Gaucher Disease

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 best characterized as 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.[1]

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression[1] :

• 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, and the disease should be viewed as a spectrum of symptoms.

Type 1 Gaucher disease is more common among individuals with Ashkenazi Jewish heritage, although all types are panethnic in their distribution.

Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and 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 or to neuroinflammation.[1, 2]

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 cytokines produced by macrophages.

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

Frequency

United States

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

International

Internationally, the 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 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 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. Type 3 Gaucher disease also appears to be the most frequent form in areas of Asia.

Mortality/Morbidity

Mortality and morbidity varies with the different types.[3]

Type 1 Gaucher disease may present in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease, although there is striking clinical variability in disease severity. Prior to the advent of treatment, bleeding and hepatic complications were more common, and patients with severe splenomegaly would routinely undergo splenectomy and have severe, sometimes fatal, bleeding complications. This risk has been dramatically reduced with the development of enzyme replacement therapy (ERT). Bone disease was a common cause of morbidity but is seen less frequently in treated patients.[1, 4, 5]

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.[1, 4, 5]

Type 3 Gaucher disease often is a less rapidly progressive neurovisceral storage disease, but it does have the largest phenotypic variation of among the GD spectrum. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood. Others, when treated, have a clinical progression like that of type 1 Gaucher disease and have very subtle neurologic findings.[1, 4, 5]

Race

All forms of Gaucher disease are panethnic. Type 1 Gaucher disease is one of the most common lysosomal storage diseases 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 and parts of Asia.

Sex

All 3 types of Gaucher disease are autosomal recessively inherited 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, bleeding events, incidental splenomegaly, 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. With an increased awareness of the connection between GD and Parkinson Disease, some patients have been diagnosed in Movement Disorder clinics at a later age.

Some individuals with type 1 Gaucher disease have few manifestations and a normal life expectancy without any intervention. The prognosis of symptomatic type 1 or type 3 Gaucher disease in patients who receive treatment is very good, with a decrease in organomegaly and an eventual rise in hemoglobin levels and platelet counts.

One study estimated life expectancy from birth in individuals with type 1 Gaucher disease to be 68 years, compared with 77 years in the reference population,[6] although this study was based on one industry-supported patient registry that may not have included many patients with milder cases who do not require therapy.

Skeletal disease is slow to respond to ERT, is generally more pronounced if a patient has undergone a splenectomy, and varies widely. Early treatment may decrease the frequency of bony involvement.

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.

The prognosis of type 2 Gaucher disease is universally poor, and depending on the age at presentation and the aggressiveness of management, life expectancy varies from several months to several years.[7]

The prognosis of type 3 Gaucher disease depends on the severity of disease and age of onset of therapy. Most patients with progressive myoclonic epilepsy associated with GD3 do not fare well. Also those with the cardiac variant associated specifically with genotype D409H/D409H, GD3C often develop valvular calcifications and die of cardiac complications in the second or third decade of life.

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 recurrence risks.

There are several ethical considerations facing patients with Gaucher disease and their medical team. With the rise of newborn screening covering lysosomal storage diseases, an increasing number of Gaucher patients are identified when asymptomatic. The question of when to begin treatment is debated and is particularly relevant with the pediatric patients who are asymptomatic. The decision whether to treat patients with type 2 GD is controversial. As there is often a diagnostic challenge discerning between acute and chronic neuronopathic Gaucher disease, current recommendation is to begin ERT if there is any question of diagnosis.

Presentation of GD has a varied symptomology and severity. In the following box the various symptoms and age of most likely manifestations are described[8] :

Newborn

• Congenital ichthyosis
• Organomegaly
• Failure to thrive
• Brain stem dysfunction - Dysphagia, apnea, difficulty with secretions, abnormal swallow
• Hepatosplenomegaly
• Hematological abnormalities (anemia, thrombocytopenia)

First year of life

• Failure to thrive
• Difficulty feeding
• Organomegaly
• Anemia/thrombocytopenia
• Brain stem dysfunction - Progressive dysfunction
• Saccadic gaze abnormalities
• Seizures
• Cardiac valvular stenosis

Childhood

• Organomegaly
• Hematological abnormalities, including bleeding events
• Bone pain crisis
• Skeletal/bone dysfunction - Avascular necrosis, osteopenia, pathologic fractures
• Saccadic gaze abnormalities
• Fatigue

Adolescence

• Organomegaly
• Abnormal bleeding
• Delayed puberty
• Skeletal/bone dysfunction
• Menorrhagia
• Fatigue
• Myoclonic epilepsy

Adult

• Organomegaly
• Malignancies
• Hematological abnormalities
• Bone dysfunction, especially osteopenia

Elderly

• Parkinson disease/dementia
• Organomegaly
• Malignancies
• Hematological abnormalities
• Bone dysfunction, especially osteopenia

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 or have delayed onset of puberty due to the increased metabolic demands of the disease.

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, multiple myeloma, 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 asymptomatic, and a diagnosis is made incidentally after evaluation for other medical problems or because of affected family members.

Type 2 Gaucher disease

Type 2 disease is rare and is characterized by a rapid neurodegenerative course with extensive visceral involvement and death generally within the first 2 years of life.[7, 9]

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 neurologic 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. Often, there is a maternal history of miscarriages without an established cause.

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. However, in some patients, visceral involvement can be extreme.

The slowing of the horizontal saccades, an oculomotor finding, is often the sole neurologic manifestation, which can be subtle and not develop until later in childhood. 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 and skeletal 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 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, wasting, and failure to thrive 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 an abnormal neurologic examination, revealing features including sensorineuronal hearing loss, EEG abnormalities, or a wide-based gait.

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.[4, 10]

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 now uncommon in treated individuals, 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 frequently 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. In neuronopathic Gaucher disease, kyphosis and scoliosis may be present and may progress, and may require surgical correction.

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. Avascular necrosis of the hips is a common complication in individuals of all ages, often resulting in early hip replacement.

Hematologic complications

Hematologic manifestations of Gaucher disease may include cytopenia, platelet dysfunction 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.

Numerous immunologic abnormalities are common in individuals with Gaucher disease, including hypergammaglobulinemia, T-lymphocyte deficiency in the spleen, and impaired neutrophil chemotaxis.

All three forms of Gaucher disease are caused by deficient glucocerebrosidase activity due to mutations in GBA1, the structural gene that encodes the enzyme. Widespread accumulation of glucosylceramide-laden macrophages results from the enzyme deficiency.

More than 400 different mutant GBA1 alleles have been identified in patients with Gaucher disease. Screening for the 6 most common GBA1 mutations in patients of Ashkenazi Jewish descent has enabled the identification of up to 90% of the mutant alleles in this population, but overall, a large number of other mutations have been described in other populations, complicating mutation screening. Screening may also miss alleles with more than one mutation on the same allele. Furthermore, atypical cases have been described that arise from Saposin C deficiency, uniparental isodisomy or new mutations.

Some mutations derive from recombination with the glucocerebrosidase pseudogene, a sequence 16 kb downstream that shares 96% sequence homology to glucocerebrosidase. Complex alleles with regions of pseudogene sequence, have been identified in some patients, but may be missed by those not familiar with the genetic architecture of the region.

Genotype/ 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 (Gaucher disease 3C, GD3C) 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, as 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.

Bone crises may occur sporadically, especially in times of growth, and may indicate 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 are a risk factor for the development of Parkinson disease.[11, 12] Of subjects with Parkinson disease and related Lewy body disorders, 3-20% carry a mutation in glucocerebrosidase, with the higher frequency being among Ashkenazi Jewish subjects.[13]

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 GBA1 mutations (ie, N370S, c.84insG, L444P, IVS2+1g>a, V394L, and R496H) account for around 90% of disease alleles. However, these variants only account for 50-75% in other ethnicities, and therefore sequencing of the exons of GBA1 is necessary in order to accurately establish the genotype. 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 always identify  the presence of recombinant alleles associated with greater disease severity. A complete analysis of the GBA1 gene is especially important in situations where either biomarkera or disease phenotype is at odds with enzymatic activity and further disease characterization is necessary for definitive diagnosis, genetic counseling or family planning.[17]

CBC count

A CBC count with a platelet count and differential should be performed 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 typically are elevated, as are total acid phosphatase and ferritin levels. These levels may normalize or may remain elevated with treatment. 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.

In recent years levels of glucosylsphingosine, a downstream metabolic product of glucosylceramide, have been shown to be a useful disease biomarker, as it correlates with disease severity and with response to therapy.[18]

Ultrasonography of the abdomen can reveal the extent of organomegaly, and can be useful especially in young children. MRI is more accurate than ultrasonography in determining organ size and is used for volumetric assessment. MRI may be useful in revealing early skeletal involvement, such as avascular necrosis and spinal degradation, as well as in delineating the degree of bone marrow infiltration. Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease. Chest radiography should be performed to evaluate pulmonary manifestations. Dual-energy x-ray absorptiometry (DEXA) is useful in evaluating osteopenia. Bone scans may be useful in diagnosing bone crises.

Echocardiograms are helpful in evaluating the possibility of pulmonary hypertension.

In neuronopathic Gaucher disease, depending on phenotypic presentation, EEG, brainstem-evoked potential, swallow studies, and neuro-ophthalmologic evaluation should be performed at regular intervals.

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 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– intracellular infection.

Bone marrow aspiration should not be the initial diagnostic test because the blood enzyme test is sensitive, specific, and much less invasive; in fact, such biopsies rarely are indicated.

Liver biopsy

Liver biopsy occasionally is performed to assess unexplained hepatomegaly. However, it should be avoided in most patients when the diagnosis is suspected because a specific diagnostic test is available.

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 mm in diameter, have a characteristic wrinkled-paper appearance, resulting from intracytoplasmic substrate deposition, and stain strongly positive with periodic acid–Schiff, PAS. Histologic evaluation of biopsy specimens should not be used as a first-line diagnostic tool.

Enzyme replacement

Enzyme replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase alfa (Elelyso). Historically, most patients received the recombinant enzyme imiglucerase.[19] 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 dose of 15-60 U/kg, with a standard adult dose being around 30 U/kg. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.

ERT 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 vary, 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 ERT remains controversial because of the lack of prognostic correlation between genotype and disease severity and the high cost of the therapy. While not formally on the Recommended Uniform Screening Panel (RUSP) for newborn screening in the United States, there are an increasing number of states or panels that include GD. This is leading to a new subclass of GD patients, often asymptomatic.[20]

For most patients with Gaucher disease in the United States, treatment with ERT 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. Those who have undergone splenectomy are particularly susceptible to the development of bone disease, even with therapy.

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.

Glucosylceramide synthase inhibitors

Glucosylceramide synthase inhibitors include miglustat (Zavesca) and eliglustat (Cerdelga). Miglustat was approved in 2003 as monotherapy for treatment of adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Patients have reported mild to moderate adverse effects with miglustat, the most frequently reported side effects being GI.

Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]).[21]

Approval was based on efficacy data from two positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2.[22, 23]

In three other studies, eliglustat was superior to placebo over nine months of treatment, outcomes were similar for patients treated with eliglustat or imiglucerase for 4 years, and outcomes of eliglustat treatment were similar when dosing regimens were determined based on CYP2D6-genotype-predicted phenotype or plasma eliglustat concentrations.[24]

Gene therapy

Currently there are no approved gene therapies for Gaucher disease. There are several clinical trials involving several gene therapy modalities including a non-integrating AAV9 vector and integrating lentiviral vector.[25]

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 with the following specialists are indicated:

• Medical geneticist

• Hematologist

• Orthopedist

• Neurologist

• Neuro-ophthalmologist

No dietary manipulation has been found to affect disease progression.

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.

Gaucher disease is inherited as an autosomal recessive trait. While 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.

Most symptomatic patients with Gaucher disease receive enzyme replacement therapy (ERT), which is provided on an outpatient basis.[13]

Monitoring for allergic reactions is essential.

Monitoring patients who receive taliglucerase or miglustat (Zavesca) every 6 months is recommended.

Patients with osteoporosis have responded favorably to bisphosphonates.

Patients not currently on therapy should be monitored at regular intervals for changes in organ size and/or hemoglobin and platelet counts.

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. Children with type 2 Gaucher disease are often hospitalized with failure to thrive or aspiration pneumonias.

Several therapies have been approved by the US Food and Drug Administration (FDA) for the treatment of type 1 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, marketed as imiglucerase (Cerezyme). Worldwide, over 4,000 patients with Gaucher disease have received ERT, which is safe and well tolerated.

In 2010, an alternate form of ERT was approved. This form of recombinant enzyme is produced in cultured human cells and is marketed as velaglucerase alfa (VPRIV).[26, 27] In May 2012, taliglucerase alfa (Elelyso) was the first plant cell–based ERT approved by the FDA; it uses engineered carrot cells.[28]

The glucosylceramide synthase inhibitors, miglustat and eliglustat, were approved for adults with type 1 Gaucher disease in 2003 and 2014 respectively.

Approximately 10-15% of patients with Gaucher disease treated with imiglucerase 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.

Class Summary

In most cases, ERT is highly effective in reversing the visceral and hematologic manifestations of type 1 Gaucher disease. Recombinant beta-glucocerebrosidase (imiglucerase [Cerezyme]) has replaced the original tissue-derived product, alglucerase (Ceredase). Alglucerase is an orphan drug and still manufactured by Genzyme Corporation on an extremely limited basis for a few patients unable to tolerate the newer recombinant product. Presymptomatic use is controversial because of the high cost and the extremely variable clinical course.

Imiglucerase is approved for children aged 2 years or older. Velaglucerase and taliglucerase are both approved for children aged 4 years or older.

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

Velaglucerase alfa (VPRIV)

Hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy for type 1 Gaucher disease. Improves symptoms associated with the disease, including anemia, thrombocytopenia, increased spleen and liver size, and cachexia.

Taliglucerase alfa (Elelyso)

Taliglucerase is a plant-based recombinant enzyme. It catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, which results in reduced spleen and liver enlargement and increased RBCs and platelets.

Class Summary

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.

Eliglustat (Cerdelga)

Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide. It is indicated for the long-term treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM) as detected by an FDA-cleared test for phenotype. Dosage is based on establishing the patient's CYP2D6 metabolizer status.