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Gaucher Disease

Gaucher's Disease

Gaucher disease is a lysosomal storage disease in which enzyme deficiency leads to accumulation of glycolipids in various tissues, mainly in the monocyte-macrophage system. It is transferred by autosomal recessive pattern of inheritance and depending on the subtype, patients may present with hepatosplenomegaly, anemia, neurological deficits and many other. The diagnosis is made by bone marrow biopsy and genetic testing, while enzyme replacement therapy is used with great success.

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Presentation

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.

Easy Bruising
  • Symptoms: Symptoms include fatigue, bleeding problems and easy bruising, enlarged abdomen, bone pain, easily fractured bones, enlarged liver or spleen, low platelet count and anemia.[jewishgeneticdiseases.org]
  • Symptoms include fatigue, anemia, bone pain and easy bruising and bleeding. Treatment commonly includes enzyme replacement therapy. more less[themighty.com]
  • This type causes many of the same symptoms seen in type 1 (easy bruising, anemia, liver and/or spleen enlargement), but it also results in severe and progressive neurological problems.[encyclopedia.com]
  • bruising Slow or stunted growth in children Intestinal problems like abdominal swelling Trouble breathing Seizures Vision problems Developmental delays In type II, rigidity and seizures may appear within the first few months of life.[uvahealth.com]
  • Gaucher disease also affects the cells responsible for clotting, which can cause easy bruising and nosebleeds.[mayoclinic.org]
Splenomegaly
  • HALS for GD patients with refractory hypersplenism and massive splenomegaly is safe and feasible in experienced hands.[ncbi.nlm.nih.gov]
  • Radiographically, hepatomegaly and splenomegaly respond more rapidly than skeletal changes. Glucosylceramide synthase inhibitors are available for patients with Type 1 GD who cannot receive enzyme replacement therapy 8 .[radiopaedia.org]
  • In symptomatic patients, splenomegaly is progressive and can become massive. Children with massive splenomegaly may be short in stature because of the energy expenditure required by the enlarged organ.[emedicine.medscape.com]
  • After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively.[ncbi.nlm.nih.gov]
  • -10-CM Diagnosis Code R16.1 Splenomegaly, not elsewhere classified 2016 2017 2018 Billable/Specific Code Applicable To Splenomegaly NOS Gaucher's E75.22 ICD-10-CM Codes Adjacent To E75.22 E75.09 Other GM2 gangliosidosis E75.1 Other and unspecified gangliosidosis[icd10data.com]
Massive Splenomegaly
  • HALS for GD patients with refractory hypersplenism and massive splenomegaly is safe and feasible in experienced hands.[ncbi.nlm.nih.gov]
  • Although Gaucher disease generally presents with massive splenomegaly, which one of the predisposing causes of a wandering spleen, literature shows only one report of a wandering spleen in a child with Gaucher disease.[ncbi.nlm.nih.gov]
  • Children with massive splenomegaly may be short in stature because of the energy expenditure required by the enlarged organ.[emedicine.medscape.com]
  • Features of skeletal involvement include: osteopaenia osteonecrosis pathological /crush fractures endosteal scalloping Erlenmeyer flask deformities H-shaped vertebrae paranasal sinus obliteration due to medullary expansion 9 MRI spleen massive splenomegaly[radiopaedia.org]
Stridor
  • This case was a girl diagnosed with type 2 Gaucher disease at 12months of age who presented with poor weight gain from infancy, stridor, hypertonia, hepatosplenomegaly, trismus and an eye movement disorder.[ncbi.nlm.nih.gov]
  • Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.[emedicine.medscape.com]
  • Failure to thrive and stridor (due to laryngospasm) are also common. Rapid neurodegenerative course with extensive visceral involvement and death (usually caused by respiratory problems) within the first two years of life.[patient.info]
Anemia
  • A 38-year-old female patient was diagnosed with anemia for 3 years.[ncbi.nlm.nih.gov]
  • A patient known for hepatosplenomegaly with hyperferritinemia, anemia, and thrombocytopenia was admitted for Lewy body dementia and bullous pemphigoid. Type 1 Gaucher disease.[ncbi.nlm.nih.gov]
  • The disorder is characterized by bruising, fatigue , anemia , low blood platelet count and enlargement of the liver and spleen , and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on[en.wikipedia.org]
  • Treatment Symptomatic treatment may include blood transfusions to treat anemia, removal of the enlarged spleen, and joint replacement.[encyclopedia.com]
  • The main clinical features include massive hepatosplenomegaly, anemia, thrombocytopenia and skeletal abnormalities such as avascular necrosisis and osteopenia.[symptoma.com]
Fatigue
  • Hematologic changes, bone pain, hepatomegaly, splenomegaly, and fatigue were the most recurrent signs and symptoms.[ncbi.nlm.nih.gov]
  • Snapshot A young boy presents with chronic fatigue and hepatosplenomegaly. Bone marrow aspirate histology is shown at the right.[medbullets.com]
  • Symptoms include fatigue, anemia, bone pain and easy bruising and bleeding. Treatment commonly includes enzyme replacement therapy. more less[themighty.com]
Weakness
  • The most commonly observed symptoms of hypersensitivity reactions were: headache, dizziness, low blood pressure, high blood pressure, nausea, tiredness/weakness, and fever.[vpriv.com]
  • Skeletal weakness and bone disease may occur, leading to collapsed hips, shoulders, and spine. Inheritance Patterns Gaucher Disease Type I is an autosomal recessive disorder.[geneticdiseasefoundation.org]
  • Complications due to Gaucher Disease include: Blood-related abnormalities Bone disorders such as loss of bone minerals leading to weak bones and joints, bone-death Massive liver and spleen enlargement Severe neurological dysfunction, epileptic seizures[dovemed.com]
  • I don’t want anyone to go what I went through with 8 hip replacements [because my bones were so weak.]” For those would-be parents who are considering having children, Krupskas has another piece of valuable advice: “Don’t put on blinders,” she said.[tabletmag.com]
  • Future issues in the therapy of Gaucher disease Nearly 200 mutations in glucocerebrosidase have been described, but for the most part, genotype-phenotype correlations are weak, and little is known about the downstream biochemical changes that occur upon[haematologica.org]
Death in Infancy
  • This causes rapidly progressive neurovisceral storage disease and death during infancy. [ 3 ] Type 3 - juvenile or Norrbottnian form (chronic or subacute neuronopathic).[patient.info]
  • Type 2 Gaucher disease causes rapidly progressive neurovisceral storage disease and death during infancy or during the first years of life.[emedicine.medscape.com]
Abdominal Pain
  • pain, upper abdominal pain, back pain, and extremity pain.[ncbi.nlm.nih.gov]
  • The signs and symptoms of Type 1 can begin at any age, and usually include anemia, bruising, bleeding, abdominal pain (caused by an increase in spleen and liver size), bone pain, and growth problems.[pfizer.com]
  • I: (adult form) - chronic noneuronopathic type; - central nervous system is spared & disease is characterized by slowly progressive visceral and osseous involvement; - enlarged spleen may cause mechanical problems, including abdominal distention and abdominal[wheelessonline.com]
  • The most common adverse reactions for ELELYSO are itching, flushing, headache, joint pain, pain in extremity, abdominal pain, vomiting, diarrhea, fatigue, back pain, dizziness, nausea, and rash.[elelyso.com]
Failure to Thrive
  • Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.[emedicine.medscape.com]
  • Failure to thrive and stridor (due to laryngospasm) are also common. Rapid neurodegenerative course with extensive visceral involvement and death (usually caused by respiratory problems) within the first two years of life.[patient.info]
  • The symptoms include: Slow back-and-forth eye movement Not gaining weight or growing as expected, called "failure to thrive" High-pitched sound when breathing Seizures Brain damage, especially to the brain stem Enlarged liver or spleen Type 3.[webmd.com]
Dysphagia
  • […] progressive condition characterized by hepatosplenomegaly and skeletal deformities; the neuronopathic forms are divided into infantile and juvenile forms; the infantile form presents at 4-5 months of age with anemia, loss of cognitive gains, neck retraction, dysphagia[icd10data.com]
  • They include: dysphagia , or difficulty swallowing problems with walking seizures These problems get worse and can ultimately be fatal.[medicalnewstoday.com]
Abdominal Mass
  • In this case presentation, a 13-year-oldadolescent with Gaucher disease on enzyme replacement treatment was presented, who was detected having an abdominal mass on a routine visit and diagnosed with partial torsion of a wandering spleen associated with[ncbi.nlm.nih.gov]
Bleeding Gums
  • As a result, Gaucher patients’ blood may not clot well, and they may experience excessive bruising, frequent nosebleeds, bleeding gums, and longer, heavier menstrual periods. 3: Low red blood cell count (anemia) Red blood cells are responsible for carrying[cerezyme.com]
Hepatosplenomegaly
  • Snapshot A young boy presents with chronic fatigue and hepatosplenomegaly. Bone marrow aspirate histology is shown at the right.[medbullets.com]
  • The main clinical features include massive hepatosplenomegaly, anemia, thrombocytopenia and skeletal abnormalities such as avascular necrosisis and osteopenia.[symptoma.com]
  • Accumulation can occur in the liver and spleen, manifesting as hepatosplenomegaly, as well as within the bone marrow. Hepatic involvement is usually diffuse but can occasionally manifest as focal liver lesions.[ncbi.nlm.nih.gov]
  • The characteristic gaucher cells, glycosphingolipid-filled histiocytes, displace normal cells in bone marrow and visceral organs causing skeletal deterioration, hepatosplenomegaly, and organ dysfunction.[icd10data.com]
  • A patient known for hepatosplenomegaly with hyperferritinemia, anemia, and thrombocytopenia was admitted for Lewy body dementia and bullous pemphigoid. Type 1 Gaucher disease.[ncbi.nlm.nih.gov]
Hepatomegaly
  • Radiographically, hepatomegaly and splenomegaly respond more rapidly than skeletal changes. Glucosylceramide synthase inhibitors are available for patients with Type 1 GD who cannot receive enzyme replacement therapy 8 .[radiopaedia.org]
  • After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively.[ncbi.nlm.nih.gov]
  • Hematologic changes, bone pain, hepatomegaly, splenomegaly, and fatigue were the most recurrent signs and symptoms.[ncbi.nlm.nih.gov]
  • The main cause of the cytopenia, splenomegaly, hepatomegaly, and bone lesions associated with the disease is considered to be the infiltration of the bone marrow, spleen, and liver by Gaucher cells.[ncbi.nlm.nih.gov]
  • Hepatomegaly is frequently observed in GD and ERT/SRT are highly effective in reducing liver volume. Nevertheless, patients with GD may be at increased risk of long-term liver complications including cirrhosis and hepatocellular carcinoma.[ncbi.nlm.nih.gov]
Jaundice
  • Investigations General assessment FBC and differential (assess the degree of pancytopenia); LFTs (minor elevations of liver enzymes are common but jaundice is a poor prognostic indicator).[patient.info]
  • The gastrointestinal features include hepatosplenomegaly, jaundice , hepatic (liver) failure, and ascites (fluid in the abdomen).[medicinenet.com]
  • Avoid in newborns due to the potential for an increase in free bilirubin, jaundice, and development of kernicterus.[naturallivingcenter.net]
Corneal Opacity
  • Clinical manifestations vary by subtype and include progressive dementia and ataxia (IIIa), bone and visceral involvement (IIIb), and supranuclear palsies with corneal opacities (IIIc). Patients who survive to adolescence may live for many years.[merckmanuals.com]
  • One rare subgroup of patients with type 3 Gaucher disease present with oculomotor findings, calcifications of the mitral and aortic valves, and corneal opacities. The phenotype is associated with homozygosity for the D409H mutant allele.[emedicine.medscape.com]
  • Corneal opacities have been seen in some patients. Oculomotor apraxia and abnormal opticokinetic responses are common in types II and III. Visual acuity may be in the range of 20/200.[disorders.eyes.arizona.edu]
Strabismus
  • Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly.[emedicine.medscape.com]
  • Type 2 Gaucher's disease Presents in infancy with increased tone, strabismus, and organomegaly. Failure to thrive and stridor (due to laryngospasm) are also common.[patient.info]
  • Patients with type 2 disease may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly.[emedicine.medscape.com]
Bone Pain
  • Hematologic changes, bone pain, hepatomegaly, splenomegaly, and fatigue were the most recurrent signs and symptoms.[ncbi.nlm.nih.gov]
  • Clinically apparent bony involvement, which occurs in more than 20% of patients with Gaucher disease, can present as bone pain or pathologic fractures.[emedicine.medscape.com]
  • Symptoms include fatigue, anemia, bone pain and easy bruising and bleeding. Treatment commonly includes enzyme replacement therapy. more less[themighty.com]
  • Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys.[ncbi.nlm.nih.gov]
  • Medicines may be given to: Replace the missing GBA (enzyme replacement therapy) to help reduce spleen size, bone pain, and improve thrombocytopenia. Limit production of fatty chemicals that build up in the body.[medlineplus.gov]
Osteoporosis
  • Type 1 Gaucher disease (GD1) is characterized by thrombocytopenia, anemia, an enlarged spleen, and liver as well as bone complications (Erlenmeyer flask deformity, osteoporosis, lytic lesions, pathological and vertebral fractures, bone infarcts, and avascular[ncbi.nlm.nih.gov]
  • Bone involvement is characterized by typical deformities, osteopenia/osteoporosis, pathological fractures, and bone marrow infiltration (avascular osteonecrosis, infarction).[ncbi.nlm.nih.gov]
  • Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms.[ncbi.nlm.nih.gov]
  • Frequent misdiagnoses include leukemia, lymphoma, rheumatoid arthritis and osteoporosis. Clinical features are extremely variable in each patient, and even within a family various members can exhibit a very different clinical problems and course.[massgeneral.org]
  • […] nodes, bone marrow, GI and GU tracts; Kupffer cells in liver; osteoclasts in bone; microglia in CNS; and alveolar macrophages in lungs ( Arch Pathol Lab Med 2008;132:851 ) Clinical features Three subtypes; all may have hepatosplenomegaly, hypersplenism, osteoporosis[pathologyoutlines.com]
Arthritis
  • Frequent misdiagnoses include leukemia, lymphoma, rheumatoid arthritis and osteoporosis. Clinical features are extremely variable in each patient, and even within a family various members can exhibit a very different clinical problems and course.[massgeneral.org]
  • Patella Sleeve Fracture Proximal Tibia Epiphyseal FX - Pediatric Proximal Tibia Metaphyseal FX - Pediatric Leg & Ankle Fractures Tibia Shaft Fracture - Pediatric Ankle FX - Pediatric Tillaux FX Triplane FX Infection Osteomyelitis - Pediatric Hip Septic Arthritis[orthobullets.com]
  • […] include enlargement of the liver and spleen (hepatosplenomegaly), a low number of red blood cells ( anemia ), easy bruising caused by a decrease in blood platelets (thrombocytopenia), lung disease, and bone abnormalities such as bone pain, fractures, and arthritis[ghr.nlm.nih.gov]
  • Some symptoms you might have are: Easy bruising Nosebleeds Fatigue Enlarged spleen or liver, which makes your belly look swollen Bone problems like pain, breaks, or arthritis Type 2. It affects the brain and spinal cord and is very serious.[webmd.com]
  • (hepatomegaly) and enlarged spleen (splenomegaly) Decreased blood cell count causing anemia Individuals with anemia may have fatigue, low energy, and decreased exercise tolerance Decreased platelet count can cause easy bruising Bone and joint pain, arthritis[dovemed.com]
Back Pain
  • pain, and extremity pain.[ncbi.nlm.nih.gov]
  • The most common adverse reactions for ELELYSO are itching, flushing, headache, joint pain, pain in extremity, abdominal pain, vomiting, diarrhea, fatigue, back pain, dizziness, nausea, and rash.[elelyso.com]
  • The most commonly reported side effects during clinical studies (in 10% of patients) were hypersensitivity reactions, headache, dizziness, abdominal pain, nausea, back pain, joint pain, increased time it takes for blood to clot, tiredness/weakness, and[vpriv.com]
Joint Swelling
Epistaxis
  • Epistaxis and ecchymoses resulting from thrombocytopenia are common. X-rays show flaring of the ends of the long bones (Erlenmeyer flask deformity) and cortical thinning.[merckmanuals.com]
Seizure
  • Vision problems Developmental delays In type II, rigidity and seizures may appear within the first few months of life.[uvahealth.com]
  • […] skin, anemia ( GeneReviews: Gaucher Disease [Accessed 26 October 2017] ) Type I: nonneuropathic, may be mild Type II (acute infantile neuropathic Gaucher disease): affects infants within a few months of birth, usually fatal within 2 years; may have seizures[pathologyoutlines.com]
  • Type 2 GD patients suffer significant progressive neurological impairment, including spasticity, opisthotonus, seizure, and apnea. The recently developed enzyme replacement therapy (ERT) has shown therapeutic benefit for GD.[ncbi.nlm.nih.gov]
  • Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly.[emedicine.medscape.com]
Peripheral Neuropathy
  • Comorbidities for peripheral neuropathy were excluded.[ncbi.nlm.nih.gov]
  • Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients.[ncbi.nlm.nih.gov]
  • A study published in the Orphanet Journal of Rare Diseases confirmed the role played by peripheral neuropathy in Gaucher pain.[raredr.com]
Opisthotonus
  • Type 2 GD patients suffer significant progressive neurological impairment, including spasticity, opisthotonus, seizure, and apnea. The recently developed enzyme replacement therapy (ERT) has shown therapeutic benefit for GD.[ncbi.nlm.nih.gov]

Workup

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].

Enlargement of the Liver
  • The disorder is characterized by bruising, fatigue , anemia , low blood platelet count and enlargement of the liver and spleen , and is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as glucosylceramidase), which acts on[en.wikipedia.org]
  • Type 1 Gaucher disease (GD1) is characterized by thrombocytopenia, anemia, an enlarged spleen, and liver as well as bone complications (Erlenmeyer flask deformity, osteoporosis, lytic lesions, pathological and vertebral fractures, bone infarcts, and avascular[ncbi.nlm.nih.gov]
  • This accumulation causes cells to form what is known as "Gaucher cells" which displace healthy cells in bone marrow, cause an enlargement of the liver and spleen, organ dysfunction, and deterioration of the skeleton.[stlouischildrens.org]
  • It results in bone fragility, neurological disturbance, anaemia, and enlargement of the liver and spleen. ‘Gene therapy is feasible, and some preliminary studies have already been carried out in Gaucher's disease.’[en.oxforddictionaries.com]
  • See all Hide authors and affiliations Science 08 May 1992: Vol. 256, Issue 5058, pp. 794-799 DOI: 10.1126/science.256.5058.794 Abstract Gaucher disease is characterized by the accumulation of glucocerebroside, leading to enlargement of the liver and spleen[science.sciencemag.org]
Enlargement of the Spleen
  • : a rare hereditary disorder of lipid metabolism caused by an enzyme deficiency and characterized by enlargement of the spleen and liver, bone lesions, and sometimes neurological impairment Note: Gaucher disease is inherited as an autosomal recessive[merriam-webster.com]
  • Its chief symptoms are an enlarged spleen and erosion of the long bones. These symptoms are often mild in effect, and the life span of persons afflicted with type 1 is only slightly reduced on average.[britannica.com]
  • Mutations in GBA lead to the accumulation of glycosylceramide in the lysosome causing an enlargement of the spleen and the liver and skeletal deformations. This disease is called Gaucher Disease.[ncbi.nlm.nih.gov]
  • Symptoms of the disease may include enlargement of the spleen and liver (a big belly or abdomen), anemia, thrombocytopenia (low platelet counts), bone pain, and bone fragility. Gaucher disease. [Internet]. Medline Plus [updated January 12, 2016].[thinkgenetic.com]
  • Symptoms: Symptoms include fatigue, bleeding problems and easy bruising, enlarged abdomen, bone pain, easily fractured bones, enlarged liver or spleen, low platelet count and anemia.[jewishgeneticdiseases.org]
Decreased Platelet Count
  • Decreased platelet counts (thrombocytopenia) as well as low hemoglobin (anemia) and decreased white blood cell counts (leukopenia) result in easy bruisability and hence black-and-blue marks (ecchymoses); easy bleeding--for example, after dental interventions[scientificamerican.com]
  • platelet count can cause easy bruising Bone and joint pain, arthritis of joints, weakening of the bones resulting in easy fractures Lung disease can cause breathing difficulties In Type I Gaucher Disease, there are no symptoms related to the central[dovemed.com]
Bone Marrow Gaucher Cells
  • 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).[orpha.net]

Treatment

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.

Prognosis

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.

Etiology

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].

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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].

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

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