AUTHOR INFORMATION

Section 1 of 11

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

Coauthored by Mary LaMarca

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

Edited by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Ellen Sidransky, MD
Editor's Email:	Robert D Steiner, MD

eMedicine Journal, February 26 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 11

Background: 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 called acid beta-glucosidase, glucosylceramidase). The disease is characterized by a continuum of phenotypes. The severity is extremely variable, with some patients presenting in childhood with virtually all the complications of Gaucher disease, while others remaining asymptomatic into their eighth decade. Gaucher disease has traditionally been divided into three clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:
Type 1 - Non-neuronopathic form
Type 2 - Acute neuronopathic form
Type 3 - Chronic neuronopathic form
Some patients, however, defy classification into these three distinct categories. All forms of Gaucher disease are autosomal recessively inherited. Type 1 Gaucher disease is encountered with an increased frequency among individuals of Ashkenazi Jewish descent, although all three types are panethnic in their distribution.

Pathophysiology: Glucosylceramide (also called glucocerebroside), the accumulated glycolipid, is derived primarily 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 contributing 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 ratio of ceramide to glucosylceramide can affect barrier formation in the epidermal layer of the skin, leading to icthyosis or a collodion skin presentation in severely affected individuals (type 2).

Frequency:

• In the US: Type 1 Gaucher disease is frequent among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 in 15, whereas the disease frequency is 1 in 855. Incidence of Gaucher disease is rare in the non-Jewish population, with an estimated frequency of 1 in 40,000.

• Internationally: Disease frequency internationally 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 patients 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 come to medical attention, contributing to an underestimation of the disease frequency. An increased frequency of type 3 disease exists in the Norrbottnian region of Sweden (1 in 50,000), which has been traced to a common founder in the 17th century.

Mortality/Morbidity: 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 the first years of life. A subset of this type, associated with congenital icthyosis and hydrops fetalis, is described as neonatal lethal and results in death in utero or perinatally.
Type 3 Gaucher disease is often a less rapidly progressive neurovisceral storage disease. There are many associated clinical courses, 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 the most prevalent genetic disorder among individuals of Ashkenazi Jewish descent. An increased incidence of type 3 disease is found 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 cases are not diagnosed until adulthood, presenting with low blood counts or bone involvement, while others are only diagnosed in the seventh to ninth decades of life because of an incidental finding of thrombocytopenia or splenomegaly. Many affected individuals never develop signs or symptoms, and do not reach 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

Section 3 of 11

History: Since Gaucher disease is inherited as an autosomal recessive trait, it is not unusual for the proband to be 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 tests; bone pain or pathologic fractures; and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds and/or bruising.
    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 frequently are 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 on routine examinations. Some patients are overtly asymptomatic, and a diagnosis is only made incidentally after evaluation for other medical problems.
  
  
  
• Type 2 Gaucher disease


• • Type 2 disease, which is rare, is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life.
    This form of the disease may present at birth or during infancy, with increased tone, seizures, strabismus, and organomegaly. There is evidence that disruption of the epidermal layers of the skin, seen on a skin biopsy study, may manifest before the onset of neurological symptoms, but this may not always be clinically apparent.
    Failure to thrive and stridor due to laryngospasm are typical in individuals with type 2 disease.
    The progressive psychomotor degeneration leads to death, usually caused by respiratory compromise.
    A severe neonatal form can present in utero or perinatally with hydrops fetalis and/or congenital ichthyosis.
  
  
  
• Type 3 Gaucher disease


• • This form of Gaucher disease is quite variable, and can present in infancy or childhood.
    In addition to organomegaly and bony involvement, neurologic involvement is present in individuals with type 3 disease.
    Often the sole neurologic manifestation is an oculomotor finding, the slowing of the horizontal saccades. 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.
  
  
  
• 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 (ages 3-7). These patients are considered to fall within the phenotypic continuum between Types 2 and 3.
  
  
  

Physical: Physical examination in type 1 disease usually reveals the presence of 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 occasionally are 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, ranging from a 5-fold to more than 80-fold increase in size 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 normal to 8.7-fold predicted normal (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 normal levels.
    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 enzymes 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 occasionally are found in individuals with Gaucher disease; however, transferrin saturation usually is normal. On liver biopsy, 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 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 are variable, 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 caused by deficiency of factor XI. However, a high incidence of genetic deficiency of factor XI occurs in individuals of Ashkenazi descent, and this may be present concomitantly in some patients with Gaucher disease.
    When cytopenia occurs in patients who have had splenectomies, it 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 the deficiency of glucocerebrosidase activity due to mutations in GBA, the structural gene encoding the enzyme. Widespread accumulation of glucosylceramide-laden macrophages results from the enzyme deficiency.
Today, more than 200 different mutant GBA alleles have been identified in patients with Gaucher disease. Screening for the presence or absence of the six most common GBA mutations in patients of Ashkenazi Jewish descent enables 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 which shares 96% sequence homology to glucocerebrosidase. Complex alleles with regions of pseudogene sequence have been identified in some patients, and cannot adequately be screened for by simple PCR-based mutation detection.
Genotype/phenotype correlations have been noted for some specific Gaucher presentations. For example, type 1 patients homozygous for the N370S mutation tend to have a later onset and a relatively mild course, and type 3 patients homozygous for the D409H mutation exhibit a rare phenotype involving cardiac calcifications, oculomotor abnormalities and corneal opacities. However, the wide variability in clinical presentation among patients with Gaucher disease frequently cannot be explained fully by the underlying mutations, since 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 subjects 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

DIFFERENTIALS

Section 4 of 11

Niemann-Pick Disease

Other Problems to be Considered:

Multiple myeloma

WORKUP

Section 5 of 11

Lab Studies:

• Enzyme activity: Diagnosis can be confirmed by measurement of glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic of the disease. Generally, heterozygotes have half-normal enzyme activity, but up to 20% overlap with activity levels of healthy controls occurs, rendering enzymatic testing for carrier status unreliable.
  Genotyping: Molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom four mutations in GBA (ie, N370S, c.84insG, L444P, IVS 2+1g>a) account for the majority of 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 tests for individual mutations, as they cannot detect the presence of recombinant alleles associated with greater disease severity.
  CBC: Obtain complete blood count and differential to assess the degree of cytopenia.
  Liver function enzymes: Minor elevations of liver enzymes are common, even in patients who are affected mildly with Gaucher disease; however, the presence of jaundice or impaired hepatocellular synthetic function merits a full hepatic evaluation
  Associated markers: Angiotensin converting enzyme typically is elevated, as is total acid phosphatase and ferritin. Levels of another enzyme, chitotriosidase, are also sometime useful in monitoring the disease

Imaging Studies:

• Ultrasonography: Ultrasonography of the abdomen can determine extent of organomegaly.



• MRI


• • MRI is more accurate in determining organ size.
    Hip MRI may be useful in detecting early avascular necrosis.
    MRI may be useful in delineating the degree of marrow infiltration and evaluating spinal involvement.
  
  
  
• Radiography


• • Skeletal radiography can detect and evaluate skeletal manifestations of Gaucher disease.
    Perform chest radiography to evaluate pulmonary manifestations.
  
  
  
• Dual-energy x-ray absorptiometry (DEXA) scanning: DEXA is useful in evaluation of osteopenia.

Procedures:

• Bone marrow aspiration


• • While in the past, diagnosis has been confirmed by the finding of classic glycolipid-laden macrophages in bone marrow aspirate collected because of hematological abnormalities, 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, and in patients with AIDS and Mycobacterium avium-intracellulare infection.
    Bone marrow aspiration should not be the initial diagnostic test, since the blood enzyme test is sensitive, specific, and much less invasive.
  
  
  
• Liver biopsy


• • Liver biopsy occasionally is performed because of unexplained hepatomegaly.
  
  
  
  • It can be avoided in most patients when the diagnosis is suspected, because a specific diagnostic test is available.
  
  
  

TREATMENT

Section 6 of 11

Medical Care: Enzyme replacement therapy (ERT) for Gaucher disease is now available, with most patients receiving recombinant enzyme (imiglucerase, Cerezyme®). This preparation is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease, but skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme. Treatment typically is administered once every other week at a high dose, but in some patients treatment is administered every week at a medium dose or up to 3 times a 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. A wide variation in severity and rate of disease progression exists, 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® typically is guided by a geneticist or a hematologist. It is advisable for a patient to receive periodic follow-up at a center familiar with Gaucher disease.
Enzyme therapy has a remarkable effect on the hepatosplenomegaly, with an overall 25% decrease, on average, in liver and spleen volume after 6 months of therapy. In most patients with anemia, hemoglobin rises 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 occasionally splenectomy has still been 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 enzyme therapy is required to achieve a radiologic response. Patients with bone crises require pain relief, hydration and close monitoring. A bone scan is needed at times to differentiate between a bone crisis and infection.
Other effects of enzyme therapy 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 responsive of patients to enzyme therapy varies widely and does not correlate with genotype, disease severity, splenectomy, or age. However, a number of factors portend a poor response to therapy, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement. The symptoms of patients with Gaucher disease with associated hematologic malignancies respond relatively poorly to enzyme treatment.
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 enzyme treatment, and these patients remain at risk of life-threatening hemorrhage from variceal bleeding.
There is no evidence of neurologic improvement with enzyme replacement therapy. While the enzyme does impact the visceral involvement in type 2 and type 3 disease, the associated brain involvement may persist or progress.

Surgical Care: In the past, partial and total splenectomy was advocated in the treatment of patients with Gaucher disease. However, with the availability of enzyme replacement therapy, considering this procedure for most patients is no longer necessary.
In addition, patients with Gaucher disease may require hip replacements or other orthopedic procedures because of their skeletal disease. This is best undertaken after the patient has received several months of enzyme replacement therapy.

Consultations:

• Medical genetics



• Hematology



• Orthopedics



• Neurology



• Neuro- ophthalmology

Diet: No dietary manipulation has been found to impact 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

Section 7 of 11

Currently, two therapies have FDA approval 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 only a minority develop any significant allergic reactions, which are controlled with pre-medication with hydrocortisone and/or antihistamines. All antibodies have been immunoglobulin G (IgG), mostly of the IgG1 subclass. A few rare patients with Gaucher disease have been described who have developed antibodies that impair enzyme activity.
Oral substrate reduction therapy, using an imino-sugar inhibitor of glucosylceramide synthase, has been approved for use in Type 1 Gaucher disease where ERT is not a therapeutic option due to allergy, hypersensitivity or poor venous access. Approved by the FDA in 2003, long-term data on efficacy and safety are not yet available.

Drug Category: Enzyme replacement therapy -- ERT, in most cases, 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 being marketed. Presymptomatic use is controversial because of the high cost and the extreme variability in clinical course among patients.

Drug Name	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
Adult Dose	30-150 U/kg IV qmo typically; dose must be individualized and varies widely; 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 Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
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 by pre-medication with hydrocortisone and/or antihistamines; may cause nausea, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia; may cause pruritus at site of injection

Drug Category: 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).

Drug Name	Miglustat (Zavesca) -- Indicated for type 1 Gaucher disease when enzyme replacement therapy is not a therapeutic option. Reduces glycosphingolipid (GSL) production by inhibiting glucosylceramide synthase. Reduces spleen and liver volume, increases hemoglobin and platelet counts.
Adult Dose	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 Dose	<18 years: Not established
Contraindications	Documented hypersensitivity; severe renal impairment
Interactions	Limited data exist; none reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution with renal impairment (decrease dose); neurological monitoring for possible peripheral neuropathy every 6 mo 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

Section 8 of 11

Further Inpatient Care:

• Patients with 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, which is provided on an outpatient basis. Monitoring for allergic reactions is essential.



• Recently, it has been recommended that patients receiving Zavesca® be monitored every 6 months for possible development of peripheral neuropathy.

Deterrence/Prevention:

• Gaucher disease is inherited as an autosomal recessive trait. Although it is panethnic, there is an increased frequency of the disorder in individuals of Ashkenazi Jewish descent. While 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, it is essential that testing is offered in conjunction with genetic counseling to provide couples at risk with a description of the range of associated phenotypes, including asymptomatic individuals, and their options, which include prenatal diagnosis

Complications:

• Bone crises may occur secondary 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.
  The latter can 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 also has 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, also are common. The malignancy multiple myeloma is seen more frequently in individuals with Gaucher disease.



• There is new evidence that mutations in the gene for glucocerebrosidase may be a risk factor for the development of Parkinson disease.

Prognosis:

• Many individuals with Gaucher disease have few manifestations and normal longevity 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 and platelet counts. Skeletal disease is slow to respond to ERT and is quite variable. Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of enzyme therapy 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

Section 9 of 11

Medical/Legal 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 who are affected with Gaucher disease have had successful pregnancies. Some patients have received treatment during pregnancy without complications. In patients who have not had treatment, hematologic status should be monitored.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 10-year-old boy with Gaucher disease type 1 presents with bone pain in the lower left extremity. What is the most likely etiology of this pain?

A: Bone infarct
B: Pathologic fracture
C: Leukemic infiltrate
D: Legg-Calvé-Perthes disease
E: Trauma

The correct answer is A: Patients with Gaucher disease may experience bone infarcts similar to those observed in sickle cell disease. Management of the bony crisis may require inpatient administration of narcotic analgesics.

CME Question 2: The parents of a 2-year-old boy recently diagnosed with Gaucher disease type 1 are concerned about the risk of Gaucher disease presenting in their next child. Which of the following statements would most appropriately be included in their counseling?

A: The parents have a 25% risk for having another child with Gaucher disease type 1.
B: The parents are at increased risk for having a child with any of the 3 types of Gaucher disease.
C: Prenatal diagnosis is possible only if the precise molecular defects have been identified in their child.
D: The parents’ risk is no greater than that of any other couple.
E: The parents are only at increased risk if their next child is also male.

The correct answer is A: Gaucher disease is inherited as an autosomal recessive trait. Therefore, the risk for another child affected with Gaucher disease is 25% with each pregnancy.

Pearl Question 1 (T/F): Gaucher disease type 1 typically presents with neurologic degeneration.

The correct answer is False: Type 1 disease is the nonneuronopathic form of Gaucher disease.

Pearl Question 2 (T/F): Bone pain can be a presentation of Gaucher disease.

The correct answer is True: Skeletal changes are common in Gaucher disease, which can present with a skeletal infarct or pathologic fracture.

Pearl Question 3 (T/F): Asymptomatic patients affected with Gaucher disease may be detected incidentally during prenatal screening.

The correct answer is True: Individuals mildly affected with Gaucher disease have been identified during prenatal screening programs for individuals of Ashkenazi Jewish descent.

Pearl Question 4 (T/F): A bone marrow biopsy is recfommended to confirm the diagnosis of Gaucher disease

The correct answer is False: A biopsy is not necessary or recommended- the diagnosis is established by enzymatic or molecular testing

BIBLIOGRAPHY

Section 11 of 11

• Amato D, Stachiw T, Clarke JT, Rivard GE: Gaucher disease: variability in phenotype among siblings. J Inherit Metab Dis 2004; 27(5): 659-69[Medline].
• Andersson HC, Charrow J, Kaplan P, et al: Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med 2005 Feb; 7(2): 105-10[Medline].
• Barton NW, Brady RO, Dambrosia JM, et al: Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991 May 23; 324(21): 1464-70[Medline].
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