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Gaucher disease
Key Points
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Gaucher disease (GD) results from the accumulation of glucosylceramide in organs and tissues throughout the body in characteristic storage cells, namely “Gaucher cells,” which are transformed macrophages.
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The disease is caused by mutations in the β-glucocerebrosidase gene (GBA1) , leading to a loss of activity of the lysosomal glucocerebrosidase, with autosomal recessive transmission.
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The most common inherited glycolipid storage disease, GD is a heterogeneous disorder with three clinical phenotypes:
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Type 1, the adult, nonneuronopathic chronic form, is characterized by organomegaly, hematologic disorders secondary to hypersplenism, and bone lesions attributable to medullary infiltration by Gaucher cells; there is no direct central nervous system (CNS) involvement, but an association with parkinsonism is possible.
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Type 2, the infantile, neuronopathic acute form, manifests with early involvement of the brain and cranial nerves and is fatal by 2 years of age.
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Type 3, the juvenile, neuronopathic subacute form, consists of involvement of visceral organs, bone, and the CNS, with neurologic symptoms appearing later and is less severe.
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Epidemiology
Type 1 is the most common form of Gaucher disease (GD) ( Table 213.1 ). Type 1 GD (GD1) is more frequent in persons of Ashkenazi Jewish heritage but is panethnic. Types 2 and 3 are rarer and predominantly affect non-Jewish individuals. A genetic isolate of type 3 has been identified in northern Sweden (so-called Norrbottnian GD). Each type is inherited as an autosomal recessive trait without any sex preponderance. The peak age at onset is variable: any age from birth to older adult for type 1, usually before 6 months of age for type 2, and juvenile (teenage years) for type 3.
Table 213.1
Key Features of the Three Types of Gaucher Disease
| Key Features | Type 1 (Nonneuronopathic) | Type 2 (Acute Neuronopathic) | Type 3 (Subacute Neuronopathic) |
|---|---|---|---|
| Incidence |
|
<1 : 100,000 | <1 : 50,000 to <1 : 100,000 |
| Gene/locus | GBA /1q22 | GBA /1q22 | GBA /1q22 |
| Transmission | Autosomal recessive | Autosomal recessive | Autosomal recessive |
| Sex distribution | 1 : 1 | 1 : 1 | 1 : 1 |
| Ethnic predilection | Panethnic/Ashkenazi Jews | Panethnic | Panethnic/Norrbottnian Sweden |
| Genetic association | Association of sporadic Parkinson disease with heterozygous variants in the GBA gene | ||
| Phenotype MIM number | 230800 | 230900 | 231000 |
| Peak age at onset | Any age from birth to old age | Infancy | Childhood or adolescence |
| Hepatosplenomegaly | + → +++ | + → ++ | + → ++++ |
| Hematologic symptoms | + → +++ | +++ | + → +++ |
| Skeletal involvement | + → +++ | Absent | ++ → ++++ |
| Neurodegeneration | Absent | +++ | + → +++ (progressive) |
| Age at death | Childhood or adulthood | Median, 9 months | Childhood or adulthood |
MIM , Mendelian Inheritance in Man.
An international registry database organized by the International Collaborative Gaucher Group (ICGG) has enrolled more than 4200 patients worldwide. It provides the largest compilation of phenotypic data and several clinical investigations on different aspects of the disease, including the natural history of GD1; diagnosis, treatment, and management; GD1 in children; bone disease and its complications; and neuronopathic GD. The Gaucher Outcome Survey (GOS) is a second international registry established in 2010 for patients with a confirmed GD diagnosis, regardless of GD type or treatment status. The objective is to evaluate the safety and long-term effectiveness of velaglucerase alfa and other GD-related treatments.
Etiology
Biochemistry
GD arises from an inherited deficiency of the activity of acid β-glucosidase (EC.3.2.1.45; lysosomal β-glucocerebrosidase), a membrane-associated monomeric glycoprotein with a molecular weight of 65 kDa. This enzyme hydrolyzes β-glucosidic ester bonds and is specialized for complex lipid substrates. Impairment of its activity results in the accumulation of glucosylceramide, linked by a β-glucosidic bond. Glucosylceramide is at the end of the glycosphingolipid catabolic pathway and is normally catabolized into ceramide and glucose by β-glucocerebrosidase. The compounds that contribute to the pool of glucosylceramide are derived from the degradation of membranes, particularly those of white blood cells ( Fig. 213.1 ).
Molecular Biology and Genetics
About 300 mutations that cause Gaucher disease have been identified in the β-glucocerebrosidase gene (GBA1) . There is also a pseudogene that is about 96% homologous with the active gene and may complicate the pattern of mutations. Mutations include both insertional and point mutations, as well as crossover mutations with the pseudogene. Four common mutations are found in 96% to 98% of the Ashkenazi Jewish population ; the most common is an A→G point mutation at nucleotide 1226, which results in substitution of serine for asparagine (p.Asn409Ser, formerly called N370S), causing decreased catalytic activity of the enzyme (down to 20% of normal activity remaining), responsible for a mild phenotype. This mutant allele is not observed in patients with the neuronopathic type 2 or 3 forms. Other common mutations with their impact on the enzyme activity and phenotype are indicated in Table 213.2 .
Table 213.2
Pattern of Mutations in Type 1 Gaucher Disease and Genotype–Phenotype Correlations
| Mutation | Biochemical Impact | Phenotype Severity |
|---|---|---|
| N370S | Decreased catalytic activity of the enzyme | Mild |
| 84GG | Shift in the reading frame with no enzyme production | Severe |
| L444P | Severe loss of enzyme activity | Very severe |
| R496H | Moderate loss of enzyme activity | Very mild |
Pathogenesis
The lysosomal storage of glucosylceramide in macrophages resulting from the defect of glucocerebrosidase leads to the characteristic engorged activated macrophages, known as Gaucher cells and contributes to the organomegaly, bone disease, and cytopenia typically encountered in patients with GD. Furthermore, glycolipid accumulation and lysosomal dysfunction in GD serve to prime macrophages to release proinflammatory cytokines in response to stimuli. It is also suggested that glucocerebrosidase deficiency directly impairs hematopoietic development and that Gaucher cells may exhibit erythrophagocytic activity.
An important role of impaired autophagy has also been pointed out. Inflammasome activation in macrophages is the result of lysosomal storage and impaired autophagy. The activation of the inflammasome, a multiprotein complex that activates caspase-1, triggers increased secretion of interleukins IL-1β and IL-6, leading to the maturation of IL-1 β in Gaucher macrophages. Interestingly, these relationships between lysosomal storage, impaired autophagy, and inflammation may explain the link between GD and Parkinson disease. The finding that GBA1 mutations confer a 20- to 30-fold increased risk for the development of Parkinson disease and that at least 7% to 10% of patients with Parkinson disease have a heterozygous GBA1 mutation emphasize the strong pathophysiologic link between these two diseases. Further, it has been suggested that induced pluripotent stem cells neuronal progenitors have altered differentiation in GD, due to Wnt/β-catenin downregulation.
An animal model suggests glucocerebrosidase deficiency has an effect on other cell types such as osteoblasts, thymic T cells, and dendritic cells. Conditional GBA1 deletion in mice recapitulates most of the features of GD1 and shows that the skeletal abnormalities could result mainly from a defect in osteoblast differentiation and function. Also, the in vitro differentiation of GD-induced pluripotent stem cells to osteoblasts revealed that these cells exhibited reduced expression of osteoblast differentiation markers and bone matrix protein and mineral deposition were defective. An imbalance in bone remodeling caused by decreased bone formation is also suggested in patients with GD1, as shown in a retrospective cohort study and review of the literature. Activation of immune cells, overproduction of proinflammatory cytokines, and uncoupling of bone resorption and bone formation could seem to be major determinants of bone alterations in GD. A decreased osteocalcin level is present in about 50% of patients and correlates with the severity of bone involvement.
Clinical Features
Type 1 GD, the most common form of the disorder (Mendelian Inheritance in Man [MIM] #230800), is very heterogeneous in terms of age at diagnosis and severity of clinical expression.
Hematologic Manifestations and Other Extraskeletal Disorders
The principal initial feature is splenomegaly, which is usually painless. Splenic rupture is rare, but splenic infarction may occur, sometimes as the initial complaint. Primary hypersplenism with thrombocytopenia, anemia, and leukopenia occurs frequently. In most patients, these abnormalities are not life threatening and may go unrecognized for many years. Hepatomegaly is also common but occurs later in the course of the disease. A moderate increase in cholestatic enzymes is frequent; cytolysis, however, is rare but, when present, may be associated with the development of irreversible fibrosis. Liver failure has been reported in a few patients with portal hypertension and extensive fibrosis.
Several other extraskeletal disorders have been described in patients with GD1, especially pulmonary involvement in the form of interstitial lung disease or pulmonary vascular disease (severe pulmonary hypertension or hepatopulmonary syndrome).
The association between Gaucher and Parkinson diseases has attracted sustained attention, and the pathophysiologic issues discussed earlier suggest close links through impaired macrophage autophagy. Moreover, in a recent epidemiologic longitudinal study of newly diagnosed incident cases of Parkinson disease, about 10% of patients with sporadic Parkinson disease had a known heterozygote mutation within the GBA1 gene or a polymorphism that may be pathogenic. These findings suggest that GBA1 mutations are involved in the pathophysiologic process of Parkinson disease.
The relationship between GD1 and cancer has been controversial for a long time, but a report from the international registry showed that the number of cancers identified in patients with GD was comparable to that expected in the reference population, except for multiple myeloma (estimated relative risk, 5.9; 95% confidence interval, 2.8–10.8). A 16% prevalence of monoclonal gammopathy in a series of 107 patients has been reported.
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