Epidemiology and natural history of Gaucher's disease

1. History 

Philippe Gaucher described Gaucher's disease in 1882, and its familial nature was recognized by Brill et al. in 1904. In 1927, Oberling et al. discovered the neurologic component of Gaucher's disease, which is more common amongst the childhood forms. In the 1960s, Brady and colleagues at the National Institute of Health in the USA made major contributions to the understanding of this disease by analysing the metabolic defect, leading to the cloning of the gene by Ginns et al. in 1984. American workers, including Gabrowski and Pastores, have made major advances in helping patients with treatment of this disease using enzyme replacement therapy, which has been available now for over 10 years.

2. Epidemiology 

The prevalence of Gaucher's disease is low. Types II and III, which have a variable degree of involvement of the neurologic system, have a very rare incidence, and occur in less than 1:100,000 of the population. Type I Gaucher's disease occurs mainly in adults and is the commonest lysosomal storage disorder. Experience in the UK suggests over 90 to 95% of patients have predominantly Type I disease, although it is still rare, occurring in about one in 30–40,000 of the population. However, epidemiological studies conducted in the USA and Israel have shown that the incidence of this disorder amongst Ashkenazi Jews is significantly higher than this, with a prevalence of about 1 in 1000 in this population, and an estimated carrier frequency of 1:14.

3. Genetic 

Gaucher's disease arises as a lack of β-glucocerebrosidase, an enzyme involved in lysosomal biochemistry, which leads to accumulation of the substrate, glucosylceramide. Several related different metabolic disorders can arise from enzyme defects in the same metabolic pathway, and these are shown in Fig. 1.

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Fig. 1. Different disorders can be caused by defects in a single metabolic pathway.

There is a good understanding of the basic and the molecular biology of Gaucher's disease. The causative gene, which codes for β-glucocerebrosidase, has been cloned, and the mutations are well understood. The gene has 11 exons, and mutations can occur at different sites, any of which can cause Gaucher's disease. Although more than a hundred different mutations have been identified, only seven are common, and six of these account for more than 95% of the genetic mutations that are seen in Gaucher's disease. Some of those (e.g., the N370S mutation) are particularly common amongst Ashkenazi Jews. Genotype–phenotype correlations are not always precise, but in patients homozygous for the N370S mutation, sufficient enzyme activity remains such that there is no central nervous system involvement. However, another mutation, L444P, is characteristic of the more severe forms of Gaucher's disease with central nervous system involvement.

4. Pathophysiology 

Gaucher's disease is one of the easiest of the lysosomal storage disorders to understand in terms of how the clinical manifestations arise. The affected cells are macrophages which have a very important role in scavenging waste material such as red and white blood cells, which have a limited life expectancy. When a macrophage engulfs the material from these dead cells, the debris is collected in lysosomes within the cell where, in a normal individual, lysosomal enzymes degrade the material (Fig. 2). In an individual with a lysosomal enzyme deficiency, degradation does not occur and instead, substrate accumulation occurs within the lysosomes.

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Fig. 2. Gaucher's disease is a lysosomal storage disorder.

5. Clinical consequences 

Substrate accumulation leads to organ damage, principally in Type I disease, manifesting as enlargement of the liver, and often-massive enlargement of the spleen. Laboratory abnormalities then lead to significant clinical abnormalities. In particular, skeletal accumulation of lipid leads to skeletal disease, which in many respects is the hallmark of adult Type I Gaucher's disease. The symptoms of adult Gaucher's disease arising as a result of this metabolic defect include bone pain, and anaemia leading to tiredness. Bruising and bleeding also occur due to thrombocytopenia, both as a result of bone marrow infiltration and splenomegaly. The enlarged spleen also causes abdominal discomfort, and in addition, there is the anxiety, and psychological and social problems that arise from having a chronic, inherited disease.

Some of the rare manifestations of Type I Gaucher's disease are significant and they are seen in patients with long-standing disease. Cirrhosis and liver disease are common, as are pulmonary, cardiac and renal disease. There is also an association with Parkinson's disease, lymphoproliferative disease, complicated pregnancy and increased foetal loss, and haemorrhage. This illustrates that Gaucher's disease is a multi-system disorder with manifestations in most organ systems.

The clinical features of the three types of Gaucher's disease are shown in Table 1. As a summary of the clinical features, Type I is the adult form, with onset never occurring in the neonatal period and often occurring as late as 60 or 70 years of age. The age at death of these patients is often well into adulthood. Principal symptoms of Type I Gaucher's disease are bone disease and organ enlargement. Types II and III patients have onset at less than 1 year, and 2–20 years, respectively. Neurologic changes also occur, with oculomotor apraxia being the major neurologic change. For Type II particularly, the outlook is extremely poor.

Table 1. Clinical features of the three types of Gaucher's disease

	Manifestation	Type 1	Type 2	Type 3
	Onset	>1 year	<1 year	2–20 years
	Hepatosplenomegaly	+	+/−	+
	Bone disease	+	–	+/−
	Cardiac valve disease	–	–	+
	Central nervous system disease	–	++	+/−
	Oculomotor apraxia	–	+	+/−
	Corneal opacities	–	+/−	+/−
	Age of death	60–90 years	<5 years	<30 years

Skeletal symptoms are the most disabling feature of adult Gaucher's disease and they present as pain, immobility, impairment of bone marrow function, and fracture, often followed by infection and osteomyelitis. MRI scans can reveal areas of necrosis and haemorrhage, and post-mortem bone samples can show infarction, necrosis, sclerosis, osteoporosis, and loss of bone. It is crucially important to prevent the progression of these skeletal symptoms to the point where they cause significant infection. Where damage occurs within the vertebrae, spinal cord symptomatology can arise because of impingement onto the neurologic system, and it is the key to patient management to prevent the progression of skeletal disease to that point.

The pathogenesis of Gaucher's disease is initially chronic substrate accumulation leading to organ damage. The secondary resultant splenomegaly is an important cause of thrombocytopenia, but there are also other mechanisms that should be emphasized. In Gaucher's disease, macrophages are activated and they secrete cytokines, particularly those involved in inflammation, such as IL-6. They also show increased expression of a range of genes, which lead to changes in the immune system, such as changes in the expression of macrophage surface molecules, in B cells, NK cells and T cells. Immune system abnormalities seen in Gaucher's disease include polyclonal hypergammaglobulinaemia, monoclonal gammopathy of uncertain significance (MGUS) and myeloma.

The increased incidence of haematological malignancy in Gaucher's disease was confirmed in a recent survey from the Gaucher's registry of more than 2700 patients, 85% of whom were under 60 years of age [1]. The incidence of haematological malignancies in this age group is normally low, but a significant increase in myeloma was found in patients with Gaucher's disease. This indicates that the macrophage disturbances lead to changes in cell biology involving abnormal inter- and intracellular signalling. Another survey from the Gaucher's centre in Israel, organized by Professor Ari Zimran, revealed 20 cancers in the 505-patient cohort [2]. Although not statistically significant, the findings appear to show an unusually high incidence of B cell malignancies and multiple myeloma in the age group studied.

If more evidence is required on the way in which complex organs are disturbed, the association of Gaucher's disease with Parkinson's disease has recently been emphasized in a study from the New England Journal of Medicine [3]. The incidence of mutations within the β-glucocerebrosidase gene was found to be markedly increased in a cohort of Ashkenazi patients with Parkinson's disease, and it appeared that β-glucocerebrosidase gene mutations predisposed this population to Parkinson's disease.

6. Therapeutics 

Prior to the 1990s, treatment was largely palliative; enzyme replacement therapy has made a major impact on the natural history of this disease. Enzyme replacement aims to reduce the accumulated waste material within these macrophages by augmenting the activity of the enzyme and attempting to restore the cell back to normality. Now patients have a choice in their treatment, as there is another way of approaching the accumulation of substrate within this disease. Substrate reduction therapy, or substrate deprivation, uses a different approach. It reduces the accumulation of the waste material in the first place, so that if an individual has residual enzyme activity, the reduction in accumulation of substrate can mean that the patient's residual enzyme is capable of restoring substrate balance.

7. Conclusion 

Gaucher's disease is an inherited metabolic disease that presents as a multi-system disease. Three phenotypes have been described. The Type I phenotype is the adult form and the most frequently identified. Skeletal complications are particularly debilitating in this phenotype, including particularly “Gaucher's bone crisis”, osteomyelitis, osteonecrosis, osteopenia and fractures. Skeletal morbidity is cumulative and appears to be accelerated by splenectomy, which should be avoided if possible. The relationship between Gaucher's disease and Parkinson's disease has been recently emphasized, suggesting that Parkinsonism constitutes a specific, although rare, complication of Gaucher's disease Type I. The pathophysiology of Gaucher's disease is not clearly understood, but the cytokine should be involved in the immune system abnormalities seen in this disease. Two therapeutic options should be considered in order to decrease glucosylceramide accumulation: enzyme replacement therapy and substrate reduction therapy. The newer substrate reduction approach to treatment can be used in stable patients with Type 1 disease who are mildly affected and cannot, or do not wish to continue with enzyme replacement therapy. It is theoretically possible that combination of substrate reduction therapy with enzyme replacement therapy may offer exciting new treatment prospects. The two options will be discussed in the next presentations of this scientific symposium.