Gaucher disease was first described by P.C.E. Gaucher in 1882, who thought that the large splenic cells of a young woman seen postmortem were evidence of a primary neoplasm.1 The term Gaucher disease appeared first in 1905, when the autosomal recessive genetic nature of the disorder was elucidated.2 In 1934, it was shown that glucocerebroside is the storage material in Gaucher disease,3 and in 1965, the primary defect was recognized as a deficiency of glucocerebrosidase resulting in an impairment of degradation of glucocerebroside.4,5 Enzymatic purification ultimately led to the cloning of the gene in 1985,6,7 unraveling of its structure, and identification of many glucocerebrosidase mutations.8 Disease-specific enzyme replacement therapy (ERT) was first introduced in 1991.9
Gaucher disease is inherited as an autosomal recessive disorder. Although panethnic, type 1 is most common among the Ashkenazi Jews, with a carriership prevalence of 1 in 17 and an expected frequency of the disease in 1 in 850 livebirths.10 Two distinct forms of Gaucher disease, type 3b and type 3c, are also relatively common in Norrbottnia in northern Sweden,11 and near the Palestinian town of Jenin, respectively.12 In the general population, the estimated frequency (based on large-scale neonatal screening projects in three countries is in the range of 1 in 50,000 to 1 in 100,000 persons.13
The high prevalence of at least two Gaucher mutation, N370S and 84GG (and possibly R496H14 and others), among Ashkenazi Jews, and the existence of other lysosomal diseases within this ethnic group, may reflect, in addition to a founder effect, a selective advantage. However, a selective advantage because of greater resistance to tuberculosis15 or superior intelligence16 has not been proven. Animal studies suggest that the selective advantage may be the higher circulating serum levels of glucocerebroside that have antiinflammatory and beneficial immunomodulary effects.17
ETIOLOGY AND PATHOGENESIS
During normal growth, development, and senescence, parts of or whole cells are continually replaced. Breakdown of complex constituents of cells requires sequential enzymatic degradation. Such degradation occurs largely in secondary lysosomes, organelles formed by the fusion of primary lysosomes with phagocytic vacuoles containing ingested material.
Gaucher disease is the result of a hereditary deficiency in the activity of a lysosomal enzyme, glucocerebrosidase, required for glycolipid degradation. The reduced activity of glucocerebrosidase results in accumulation of glucocerebroside in macrophages engorgement with glucocerebroside induces increased cell size and cytoplasmic striations, leading to the formation of “Gaucher cells” (see Fig. 72–1). Inherent in subsequent lysosomal dysfunction is a dysregulation of metabolites and the consequent lack of coordination of cellular metabolism. These changes may explain the elaboration of various cytokines and other biomarkers because of engorgement of macrophages.
Accumulating evidence indicates that in addition to the glucocerebrosidase enzyme (GBA1), a second, nonlysosomal glucocerebrosidase, GBA2, a cytosolic protein that tightly associates with cellular membranes, may be integral to the pathogenesis of Gaucher disease, affecting its phenotype by potentially interacting with GBA1.18,19,20
In rare instances, severe forms of Gaucher disease are associated with deficiency of saposin C, a heat-stable glucocerebrosidase co-factor.21,22
GENETIC BASIS OF GAUCHER DISEASE
The glucocerebrosidase gene is located on chromosome 1q21. A pseudogene, with 96 percent sequence homology, has been identified approximately 16 kb downstream from the functional gene. Nearly 300 point mutations causing Gaucher disease have been described8,23; most are point mutations, missense, nonsense, frameshift, and splice-site mutations, but there are also insertions, deletions, and recombinant alleles. Some mutations result from recombinant events between the functional gene and its pseudogene.8 Since 2000, approximately 20 of these mutated enzymes have undergone crystallography showing the divergence of ligands in the active site and with various degrees of glycosylation.23
Among Ashkenazi Jews, the predominant mutation is N370S which accounts for approximately 75 percent of mutant alleles among Jewish patients and approximately 30 percent of the alleles among non-Jewish patients. Homozygosity for N370S is characterized by relatively milder phenotypes (although the phenotype is very heterogenous and severe cases are seen24). N370S has heretofore been considered “protective” against the development of neuronopathic features. The second common mutation found almost exclusively among Ashkenazi Jews is one that usually causes a severe phenotype. Five or six common mutations account for approximately 97 percent of alleles among Jews, but account for less than 75 percent of alleles among non-Jews.8,25,26,27 Although controversial, premarital/prenatal screening for common mutations has become frequent among Ashkenazi Jews.28,29,
The second most common mutation is L444P, which when homozygous accounts for most patients with the neuronopathic type 3 disease, and is the most prevalent mutation in Asians, Arabs, and Norrbottnians. Patients with the unique variant of progressive calcifications of cardiac valves, type 3c, are uniformly homozygous for a point mutation D409H.12
Despite some relationship between specific mutations and the clinical course, genotype–phenotype correlation is imperfect. Elucidation of the three-dimensional structure of the glucocerebrosidase by crystallography has also not improved prediction of disease severity based on the location of mutations in the native protein.30
The majority of the mutations cause glucocerebrosidase misfolding, which may lead to early degradation of the enzyme in the endoplasmic reticulum.31,32 The investigation of the proteotoxic effect of the misfolded mutant enzyme in the endoplasmic reticulum has led to the development of the new therapeutic modality of pharmacologic chaperones (PCs). PCs are targeted to stabilize the mutated glucocerebrosidase and allow its appropriate trafficking from endoplasmic reticulum to Golgi and, finally, to the lysosome.
Three major types of Gaucher disease are differentiated clinically based on absence (type 1) or presence of neurologic features (types 2 and 3).33 Table 72–1 summarizes key clinical, genetic, and demographic features. Although it has been suggested that there is a phenotypic continuum,34,35 it is still useful to think of Gaucher disease as three distinct forms to facilitate genetic counseling and management decisions.
Table 72–1.Characteristics of the Three Types of Gaucher Disease ||Download (.pdf) Table 72–1. Characteristics of the Three Types of Gaucher Disease
| ||TYPE 1 ||TYPE 2 ||TYPE 3 |
|Subtype ||Asymptomatic ||Symptomatic ||Neonatal ||Infantile ||3a ||3b ||3c |
|Common genotype ||N370S/N370S or 2 mild mutations ||N370S/other or 2 mild mutations ||Two null or recombinant mutations ||One null and one severe mutations ||None ||L444P/L444P ||D409H/D409H |
|Ethnic predilection ||Ashkenazi Jews ||Ashkenazi Jews ||None ||None ||None ||Norrbottnians, Asians, Arabs ||Palestinian Arabs, Japanese |
|Common presenting features ||None ||Hepatosplenomegaly, hypersplenism, bleeding, bone pains ||Hydrops fetalis; congenital ichthyosis ||SNGP, strabismus, opisthotonus, trismus ||SNGP; myoclonic seizures ||SNGP; hepatosplenomegaly growth retardation ||SNGP; cardiac valves’ calcifications |
|CNS involvement ||None ||None ||Lethal ||Severe ||SNGP; slowly progressive neurologic deterioration ||SNGP; gradual cognitive deterioration ||SNGP; brachycephalus |
|Bone involvement ||None ||Mild to severe (variable) ||None ||None ||Mild ||Moderate to severe; kyphosis (gibbus) ||Minimal |
|Lung involvement ||None ||None to (rarely) severe ||Severe ||Severe ||Mild to moderate ||Moderate to severe ||Minimal |
|Life Expectancy ||Normal ||Normal/near-normal ||Neonatal death ||Death before age 3 years ||Death during childhood ||Death in mid-adulthood ||Death in early adulthood |
There is variability in disease severity of all types of Gaucher disease. Type 1 disease may be asymptomatic and be discovered in the course of population surveys of Ashkenazi Jews,28 or incidentally during evaluation of an unrelated hematologic disorder.
Fatigue is a common complaint, usually not invariably related to anemia, but also quite common in nonanemic patients and may be a result of elevated inflammatory cytokines.36
In symptomatic patients, the spleen is typically enlarged,37 whether barely palpable or massively enlarged causing positional symptoms, such as early satiety or abdominal discomfort. Splenic infarction and subcapsular hematoma are uncommon. Hepatomegaly is usually asymptomatic, but it may cause abdominal discomfort and in splenectomized patients or others with very severe disease, liver fibrosis and later cirrhosis,38 with or without portal hypertension, may occur; hepatocellular carcinoma may evolve.39 An increased incidence of nonalcoholic fatty liver disease has been observed.40
Lymphadenopathy has been described,41 including a severe protein-losing form,42 which is a clinical management problem.
Epistaxis, easy bruising, and hemorrhage after surgical or dental procedures and bleeding during labor are common presenting symptoms. These manifestations usually are related to thrombocytopenia as the result of hypersplenism or marrow replacement by Gaucher cells, but platelet dysfunction and decreased levels of coagulation factors have also been described and hence should be assessed prior to surgical procedure or before delivery.43,44,45 Coagulation factor deficiencies may result from liver disease or consumption coagulopathy.
Reduced hemoglobin levels are also primarily a result of hypersplenism and marrow replacement by Gaucher cells, but additional causes include iron deficiency, vitamin B12 deficiency, and autoimmune hemolysis.46,47
“Gaucheromas” (Fig. 72–2), which are possibly extraosseous in origin48 and/or may mimic a malignant process,49,50 appear idiosyncratically, but possibly after some invasive procedure such as hip surgery; these have been described to be at increased risk of hemorrhaging when manipulated.
A. Histologic section of “Gaucheroma” showing hemorrhagic mass with nucleated red blood cells covered by a fibrous capsule. B. Histologic section at a higher magnification showing nucleated red blood cells admixed with numerous Gaucher cells. (Used with permission ofProf. Eliezer Rosenmann, Shaare Zedek Medical Center, Jerusalem, Israel.)
Severe pulmonary disease with cyanosis and clubbing occurs in some patients with advanced liver involvement, and is usually a consequence of hepatopulmonary syndrome with or without infiltration of the lungs by Gaucher cells.51,52 Mild pulmonary hypertension may be detected by echocardiography,53 but may (rarely) be severe especially among splenectomized patients54; it has not been reported in children.55 Pulmonary function tests may reveal abnormalities, such as reduced diffusion capacity in approximately two-thirds of patients.56
Bone involvement is usually the main cause of morbidity in symptomatic patients and can occur in any long bone.57 Patchy areas of bone demineralization and infarction are seen (Fig. 72–3A), and asymptomatic widening of the distal femur known as Erlenmeyer flask deformity is very common (Fig. 72–3B). Bone metabolism markers indicate that bone resorption predominates,58 but the overall mechanisms underlying development of bone lesions are poorly understood. Children may have delayed bone age and delayed eruption of the teeth.59 Bone pain is probably the most troublesome symptom of Gaucher disease. Bone pain may be related to the pathologic processes evident by radiography, magnetic resonance imaging (MRI), and computerized tomography, or have the character of a “crisis,” which is a self-limiting, albeit exquisitely painful event, associated with signs of acute local and/or systemic inflammation (Fig. 72–3D). Aseptic necrosis of large joints, mainly the femoral heads but also the shoulders and knees (and rarely even in smaller joints) and vertebral collapse are particularly common typically among untreated patients with genotypes resulting in more severe phenotypes (Fig. 72–3C and E).
Gaucher-related skeletal involvement including (A) humerus with chevron or herring-bone pattern; (B) Erlenmeyer flask deformity of the proximal femur; (C) plain radiograph of osteonecrosis of the left hip; (D) magnetic resonance image of pelvis and thighs that was performed 2 weeks after bone crisis of the right thigh. Bone edema is seen in the upper part of the femur at the level of lesser trochanter. Chronic marrow signal changes are seen in both femurs; (E) vertebral collapse. (Used with permission of Dr. Ehud Lebel, Shaare Zedek Medical Center, Jerusalem, Israel.)
Gynecologic Manifestations and Fertility
Gynecologic and obstetric problems are common and are mainly related to bleeding tendency,60 which may explain why females are more likely to be diagnosed. Delayed menarche and menorrhagia are common, and increased risk of recurrent abortions has been reported.61 Fertility is unaffected in males and females.
Organs other than the spleen, liver, bones, and lungs may be affected. Many patients have pinguecula and a few a pterygium at the corneoscleral limbus.62 Additional findings include uveitis and preretinal white spots in rare cases.63
Renal manifestations are rare and limited to case reports of nephrotic syndrome and renal cell carcinoma.64 Nonetheless, many patients seem to have benign urinary hyperfiltration.65
Neurologic symptoms constitute the hallmark of types 2 and 3 diseases.66 Particularly notable and pathognomonic are oculomotor abnormalities, especially supranuclear gaze palsy (SNGP), which is typically noted horizontally,67 but might occur in the vertical plane as well. Patients with type 2 disease develop hypertonia of the neck muscles with extreme arching of the neck (opisthotonus), bulbar signs, limb rigidity, seizures, and sometimes choreoathetoid movements. In these patients, the SNGP becomes a fixed convergent squint, often facilitating differentiating between type 2 patients, who are terminal by 2 to 3 years of age, and the severe type 3a patients, who may survive longer. Patients with type 3a disease exhibit progressive neurologic abnormalities such as myoclonus and dementia.68 Patients with type 3b disease display aggressive visceral and skeletal involvement but neurologic manifestations are largely limited to horizontal SNGP.68 Patients with type 3c disease exhibit SNGP, mild visceral involvement, and fatally progressive calcifications of mitral and tricuspid valves and of the large arteries.12,68,69,70
Several neurologic abnormalities have been observed in patients with type 1 disease, including peripheral neuropathy71,72 and an increased prevalence of Parkinson disease (the latter also among carriers of a single mutation).73,74,75,76,77 Carriers of severe mutations (e.g., null alleles) were reported to have a 13.6-fold increased risk of Parkinson disease compared to controls, whereas carriers of the more benign mutations have a 2.2-fold increased risk.78 A meta-analysis of patients with Parkinson disease has confirmed this strong association between mutations in the glucocerebrosidase gene and Parkinson disease, which is marked by an earlier age of onset and higher prevalence of cognitive changes.78,79
Predisposition to Infections
An increased tendency to infections is sometimes seen, occurring among splenectomized patients or severely affected patients, some of whom may have defective neutrophil chemotaxis.80,81 Bacterial osteomyelitis is most often iatrogenic following surgical intervention at the site of a bone crisis. In children, linear growth retardation is common regardless of disease severity,82 but a compensatory “catch-up” growth may occur by early adulthood.83
Predisposition to Neoplasia
There is a higher prevalence of neoplastic disorders in patients with Gaucher disease.84,85 Myeloma has been established to be more prevalent.84,85 Other hematologic malignancies,86 hepatocellular carcinoma, and renal cell carcinoma, may also have increased prevalence.87 Although elevated levels of interleukin-6 in patients with Gaucher disease may link Gaucher disease and myeloma,88 there is no explanation at present for increased incidence of other types of cancer. Some malignancies may be less common.87 The impact of ERT on either an increased or decreased development of malignancies has not been determined.
The complete blood count in patients with Gaucher disease may be normal or may reflect the effects of hypersplenism. A normocytic, normochromic anemia is frequently present, but hemoglobin levels only rarely fall below 8 g/dL. A modest reticulocytosis is often present in anemic patients. The white cell count may be decreased to as low as 1.0 × 109/L, but milder degrees of leukopenia are more common. The differential count is normal, but splenectomized patients tend to show a lymphocytosis. A defect of leukocyte chemotaxis which may be corrected by ERT,89 and in some patients is associated with a tendency to bacterial infections80; monocyte dysfunction has also been reported.81 Thrombocytopenia is typically more prominent than anemia.46 In an anemic patient with an intact spleen and normal range platelet counts, there is probably an alternative reason for the low hemoglobin level, unrelated to Gaucher disease. Thrombocytopenia may be quite severe, even in an otherwise mildly affected patient. In splenectomized patients, anemia is more likely in the absence of thrombocytopenia; white cell count and platelet counts are usually higher than normal. Severe anisocytosis and poikilocytosis also occur in splenectomized patients, with many target cells, some nucleated red cells and Howell-Jolly bodies. During bone crises, leukocytosis, thrombocytosis, and elevated erythrocyte sedimentation are seen. Other markers of inflammation have been noted regardless of disease severity: elevated fibrinogen levels, elevated high-sensitivity C-reactive protein, and increased adhesion and aggregation of red blood cells.90,91
Other Hematologic Findings
Clotting factor abnormalities may be induced by activated macrophages41,42 or may be found when there is liver involvement. Factor IX deficiency may be a laboratory artifact related to the effect of accumulated lipid on platelet membranes.92 Factor XI deficiency is common among Ashkenazi Jewish patients because of its high coincidental prevalence in this ethnic group.93
Bleeding tendency may also result from defective aggregation or adhesion of platelets33 and therefore platelet function and/or thromboelastography should be tested before surgical and dental procedures and labor.44,94
Biochemical and Immunologic Findings
In most patients, liver function tests are within normal limits but in conjunction with more severe disease, splenectomy, and/or comorbidities (hepatitic B and/or C, or autoimmune diseases) abnormal liver function tests may be seen. Because of the increased prevalence of cholelithiasis,95,96 cholestatic findings may occur. Renal function tests are usually normal.64
Many patients present with polyclonal gammopathies. Monoclonal gammopathies are found in 1 to 20 percent of patients, particularly older patients.79,80,81,82 Increased levels of autoantibodies have been reported,97 and may indicate coincide with autoimmune diseases such as Hashimoto thyroiditis, rheumatoid arthritis, or immune hemolytic anemia.
Biochemical abnormalities have been used as surrogate markers in Gaucher disease. In the past, increased activities of serum acid phosphatase, angiotensin-converting enzyme, serum ferritin, and other hydrolases, such as β-hexosaminidase or β-glucuronidase, were used. Other biomarkers correlate better with the extent of glucocerebroside storage. The most widely used biomarker is chitotriosidase,98 which is undetectable in healthy subjects (its physiologic role is unknown), but is elevated, often several thousand-fold, in patients with Gaucher disease. Chitotriosidase measurement is useful for monitoring both untreated patients, to assess stability versus deterioration, and treated patients, to assess response to therapy. A change in chitotriosidase levels rather than absolute values is used for monitoring. In approximately 6 percent of people, it is undetectable, and for those patients, measurements of chemokine CCL18/PARC which is predominantly produced by Gaucher cells, can be used.99
A potentially more sensitive and more specific biomarker has been identified: the lyso-glucosylsphingosine (lyso-Gb1),100 which may be preferred as a more reproducible biomarker, using a more operator-friendly assay.
Serum iron levels may be low in patients because of iron deficiency related to bleeding or chronic inflammation. Deficiencies of vitamin B12101 and vitamin D102 have been described, albeit these are also very common in the general population. Serum ferritin levels are usually elevated.
Gaucher cells, found mainly in the marrow, spleen, and liver (Fig. 72–4), have small, usually eccentrically placed nuclei and cytoplasm with characteristic crinkles or striations. The cytoplasm is stained by the periodic acid-Schiff technique. Electron microscopy demonstrates cytoplasmic spindle- or rod-shaped, membrane-bound inclusion bodies 0.6 to 4 μm in diameter, consisting of numerous small tubules, 130 to 750 Å in diameter, that are composed of twisted multilayers in negatively stained preparations.103
A. “Gaucher cell” from the marrow of a patient with Gaucher disease. B. Histomicrograph of a Gaucher spleen with marked infiltration of the red pulp by Gaucher cells. C. Liver infiltrated by Gaucher cells (the pale pink cells). (Marrow image used with permission of Prof. Chaim Hershko, Shaare Zedek Medical Center, Jerusalem, Israel; spleen and liver images used with permission of Prof. Gail Amir, Hadassah Medical Center, Jerusalem, Israel.)
The diagnosis of Gaucher disease should be considered in (1) any patient who presents with unexplained splenomegaly, thrombocytopenia, frequent nosebleeds, anemia, acute or chronic bone pain; (2) children with short stature for their age; and (3) nontraumatic avascular necrosis of a large joint at any age, especially if is associated with any of the above features.
A definitive diagnosis requires a reduced enzymatic activity of β-glucocerebrosidase in leukocytes,104,105 cultured fibroblasts, or amniocytes obtained during prenatal diagnosis. Measurement of glucocerebrosidase levels is supplemented by mutational analysis. This is important for prognosis, particularly in children, and for detection of carriers among affected families. While rapid polymerase chain reaction-based tests are often performed for five or seven common mutations, especially among Ashkenazi Jews as a “first-pass,” it is highly recommended to perform whole-genome sequencing106 to rigorously establish the molecular diagnosis.
Marrow aspiration as a means of diagnosis is only indicated when other hematologic diseases must be considered.94,105 Gaucher cells are often sparse and thorough examination under low-power may be required to find them. Cells indistinguishable by light microscopy from typical Gaucher cells may also be seen in patients with other disorders such as chronic myelogenous leukemia, Hodgkin lymphoma, myeloma, and acquired immunodeficiency syndrome. The latter patients do not lack the ability to catabolize glucocerebroside, but the great inflow of globoside into phagocytic cells exceeds their capacity to hydrolyze glucocerebroside, forming “pseudo-Gaucher cells.”
Prenatal diagnosis can be established by examining cultured amniocytes obtained by amniocentesis for measurement of glucocerebrosidase activity104 or by examining amniocytes or chorionic villi DNA for known mutations.
Heterozygotes for Gaucher disease have neither Gaucher cells in their marrow nor stigmata of Gaucher disease (other than the increased risk of Parkinson disease). Existence of a carrier state can be demonstrated by reduced glucocerebrosidase activity to approximately 50 percent of normal values. However, regardless of methodology, enzyme activity among heterozygotes overlaps the normal range and hence definitive diagnosis of heterozygous status only can be made by mutational analysis. Currently various methodologies are being developed to allow noninvasive prenatal diagnosis of monogenic diseases like Gaucher disease; the most promising of these is molecular analysis of cell-free fetal DNA.107
Symptoms and signs related to massive enlargement of the spleen (e.g., pancytopenia, early satiety, abdominal discomfort, and growth retardation in children) can be resolved by splenectomy. However, because of the efficacy of ERT, splenectomy should only be a last resort as it often induces progressive liver and bony complications, and increases the risk of infection with encapsulated organisms. Partial splenectomy has not proved useful, with both regrowth of the remnant and risk of osteonecrosis.
When bone lesions result in fractures or osteonecrosis (see Fig. 72–3D), orthopedic procedures may be required. Joint replacement is generally uneventful, with good functional outcome and quality of life. The success of arthroplasties is enhanced by adherence to preoperative protocols including assessment of bleeding tendency, prophylactic use of antibiotic therapy, particularly in splenectomized patients, and early post-operative ambulation.108
Deficiencies of iron, vitamin B12, or vitamin D should be corrected and calcium supplementation is recommended in patients with osteoporosis receiving bisphosphonates.109 Use of erythropoietin may be required for management of anemia because of marrow failure.110
Enzyme Replacement Therapy
The use of alglucerase,9 the first mannose-terminated, placental-derived enzyme, was approved in 1991, and the recombinant form, imiglucerase, albeit with one amino acid R495H that differs from the wild-type protein owing to a cloning artifact in the original complementary DNA (cDNA), was introduced in 1994.111 Two intravenous preparations, one with the perfect native-enzyme sequence developed in a human cell line, velaglucerase alfa,112 and the other, a carrot root cell-derived with the imiglucerase core sequence, taliglucerase alfa,113 have completed phase 3 clinical trials and are available. Phase 2 clinical trials with taliglucerase alfa are currently underway in which the same carrot cells, expressing taliglucerase alfa, are used as vehicle for oral delivery of the enzyme.
The response to ERTs is most gratifying.9,111,112,113,114,115,116 Decreased spleen and liver volumes and increased hemoglobin levels and platelet counts usually occur within 6 months of therapy with biweekly doses between 15 and 60 U/kg. Platelet counts in patients with massively enlarged spleens may require longer periods to respond, but improvement continues within the first 2 years of therapy. Thereafter, patients treated with imiglucerase stabilize even while on the same dose.116
The bone response is slower and less predictable. Osteonecrosis and lytic lesions do not respond to ERT. Quantitative chemical shift imaging, a sensitive modality to show changes in the marrow, including response to ERT (Fig. 72–5),117 is a resource available in only one site worldwide and, hence, various other imaging modalities, especially MRI-based modalities, but also bone densitometry and plain radiographs, are used as needed to document skeletal status.
Color-coded fat fraction measurements using quantitative chemical shift imaging in an adult patient with type 1 Gaucher disease. Annual measurements show increase in fat fraction with specific therapy (mean value in 1994 = 0.11; mean value in 2001 = 0.45). (Used with permission of Dr. Mario Maas, Academic Medical Center, Amsterdam, The Netherlands.)
ERT may or may not improve pathologic pulmonary findings. Because the enzyme is a large molecule, it does not cross the blood–brain barrier, and hence, does not impact neuronopathic features.118,119
All ERTs are safe, having few side effects that are usually transient.112,113,120 Hypersensitivity reactions have been reported with each type of ERT, but only rare cases of anaphylaxis. Most patients with such reactions may continue ERT with or without premedication; it is advisable to avoid the administration of glucocorticoids for this purpose because of an increased risk of osteonecrosis. For each ERT there is a different percent of patients who may develop antibodies either shortly after initiation of treatment or over time.
Another side effect is weight gain with some concerns about changes in insulin resistance and the development of metabolic syndrome,121 including steatohepatitis. Because of the excellent safety profile, many patients receive therapy at home122 and many female patients are comfortable continuing with ERT during pregnancy and lactation.123,124 The effects of treatment are unaffected by switching from imiglucerase to velaglucerase alfa125 or taliglucerase alfa.126
The two major disadvantages of ERTs are the apparent lifetime dependency on intravenous infusions and the extremely high cost. Guidelines and/or expert opinions usually recommend the use of relatively high doses.127,128 Yet, it is evident that for most symptomatic patients, there is no justification for doses higher than 30 to 60 U/kg per month, and for patients with asymptomatic type 1 disease, ERT should not be encouraged.129
Substrate Reduction Therapy
The possibility that decreasing the formation of glucocerebroside from ceramide and glucose, referred to as substrate reduction therapy (SRT),130 might favorably impact disease parameters was proposed in the 1970s.131 Oral miglustat (N-butyldeoxynojirimycin),130 a glucose analogue that inhibits glucocerebroside synthase, has been licensed for treatment of patients for whom ERT is not suitable or not a therapeutic option according to the two preeminent regulatory authorities’ definitions. This circumscribed approval stems from inferior efficacy of miglustat relative to ERT and a problematic safety profile including peripheral neuropathies, tremor, and memory impairment. Miglustat is effective in reducing hepatosplenomegaly in Gaucher disease when given as 100 mg, three times daily.132 Response to miglustat is dose-dependent; lower doses yield suboptimal improvement without reducing frequency of side effects.133 Miglustat has also been studied as maintenance therapy in patients previously treated with imiglucerase.133 A practical advantage was that it could be considered in type 3 patients because as a small molecule it crosses the blood–brain barrier and impacts neurologic signs. Unfortunately, a clinical trial failed to achieve the end points and, hence, there is no indication for this drug in neuronopathic Gaucher disease.
Another SRT, a ceramide analogue, eliglustat tartrate,134 has been granted FDA approval. However, it has a more problematic safety profile compared to ERT (including cardiac events), the efficacy parameters.135 The robust database derived from long-term followup from phase 2 and from three different phase 3 clinical trials136 indicates it can be useful. However, unlike miglustat, it cannot cross the blood–brain barrier and should be targeted to type 1 patients only.
A new approach to lysosomal storage diseases is “chaperone therapy.” PC therapy is based on in vitro experiments showing that some misfolded mutants of glucocerebrosidase are destroyed prior to their export from the endoplasmic reticulum to the lysosome.137,138 Under these circumstances, a reversible inhibitor stabilizes the mutant enzyme, enabling its passage to the lysosome without losing activity. Clinical trials with the first PC for Gaucher disease, isofagomine tartrate which had been shown to increase mutant enzyme activity in cells, tissues,139 and healthy volunteers during the phase 1 trial, failed in the phase 2 clinical trial when only 1 of 18 patients with type 1 showed a beneficial effect.140
Another PC, ambroxol, an expectorant that is available without prescription in many countries and has decades-long safety experience, was administered in a pilot study to adult type 1 patients141; clinical trials in type 3 patients are planned.
Because the macrophage is a derived from hematopoietic stem cells, allogeneic hematopoietic stem cell transplantation should cure Gaucher disease. Although some enthusiasm was expressed for this approach, the short-term risks of transplantation markedly limit the number of suitable candidates. Effective ERT further limits the appropriateness of transplantation. Liver transplantation has been performed in a few patients with severe hepatic failure.142
Age of onset, severity of clinical manifestations, and degree of progression are partially related to genotype. Patients homozygous for the N370S mutation tend to present with symptoms and signs at an older age with relatively milder manifestations, and usually have a relatively stable disease. By contrast, compound heterozygotes for N370S and a “severe” mutation (such as N370S/84GG or N370S/L444P) usually present with the disease during childhood, and if untreated, progress continuously with both visceral and skeletal complications.108,143,144 Patients homozygous for the L444P mutation will develop neuronopathic disease with deteriorating neurologic signs and symptoms and their life span is reduced.65
Although the genotype of the patient provides a benchmark for prognosis, there is much variability in patients with the same genotype, including between siblings with the same genotype. The availability of ERT has changed the natural course of the disease allowing normal growth and development in most patients, even in those with “severe” genotypes. Nevertheless, some patients still develop skeletal complications despite ERT and there is concern regarding development of associated diseases, such as myeloma, other malignancies, or Parkinson disease.120
Prior to the availability of ERT, patients with severe type 1 or type 3, died at an early age because of liver disease, bleeding, or sepsis. With the advent of ERT, typical causes of death are malignancy, cardiovascular disease, and cerebrovascular disease.145 In type 2 disease, death usually results from neurologic complications within the first 4 years of life65; there is also a lethal neonatal variant. Total absence of glucocerebrosidase may not be compatible with life.