Patients with GD may present at a different age and clinical subtypes are [3]:

• Type 1 - This subtype comprises between 95-99% of all clinical presentations encountered in medical practice [1]. The main clinical features include massive hepatosplenomegaly, anemia, thrombocytopenia and skeletal abnormalities such as avascular necrosisis and osteopenia. Growth retardation, pulmonary disease, bleeding tendencies and hypermetabolic states may also be reported in these patients [13].
• Type 2 - The most severe form of GD is characterized by the onset of convulsions, dementia, mental disability, myoclonus and muscle apraxia [3]. Symptoms are rapidly progressive and the majority of children die up to 5 years of age despite treatment [3].
• Type 3 - Usually, this form is most common in juvenile period and presents with similar but less severe complaints compared to type 2.

The diagnosis of GD cannot be made solely on clinical criteria, which is why laboratory and imaging studies are used to make the diagnosis.

Although the diagnosis can't be made solely on physical signs, a clinical suspicion toward this condition should be made in patients where other causes have been excluded, such as lymphomas and leukemias, as well as other lysosomal storage diseases that have a similar clinical presentation [3]. Workup starts with a complete blood count (CBC) that almost always reveals anemia and thrombocytopenia, while ultrasonography or computed tomography (CT) can confirm hepatosplenomegaly. The first major diagnostic tool is bone marrow biopsy, which will show the presence of Gaucher cells in macrophages that contain a granullar blue-to-gray cytoplasm and a characteristic wrinkled-paper appearance [3]. Periodic acid-Schiff staining is positive in the setting of GD, whereas special immunohistochemical staining (CD68) is positive as well [3]. Once Gaucher cells have been identified, further confirmation can be obtained by performing genetic testing, to determine the exact mutations that are responsible for this disease [4].

GD is the first lysosomal storage disease that is treated by enzyme replacement therapy. Imiglucerase and velaglucerase are two compounds that are administered as injections and are true analogs of human glucocerebrosidase [7]. Their administration has shown almost complete reversal of symptoms within months of treatment [14]. Through early and regular administration, enzyme-replacement therapy has shown marked improvements in survival and overall quality of life, but since imiglucerase does not cross the blood-brain barrier [3], types 2 and 3 are not as effectively treated as type 1. Equally effective is miglustat, a drug that is given orally and inhibits formation of the compound that accumulates inside lysosomes, thus contributing to the same effect having almost equal efficacy.

The prognosis of patients suffering from GD depends on two factors: the clinical subtype and time of treatment initiation. Type 2 clinical presentation carries a very poor prognosis, as severe neurological symptoms are universally fatal by the age of 5 [1]. On the other hand, types 1 and 3 carry a much better prognosis. Type 1 has an adult onset of non-neurological symptoms and since the discovery and use of enzyme replacement therapy, life expectancy is close to near-normal [12], but an early recognition of the disease and prompt initiation of therapy is detrimental [3]. Adult forms (type I) have shown to achieve normal life expectancy in many studies. Although type 3 is associated with a relatively milder clinical course in regard to type 2, the prognosis is not as good as in type 1 patients.

The cause of GD is deficiency of glucocerebrosidase, an enzyme that should normally break down glycolipids, primarily glucocerebroside (also known as glycoceramide) [8]. Enzyme deficiency occurs as a result of gene mutations that code the glucocerebrosidase enzyme, located on chromosome 1q21 and the mode of inheritance is shown to be autosomal recessive. More than 200 mutations have been documented so far and it is shown that different mutations lead to different clinical symptoms [3].

Estimated incidence rates suggest that GD is one of the most common lysosomal storage diseases, occurring in approximately 1 in 57,000 live births [5]. Various studies have shown a significantly higher incidence rate in Ashkenazi Jews that reaches up to 1 in 1,000 live births, as up to 7% of all Asheknazi Jews are shown to be heterozygotes for GD [3]. Having in mind the autosomal recessive pattern of inheritance, genders are equally affected, but age of onset significantly varies on the clinical subtype. Type 1 appears in adulthood, type 2 appears in early infancy, while the onset of type 3 is most frequently observed during the juvenile period [3].

The hallmark of GD is deficiency of glucocerebrosidase, the enzyme responsible for degradation of glucocerebroside, a membrane glycolipid that is present on virtually all cells in the body. Glucocerebroside (also known as glucosylceramide) is an important constituent of the cell membrane [9], and due to various mutations that have been identified, enzyme deficiency leads to accumulation of glucocerebroside inside lysosomes, primarily in macrophages and monocytes [10]. As a result, the primary and secondary lymphoid organs are affected, including the bone marrow, spleen, liver and kidneys, while neuroinflammation and degeneration have been hypothesized as main mechanisms of neuronal injury [11]. Animal models show that activation of numerous cytokines, such as interleukin 1 (IL-1), IL-6, tumor necrosis α (TNF-α) and many other lead to a chronic inflammatory response in the presence of macrophages containing Gaucher cells [11].

Wide-scale screening, especially in Ashkenazi Jews, but in families with confirmed GD patients can be a helpful measure in determining the risk for further development of GD. In such circumstances, genetic counseling may be conducted, but other than screening, preventive measures currently do not exist, although much has been discovered in terms of pathophysiology and treatment.

Gaucher disease (GD) is a genetic disorder in which deficiency of glucocerebrosidase, an enzyme that is responsible for degradation of a glycolipid-glucocerebroside, is transferred by autosomal recessive pattern of inheritance [1]. It is the most common and earliest lysosomal storage disease discovered, dating back to the end of the 19th century [2], but the exact cause was determined at the end of the 20th century, when first gene mutations were identified [3]. Numerous mutations in the glucocerebroside gene, whose location is on chromosome 1q21, have been discovered, with more than 200 being described so far. As a result of enzyme deficiency, accumulation of glucocerebroside in cells occurs, primarily in monocytes and macrophages [4]. Although the exact mechanism of intracellular damage is unclear, macrophages that have stored glucocerebroside (Gaucher cells) accumulate in the liver, spleen, kidneys and bone marrow, organs that are principally affected by this condition [4]. Incidence rates suggest that this disorder appears in approximately 1 in 57,000 live births [5], but a significant ethnic predilection in Ashkenazi Jews has been established. Almost 7% of people in this ethnic group are heterozygous for GD and the estimated incidence rate is estimated to be 1 in 1000 [5]. There are three distinct clinical subtypes of GD:

• Type 1 represents more than 90% of all cases and is characterized by hepatosplenomegaly, anemia, thrombocytopenia and skeletal manifestations such as osteopenia and avascular necrosis [6].
• Type 2 is distinguished by an early and aggressive onset (< 2 years) of severe neurological symptoms, including convulsions, severe mental disability and involvement of the brainstem.
• Type 3 also causes neurological symptoms, but develops usually later in life and is less severe compared to type 2 [3].

The diagnosis can often be delayed due to the nonspecific clinical presentation of patients. Laboratory studies that show anemia and other hematological abnormalities, together with marked hepatosplenomegaly will usually indicate a bone marrow biopsy, which will show the presence of enlarged Gaucher cells that have a blue-to-gray cytoplasm that is filled with granules or fibrills [3]. Genetic testing, when possible, can be performed, to assess the presence of gene mutations. Fortunately, GD is one of the first diseases in which enzyme replacement therapy has shown marked success and various forms exist. Alglucerase and imiglucerase, analogs of human glucocerebrosidase, are administered as injections and are well tolerated [7], while Miglustat is an oral drug that serves as an inhibitor of glucocerebroside formation [4]. The prognosis mainly depends on clinical presentation, as type II is usually fatal before 5 years of age. Life expectancy in patients suffering from type 1 or type 3, on the other hand, may be significantly prolonged if therapy is started early on. For this reason, GD must be diagnosed in early stages so that treatment can result in better outcomes.

Gaucher disease (GD) arises from deficiency of an enzyme, glucocerebrosidase, and subsequent deposition of substances (cell membrane constituents known as glucocerebrosides or glycoceramides) inside small organelles called lysosomes which would otherwise be degraded. Together with other disease, such as Tay-Sachs and Niemann-Pick disease, GD belongs to the group of lysosomal storage diseases. Enzyme deficiency stems from mutations in genes that code for this enzyme and these gene alterations are transmitted by an autosomal recessive pattern of inheritance. Normally, a person carries two genes for this enzyme, and if a single gene is transmitted from one parent, the disease will not develop, but if both parents transmit their mutated gene, it will result in GD. Because of enzyme deficiency, substances accumulate inside various cells in the body, but mainly in white blood cells that travels to various organs where they exert their effects on tissues. Although the exact mechanism of disease is not known, chronic inflammation and degeneration of nervous tissue as a result of defective white blood cell functioning is the current theory. It is established that GD occurs in approximately 1 child per 57,000 births and there are three main clinical subtypes. Type 1 is by far the most common, representing between 95-99% of all cases. Symptoms appear in adulthood and include enlarged liver and spleen, anemia, low thrombocyte count and skeletal abnormalities; Type 2 is the most severe form that develops in early life (symptoms appear at < 2 years of age) and involves severe neurological deficits - convulsions, mental disability and is fatal within a few years; Type 3 also involves the nervous system, but in a much milder fashion and is primarily seen in childhood and adolescence. To make the diagnosis, blood tests and bone marrow biopsy are necessary, which will show the presence of defective macrophages - Gaucher cells in bone marrow. Once they are observed, genetic testing may be used to identify the specific mutations that are responsible for the disease. Luckily, GD is one of the first lysosomal storage diseases that are treatable and drugs that are used are either supplements of the deficient enzyme or compounds that reduce production of content that accumulates inside cells. But treatment can be most effective when it is administered in earlier stages of the disease, as damage caused by inflammation and other processes may be permanent if not stopped on time. Early use of therapy has significantly prolonged life expectancy in these patients and is estimated to be as normal for type 1, but type 2 is universally fatal by the age of 5 despite treatment. The outcome of patients with type 3 severely depends on the severity of symptoms and onset of therapy.

1. Moyses C. Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease. Philos Trans R Soc Lond B Biol Sci. 2003;358:955.
2. Mehta A, Beck M, Sunder-Plassmann G, editors. History of lysosomal storage diseases: an overview. In Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.
3. Chen M, Wang J. Gaucher disease: review of the literature. Arch Pathol Lab Med. 2008;132(5):851-853.
4. Cox TM, Aerts JM, Andria G, et al. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis. 2003;26:513.
5. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281:249–254.
6. Packman W, Crosbie TW, Behnken M, et al. Living with Gaucher disease: Emotional health, psychosocial needs and concerns of individuals with Gaucher disease. Am J Med Genet A. 2010;152A:2002.
7. Zimran A, Altarescu G, Philips M, et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010;115:4651.
8. Beutler E, Grabowski GA. Gaucher disease. In: Metabolic and molecular bases of inherited disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York; 2001. p.3635.
9. Messner MC, Cabot MC. Glucosylceramide in humans. Adv Exp Med Biol 2010;688:156.
10. Cox TM, Aerts JM, Belmatoug N, et al. Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. J Inherit Metab Dis. 2008;31:319.
11. Vitner EB, Farfel-Becker T, Eilam R, Biton I, Futerman AH. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease. Brain. 2012;135(6):1724-1735.
12. Weinreb NJ, Deegan P, Kacena KA et al. Life expectancy in Gaucher disease type 1. Am J Hematol. 2008;83(12):896-900.
13. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41:4.
14. Baldellou A, Andria G, Campbell PE, et al. Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and monitoring. Eur J Pediatr. 2004;163:67.