eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Gaucher Disease

Ellen Sidransky, MD, Senior Investigator, Consulting Staff, Chief, Section on Molecular Neurogenetics, Clinical Neuroscience Branch, National Institute of Mental Health; Senior Investigator, Acting Chief, Medical Genetics Branch, National Human Genome Research Institute

Updated: Oct 16, 2009

Introduction

Background

Gaucher disease is a lipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of a specific lysosomal hydrolase, glucocerebrosidase (also termed acid beta-glucosidase, glucosylceramidase). The disease is characterized by a continuum of phenotypes. The severity widely varies; some patients present in childhood with virtually all the complications of Gaucher disease, whereas others remain asymptomatic into the eighth decade of life.

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:

• Type 1 - Nonneuronopathic form
• Type 2 - Acute neuronopathic form
• Type 3 - Chronic neuronopathic form

However, some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited.

Autosomal recessive inheritance pattern.

Pathophysiology

Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and, to a lesser extent, from erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpled–tissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity.

Glucosylceramide accumulation in the bone marrow, liver, spleen, lungs, and other organs contributes to pancytopenia, massive hepatosplenomegaly, and, at times, diffuse infiltrative pulmonary disease. Progressive infiltration of Gaucher cells in the bone marrow may lead to thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. These bony features may also be related to macrophage-produced cytokines.

Disruption of the ceramide-to-glucosylceramide ratio can affect barrier formation in the epidermal layer of the skin, leading to ichthyosis or a collodion skin presentation in individuals who are severely affected (those with type 2).

Frequency

United States

Type 1 Gaucher disease more common among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 per 15 population, whereas the disease frequency is 1 per 855 population. Gaucher disease is rare in the non-Jewish population, with an estimated frequency of 1 per 40,000 population.

International

International disease frequency is similar to that in the United States, except for areas of the world with large Ashkenazi Jewish populations. Most patients worldwide are non-Jewish. As many as 60% of persons of Ashkenazi origin are estimated to be homozygous for the mild N370S mutation, which accounts for 75% of disease alleles in this population. Many individuals with this genotype never seek medical attention, contributing to an underestimation of the disease frequency. Type 3 disease is more common in the Norrbottnian region of Sweden (1 per 50,000 population), which has been traced to a common founder in the 17th century.

Mortality/Morbidity

Mortality and morbidity varies with the different types as follows:¹

• Type 1 Gaucher disease often presents in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease, although striking clinical variability occurs in disease severity.
• Type 2 Gaucher disease causes rapidly progressive neurovisceral storage disease and death during infancy or during the first years of life. A subset of this type, associated with congenital ichthyosis and hydrops fetalis, is described as neonatal lethal and results in perinatal or in utero death.
• Type 3 Gaucher disease is often a less rapidly progressive neurovisceral storage disease. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood.

Race

All forms of Gaucher disease are panethnic. Type 1 Gaucher disease is the most common lysosomal storage disease and is the most prevalent genetic disorder in individuals of Ashkenazi Jewish descent. Type 3 disease is more common in the Norrbottnian region of Sweden.

Sex

All 3 types of Gaucher disease are inherited as autosomal recessive traits and have an equal sex distribution.

Age

Patients with type 1 Gaucher disease may present in childhood with hepatosplenomegaly, pancytopenia, and crippling skeletal disease. Some patients are not diagnosed until adulthood, when they present with low blood counts or bone involvement, whereas others are diagnosed in the seventh to ninth decades of life after an incidental finding of thrombocytopenia or splenomegaly. Many affected individuals never develop signs or symptoms and do not seek medical attention. Types 2 and 3 Gaucher disease typically present in early childhood. Some subjects with parkinsonism have been found to have Gaucher disease at a later age.

Clinical

History

Because Gaucher disease is inherited as an autosomal recessive trait, the proband is commonly the first affected individual in the family.

• Type 1 Gaucher disease
  • At onset, patients with type 1 Gaucher disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both.
  • 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.
  • Most patients with type 1 Gaucher disease have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur, which is an early skeletal change. Clinically apparent bony involvement, which occurs in more than 20% of patients with Gaucher disease, can present as bone pain or pathologic fractures. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis or osteopenia may be evident at an early age. Bone crises with severe pain and swelling can occur in individuals with type 1 Gaucher disease and are frequently mistaken for synovitis or osteomyelitis until other symptoms become apparent.
  • Occasional patients with type 1 Gaucher disease develop pulmonary involvement, parkinsonism, or portal hypertension.
  • Patients with milder presentations of Gaucher disease are diagnosed later in life during evaluations for hematologic or skeletal problems or are found to have splenomegaly during routine examinations. Some patients are overtly asymptomatic, and a diagnosis is made incidentally after evaluation for other medical problems.
• Type 2 Gaucher disease
  • Type 2 disease is rare and is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life.
  • Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Disruption of the epidermal layers of the skin, observed on skin biopsy findings, may manifest before the onset of neurological symptoms, but this may not always be clinically apparent.
  • Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.
  • The progressive psychomotor degeneration and brain stem involvement leads to death, usually caused by aspiration and respiratory compromise.
  • A severe neonatal form can present in utero or perinatally with hydrops fetalis, congenital ichthyosis, or both.
• Type 3 Gaucher disease
  • This form of Gaucher disease widely varies and can present in infancy or childhood.
  • In addition to organomegaly and bony involvement, individuals with type 3 disease have neurologic involvement.
  • The slowing of the horizontal saccades, an oculomotor finding, is often the sole neurologic manifestation. Some patients develop myoclonic epilepsy, exhibit learning disabilities, or develop dementia.
  • 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.
  • Another rare subgroup of patients with type 3 Gaucher disease is a genetic isolate from the Norrbottnian region of Sweden, homozygous for the L444P mutation. These individuals present in early childhood with visceral involvement and oculomotor abnormalities and may develop seizures, cognitive disabilities, and dementia.
  • Some specific learning disabilities are common in children with type 3 Gaucher disease.
• Type 2-3 intermediate Gaucher disease: Some patients present with severe neurovisceral manifestations in infancy or early childhood but survive past the second year of life, with death occurring in mid childhood (age 3-7 y). These patients are considered to fall within the phenotypic continuum between types 2 and 3.

Physical

Physical examination findings in type 1 disease usually include hepatosplenomegaly. Splenomegaly may be dramatic, with the splenic tip extending to the pelvis. Bruising along the anterior aspect of the shins and petechiae may be evident in patients with thrombocytopenia. Short stature and wasting are occasionally found in patients with massive organomegaly. In addition to these findings, patients with types 2 and 3 disease may have developmental delay, oculomotor abnormalities, and abnormal neurologic examinations.

• Splenomegaly
  • Patients present with highly variable degrees of splenomegaly, with a size increase that ranges from 5-fold to more than 80-fold when adjusted for body weight (average spleen is approximately 0.2% of body weight). The absolute size of the spleen has been known to vary between 300 g to more than 10 kg, accounting for up to 25% of body weight.
  • Enlargement of the spleen appears to be most rapid in children with Gaucher disease. Rapid enlargement of the spleen in an adult with the disease should prompt suspicion of an associated disorder that may increase glycolipid turnover, such as hematologic malignancy, immune thrombocytopenia, or autoimmune hemolytic anemia.
  • Nodules on the surface of the spleen may represent regions of extramedullary hematopoiesis, collections of Gaucher cells, or resolving infarcts. Evidence of old infarcts is common in spleens that are enlarged more than 20-fold. Most splenic infarcts are asymptomatic, but subcapsular infarcts can present as localized abdominal pain. Intracapsular bleeding may also occur.
• Hepatomegaly 
  • Hepatomegaly occurs in more than 50% of patients with type 1 Gaucher disease. In a series of 88 patients, liver volumes ranged from within the reference range to 8.7-fold more than the predicted normal weight (normal is 2.5% of body weight), with a median of 1.75%.
  • Hepatic glucocerebroside levels are elevated from 23-fold to 389-fold above the reference range.
  • The massively enlarged liver is usually firm to palpation, with an irregular surface. Cirrhosis and portal hypertension are uncommon but occur in a small number of patients with Gaucher disease. Compression of the sinusoids by Gaucher cells can accentuate portal hypertension.
  • Death from variceal bleeding has been reported, especially prior to enzyme replacement therapy. Minor elevations of liver enzyme levels are common, even in patients who are mildly affected, but the presence of jaundice or impaired hepatocellular synthetic function is a poor prognostic indicator. Jaundice in a patient with Gaucher disease is usually a result of infection, the development of chronic hepatitis, or, rarely, hepatic decompensation in the late stages. The presence of unconjugated hyperbilirubinemia is more suggestive of hemolysis.
  • Elevated levels of serum ferritin are occasionally found in individuals with Gaucher disease; however, transferrin saturation is usually normal. Glycolipid-laden Gaucher cells are evident in the sinusoids on liver biopsy findings, but the hepatocytes do not manifest overt glycolipid storage, presumably because of biliary excretion of glucocerebroside and the fact that exogenous glycolipid turnover is handled by the mononuclear phagocytes. Sparing of hepatocytes is consistent with the low incidence of liver failure in individuals with Gaucher disease.
• Skeletal manifestations
  • Skeletal manifestations of Gaucher disease vary, ranging from asymptomatic Erlenmeyer flask deformity of the distal femora to pathologic fractures, vertebral collapse, and acute bone crises that can be confused with acute osteomyelitis.
  • Painful bone crises result from episodes of bone infarction, leading to osteosclerosis analogous to that occurring in sickle cell disease.
  • In children with Gaucher disease, acute hip lesions can be misinterpreted as Legg-Calvé-Perthes disease, and avascular necrosis of the hips is a common complication in individuals of all ages.
• Hematologic complications
  • Hematologic manifestations of Gaucher disease include cytopenia and acquired coagulopathy due to factor XI deficiency. However, genetic factor XI deficiency is common in individuals of Ashkenazi descent and may be present in some patients with Gaucher disease.
  • Cytopenia that develops in patients who have undergone splenectomy reflects advanced marrow infiltration by Gaucher cells. Bone marrow failure and myelofibrosis occur in a small number of these patients.
  • A number of immunologic abnormalities are common in individuals with Gaucher disease, including hypergammaglobulinemia, T-lymphocyte deficiency in the spleen, and impaired neutrophil chemotaxis.

Causes

• All 3 forms of Gaucher disease are caused by glucocerebrosidase activity deficiency due to mutations in GBA, the structural gene that encodes the enzyme. Widespread accumulation of glucosylceramide-laden macrophages results from the enzyme deficiency.
• More than 200 different mutant GBA alleles have been identified in patients with Gaucher disease. Screening for the 6 most common GBA mutations in patients of Ashkenazi Jewish descent has enabled the identification of 90-95% of the mutant alleles in this population, but a large number of other mutations have been described in other populations, making screening impractical.
• Some mutations derive from recombination with the glucocerebrosidase pseudogene, a sequence 15 kb downstream that shares 96% sequence homology to glucocerebrosidase. Complex alleles with regions of pseudogene sequence, in which simple polymerase chain reaction (PCR)–based mutation detection screening is inadequate, have been identified in some patients.
• Genotype and phenotype correlations have been noted in some specific Gaucher presentations. For example, patients with type 1 Gaucher disease who are homozygous for the N370S mutation tend to have a later onset and a relatively mild course, and patients with type 3 Gaucher disease who are homozygous for the D409H mutation exhibit a rare phenotype that involves cardiac calcifications, oculomotor abnormalities, and corneal opacities. However, clinical presentation in patients with Gaucher disease widely varies and frequently cannot be fully explained by the underlying mutations because severity can vary even among siblings who have identical genotypes.
• Similarly, the amount of residual enzymatic activity does not accurately predict disease subtype and severity, with the exception that many of the mutations identified in patients with severe type 2 Gaucher disease express little, if any, enzymatic activity in vitro. These are frequently nonsense, frame-shift, or recombinant alleles that cannot form a complete protein and are essentially null alleles.

Differential Diagnoses

Niemann-Pick Disease

Other Problems to Be Considered

Multiple myeloma

Workup

Laboratory Studies

The following studies are indicated in Gaucher disease:

• Enzyme activity testing: Diagnosis can be confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic. Heterozygotes generally have half-normal enzyme activity, but as much as 20% overlap with activity levels of healthy controls has been reported, rendering enzymatic testing for carrier status unreliable.
• Genotype testing: Molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom 6 GBA mutations (ie, N370S, c.84insG, L444P, IVS2+1g>a, V394L, and R496H) account for most disease alleles. Mutation analysis has some, albeit limited, predictive value with respect to disease progression. Caution should be taken in relying solely on PCR-based test results for individual mutations because they cannot reveal the presence of recombinant alleles associated with greater disease severity.
• CBC count: Obtain CBC count and differential to assess the degree of cytopenia.
• Liver function enzyme testing: Minor elevations of liver enzyme levels are common, even in patients who are mildly affected with Gaucher disease; however, the presence of jaundice or impaired hepatocellular synthetic function merits a full hepatic evaluation. Coagulations studies should be monitored.
• Associated marker testing: Angiotensin-converting enzyme levels are typically elevated, as are total acid phosphatase and ferritin levels. Monitoring levels of another enzyme, chitotriosidase, is also useful in monitoring the disease, except in the 10% of the population who have a deficiency in this protein.

Imaging Studies

• Ultrasonography: Ultrasonography of the abdomen can reveal the extent of organomegaly.
• MRI
  • MRI is more accurate than ultrasonography in determining organ size.
  • Hip MRI may be useful in revealing early avascular necrosis.
  • MRI may be useful in delineating the degree of marrow infiltration and evaluating spinal involvement.
• Radiography
  • Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease.
  • Perform chest radiography to evaluate pulmonary manifestations.
• Dual-energy x-ray absorptiometry scanning: Dual-energy x-ray absorptiometry (DEXA) is useful in evaluating osteopenia.

Procedures

• Bone marrow aspiration 
  • In the past, the diagnosis was confirmed with the finding of classic glycolipid-laden macrophages in bone marrow aspirate collected because of hematological abnormalities; however, aspiration is not a recommended diagnostic tool. Similar pseudo-Gaucher cells have also been described in individuals with other disorders, including chronic granulocytic leukemia, thalassemia, multiple myeloma, Hodgkin disease, plasmacytoid lymphomas, acquired immunodeficiency syndrome (AIDS), and Mycobacterium avium– intracellulare infection.
  • Bone marrow aspiration should not be the initial diagnostic test because the blood enzyme test is sensitive, specific, and much less invasive.
• Liver biopsy
  • Liver biopsy is occasionally performed to assess unexplained hepatomegaly.
  • It can be avoided in most patients when the diagnosis is suspected because a specific diagnostic test is available.

Histologic Findings

• In Gaucher disease, classic glycolipid-laden macrophages are found in bone marrow aspirate or in liver biopsy samples. On liver biopsy samples, glycolipid-laden Gaucher cells are evident in the sinusoids, but the hepatocytes do not manifest overt glycolipid storage, presumably because of biliary excretion of glucocerebroside and because exogenous glycolipid turnover is handled by the mononuclear phagocytes. The sparing of hepatocytes is consistent with the low incidence of liver failure in individuals with Gaucher disease.
• The pathologic hallmark of Gaucher disease is the presence of Gaucher cells in the macrophage-monocyte system, particularly in the bone marrow. These cells, which are 20-100 m m in diameter, have a characteristic wrinkled-paper appearance, resulting from intracytoplasmic substrate deposition, and stain strongly positive with periodic acid–Schiff. Histologic evaluation of biopsy specimens should not be used as a first-line diagnostic tool.

Treatment

Medical Care

Enzyme replacement therapy (ERT) for Gaucher disease is now available, with most patients receiving recombinant enzyme (imiglucerase [Cerezyme]).² This preparation is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme. Treatment is typically administered once every other week at a high dose, but, in some patients, treatment is administered every week at a medium dose or as many as 3 times per week at low doses. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.

ERT with imiglucerase is indicated for patients with type 1 Gaucher disease who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly. Severity and rate of disease progression widely varies, especially in adults, which makes treatment decisions extremely difficult in some patients. Generally, children who present symptomatically, rather than because of family history, may have severe disease manifestations that require early treatment. Presymptomatic treatment with imiglucerase remains controversial because of the lack of prognostic correlation between genotype and disease severity and the high cost of the therapy.

For most patients with Gaucher disease in the United States, treatment with Cerezyme is typically guided by a geneticist or a hematologist. Patients should receive periodic follow-up at a center familiar with Gaucher disease, if possible.

ERT has a remarkable effect on hepatosplenomegaly, with an average overall decrease of 25% in liver and spleen volume after 6 months of therapy. In most patients with anemia, hemoglobin levels rise by 1.5 g/dL during the first 4-6 months of therapy. An additional increase of 1 g/dL is observed in the subsequent 9-18 months in patients with persistent anemia. The platelet count responds more slowly, doubling on average over 1 year. The hematologic status of patients with splenomegaly must be closely monitored, and splenectomy is still occasionally necessary.

Skeletal disease is the slowest to respond, with symptomatic improvement described by some within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response. Patients with bone crises require pain relief, hydration, and close monitoring. A bone scan is sometimes needed to differentiate between a bone crisis and infection.

Other effects of ERT in children with Gaucher disease include an increased growth velocity, weight gain, increased energy levels, and a correction of both delayed puberty and hypermetabolic state.

The response of patients to ERT widely varies and does not correlate with genotype, disease severity, splenectomy, or age. However, a number of factors, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement, portend a poor response to therapy.

The symptoms of patients with Gaucher disease who have associated hematologic malignancies respond relatively poorly to ERT. To overcome these difficulties, increased dosage and frequency of enzyme infusions have been attempted. The symptoms of patients with decompensated liver disease do not appear to respond well to ERT, and these patients remain at risk for life-threatening hemorrhage due to variceal bleeding.

No evidence shows that ERT results in neurologic improvement. Although the enzyme affects the visceral involvement in types 2 and 3 disease, the associated brain involvement may persist or progress.

Surgical Care

Partial and total splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.

In addition, patients with Gaucher disease may require hip replacements or other orthopedic procedures to treat skeletal disease. This is best undertaken after the patient has undergone several months of ERT.

Consultations

Consultations with the following specialists are indicated:

• Medical geneticist
• Hematologist
• Orthopedist
• Neurologist
• Neuro-ophthalmologist

Diet

No dietary manipulation has been found to affect disease progression.

Activity

Patients with massive splenomegaly or severe thrombocytopenia should avoid contact sports and any other activities that place them at risk for splenic rupture or bleeding

Medication

Two therapies have been approved by the US Food and Drug Administration (FDA) for the treatment of Gaucher disease. Enzyme replacement therapy (ERT) with glucocerebrosidase purified from human placenta was FDA approved in 1991, followed by approval in 1994 of a recombinant form of the enzyme produced in cultured Chinese hamster ovary (CHO) cells. Worldwide, over 4,000 patients with Gaucher disease have received ERT, which is safe and well tolerated.

Approximately 10-15% of patients with Gaucher disease develop antibodies to the enzyme protein, but few develop any significant allergic reactions, which are controlled with premedication with hydrocortisone, antihistamines, or both. All antibodies have immunoglobulin G (IgG), mostly of the IgG1 subclass. A few patients with Gaucher disease have developed antibodies that impair enzyme activity.

Oral substrate reduction therapy, using an aminosugar inhibitor of glucosylceramide synthase, has been approved for use in patients with type 1 Gaucher disease in whom ERT is not a therapeutic option because of allergy, hypersensitivity, or poor venous access. Although oral substrate reduction therapy was approved by the FDA in 2003, long-term data regarding efficacy and safety are not yet available.

Enzyme replacement therapy

In most cases, ERT is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. Recombinant beta-glucocerebrosidase (imiglucerase [Cerezyme]) has replaced the original tissue-derived product, alglucerase (Ceredase), which is no longer marketed. Presymptomatic use is controversial because of the high cost and the extremely variable clinical course.

Imiglucerase (Cerezyme)

A recombinant-derived analog of beta-glucocerebrosidase produced in mammalian cell culture and chemically modified by mannose termination of glycosylated amino acids. Catalyzes hydrolytic cleavage of glucocerebroside (a glycoprotein) to glucose and ceramide within the lysosomes of phagocytic cells in the reticuloendothelial system. Treatment with recombinant enzyme improves anemia and thrombocytopenia, reduces spleen and liver size, and decreases cachexia

Dosing

Adult

30-150 U/kg IV qmo typically; dose must be individualized and widely varies; initial dose may range from 2.5 U/kg 3 times/wk to 60 U/kg q2wk
Dilute in 0.9% NaCl and infuse over 1-2 h

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May develop IgG antibodies (15%) and hypersensitivity (6-7%); allergic reactions easily controlled with premedication with hydrocortisone, antihistamines, or both; may cause nausea, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia; may cause pruritus at injection site

Glucosylceramide synthase inhibitors:

These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. The goal of treatment is to reduce the rate of glucocerebroside biosynthesis so that the amount is reduced to a level that allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy).

Miglustat (Zavesca)

Indicated for type 1 Gaucher disease in patients in whom ERT is not a therapeutic option. Reduces GSL production by inhibiting glucosylceramide synthase. Reduces spleen and liver volume and increases hemoglobin and platelet counts.

Dosing

Adult

100 mg PO tid
In patients with renal impairment, dosage should be reduced as follows:
CrCl 50-70 mL/min: 100 mg PO bid
CrCl 30-50 mL/min: 100 mg PO qd
CrCl <30 mL/min: Not recommended

Pediatric

<18 years: Not established

Interactions

Limited data exist; none reported

Contraindications

Documented hypersensitivity; severe renal impairment

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Caution in renal impairment (decrease dose); neurological monitoring for possible peripheral neuropathy q6mo is indicated; may cause tremor (30%); diarrhea and weight loss are common (85% and 65%, respectively); adversely affects spermatogenesis; use reliable contraceptive method and maintain for 3 mo after discontinuing drug

Follow-up

Further Inpatient Care

• Patients with Gaucher disease who have bone crises may require admission for pain relief.
• Patients with severe hematologic manifestations may have episodes of bleeding that require inpatient treatment.

Further Outpatient Care

• Most symptomatic patients with Gaucher disease receive enzyme replacement therapy (ERT), which is provided on an outpatient basis.³ Monitoring for allergic reactions is essential.
• Monitoring patients who receive miglustat (Zavesca) every 6 months for possible development of peripheral neuropathy is recommended.
• Patients with osteoporosis have responded favorably to bisphosphonates.

Deterrence/Prevention

• Gaucher disease is inherited as an autosomal recessive trait. Although it is panethnic, Gaucher disease is more common in individuals of Ashkenazi Jewish. Although carrier-screening programs in this population have been established at some centers to identify couples at risk for having a child affected with Gaucher disease, testing must be offered in conjunction with genetic counseling to provide couples at risk, even asymptomatic individuals, with a description of the range of associated phenotypes and their options, which include prenatal diagnosis.

Complications

• Bone crises may occur secondarily to infarcts. Avascular necrosis of the hip is not uncommon.
• Splenic rupture can result from trauma.
• Cirrhosis is a rare complication.
• Rarely, pulmonary infiltration by Gaucher cells may manifest as overt lung disease, which may present as pulmonary infiltrates and lung consolidation; this pattern is especially common in patients with type 2 disease.
• Parenchymal infiltration with fibrosis has been described in children with type 3 disease.
• Intrapulmonary vascular dilatation in the presence or absence of portal hypertension has also been described in some patients with Gaucher disease, resulting in hypoxic lung disease.
• Adult patients with pulmonary hypertension in the absence of infiltrative disease have been described; these patients may follow an inexorable progressive course despite therapy.
• Hematologic abnormalities, including anemia, thrombocytopenia, and leukopenia, are common in individuals with Gaucher disease
• Immunologic abnormalities, including hypergammaglobulinemia, T-lymphocyte deficiency in the spleen, and impaired neutrophil chemotaxis, are also common. The malignancy multiple myeloma is more common in individuals with Gaucher disease.
• New evidence suggests that mutations in the gene for glucocerebrosidase may be a risk factor for the development of Parkinson disease.⁴

Prognosis

• Many individuals with Gaucher disease have few manifestations and a normal life expectancy without any intervention.
• The prognosis for symptomatic patients with type 1 or type 3 Gaucher disease who receive treatment is very good, with a decrease in organomegaly and an eventual rise in hemoglobin levels and platelet counts.
• A recent study estimated life expectancy at birth in patients with type 1 Gaucher disease to be 68 years, compared with 77 years in the reference population.⁵
• Skeletal disease is slow to respond to ERT and widely varies.
• Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.

Patient Education

• Patients with Gaucher disease and their families require education regarding the disease manifestations, variability in symptoms and disease progression, and potential complications. In addition, they should be counseled regarding the genetic risks

Miscellaneous

Medicolegal Pitfalls

• Discussion of the genetic etiology and autosomal recessive pattern of inheritance of Gaucher disease with patients and their families is imperative. Full genetic counseling should be offered.

Special Concerns

• Women with Gaucher disease have had successful pregnancies.⁶ Some patients have received treatment during pregnancy without complications. In patients who are not undergoing treatment, hematologic status should be monitored.

Multimedia

Media file 1: Autosomal recessive inheritance pattern.

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Keywords

Gaucher disease, Gaucher’s disease, glucocerebrosidase deficiency, cerebroside lipidosis, acid beta-glucosidase deficiency, splenomegaly, anemia, lipid storage disease, lysosomal storage disease, glucocerebrosidase, glucosylceramidase, GBA, pancytopenia, massive hepatosplenomegaly, diffuse infiltrative pulmonary disease, parkinsonism, Lewy body

Contributor Information and Disclosures

Author

Ellen Sidransky, MD, Senior Investigator, Consulting Staff, Chief, Section on Molecular Neurogenetics, Clinical Neuroscience Branch, National Institute of Mental Health; Senior Investigator, Acting Chief, Medical Genetics Branch, National Human Genome Research Institute
Ellen Sidransky, MD is a member of the following medical societies: American Society of Human Genetics, Society for Inherited Metabolic Disorders, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Co-Director: Pediatric and Child Health Research, Oregon Clinical and Translational Research Institute (CTSA).
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting; Amicus  Consulting

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

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