit/risk ratio and the other effective and well-tolerated therapies. However, pharmacological chaperones, because of their ability to cross the blood brain barrier, can be potentially ameliorating for GD type 3 and 2. Gene therapy is still in the basic stages of the research. New insights into the molecular pathophysiology of the disease has opened a pathway for developing innovative therapeutic strategies in future.Frequent and regular monitoring of clinical examination, laboratory test and imaging studies even in asymptomatic patients is recommended to evaluate the efficacy of treatment in symptomatic cases or to detect any complications in progressive disease