A guide toGaucher disease

IntroductionGaucher disease is an inherited metabolic disor-der whereby deficiency of the lysosomal enzyme glucocerebrosidase results in accumulation of un-degraded glycosphingolipids primarily within cells of the reticuloendothelial system. Clinically this manifests as a multi-system disorder with hepatosplenomegaly, peripheral blood cytope-nias, bone disease and, in some cases, CNS involvement. As with many rare diseases, aware-ness of the potential diagnosis and a high index of clinical suspicion is required to make a timely diagnosis.

Historically the condition was managed sup-portively with transfusions, splenectomy and orthopaedic surgery. The development of spe-cific therapy, initially in the form of enzyme replacement therapy in the 1990s, has dramati-cally improved therapeutic outcomes and the prognosis for patients. Subsequently develop-ments include recombinant enzyme replace-ment therapy and substrate reduction therapy. Treatment of the neurological complications remains a significant challenge but new thera-peutic strategies such as gene therapy offer promise in this area.

Dr Alison Thomas is Consultant Haematologist in the Department of Haematology, St. George’s Hospital, London SW17 0QT and Professor Atul Mehta is Consultant Haematologist in the Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital, London

Correspondence to: Dr A Thomas (alison.thomas6@nhs.net)

The production of this guide was supported by

Shire Pharmaceuticals Limited who funded its publication and were involved in reviewing and approving the content.

EpidemiologyGaucher disease is one of the commonest lyso-somal storage disorders with an estimated preva-lence of 1:50 000–1:100 000 (Meikle et al, 1999; Poupětová et al, 2010). It is pan-ethnic but particu-larly prevalent in Ashkenazi Jews among whom the estimated carrier rate is 1:12. The glucocerebrosi-dase gene is located on chromosome 1. Complete absence of enzyme activity caused by null muta-tions is incompatible with life.

The commonest form of the disease (type 1) is associated with sufficient residual activity to protect against CNS involvement. Type 2 Gaucher disease is very rare, severe and untreatable, whereas type 3 Gaucher disease accounts for about 10% of cases in Europe and North America (but up to 40% in Asia) and does involve the CNS. While >300 muta-tions have been described, the N370S and L444P mutations are common in both Ashkenazi and non-Ashkenazi populations. Correlations between genotype and phenotype are often weak, but the presence of an L444P mutation on one or both alleles confers low residual activity and is found almost exclusively in patients with the neurono-pathic form of Gaucher disease (type 3), while at least one allele with a N370S mutation raises residual activity sufficiently to protect the CNS.

PathophysiologyLysosomes are membrane-bound intracellular organelles responsible for the degradation and recycling of many macromolecules including car-bohydrates, lipids and proteins. This process is carried out by >50 lysosomal hydrolases, active at acidic pH. Glucocerebrosidase hydrolyses the glycosphingolipid glucosylceramide to glucose and ceramide. Mutations in the glucocerebrosidase gene leading to insufficient functional glucocer-ebrosidase result in accumulation of glucosylcera-mide in lysosomes within cells.

The mechanisms whereby glucocerebrosidase deficiency leads to the clinical manifestations of Gaucher disease remain uncertain, and there is increasing evidence to support broader cellular dysfunction beyond simple substrate accumula-tion. These include abnormal cytokine secretion, resulting in an altered inflammatory state and acti-vation of signal transduction pathways, outlined in Figure 1. More recently, through investigation of patients with glucocerebrosidase mutations and Parkinsonism, evidence has emerged to support a role of the abnormal glucocerebrosidase protein itself in the disease pathology through activation of the unfolded protein response (Maor et al, 2013).

Figure 1. Pathophysiology of Gaucher disease. GBA = glucocerebrosidase.

Abnormal GBA folding in endoplasmic reticulum

Abnormal/deficient GBA synthesis

Reduced GBA transported to lysosomes

Impaired glycosphingolipid degradation

Activation unfolded protein response Intracellular

lipid accumulation

Altered membrane composition

Release pro-inflammatory cytokines

Impaired cell signalling

ChemotaxisGlycosphingolipid accumulation

Mutation in GBA gene

Clinical manifestationsThe clinical manifestations of Gaucher disease are the result of accumulation of undegraded glycosphingolipids and the subsequent effects on cellular and organ function. Accumulation occurs primarily within monocytes and macrophages of the reticuloendothelial system, but storage can occur within the CNS. The clinical features of Gaucher disease are summarized in Figure 2.

Type 1 Gaucher disease is the commonest subtype. This can present at any age from early childhood to late adulthood and is associated with survival into old age. The main organs involved are the spleen, bone marrow, osseous skeleton and liver (Charrow et al, 2000; Taddei et al, 2009). Macrophages within the spleen degrade senescent erythrocytes whose membranes are rich in glycosphingolipids. Inability to fully degrade these glycosphingolipids as a result of lack of glucocerebrosidase results in accumulation of the glycosphingolipid substrates within the spleen. Subsequent expansion of the spleen can lead to

massive, symptomatic splenomegaly. Pooling of blood within the enlarged spleen contributes to the anaemia and thrombocytopenia commonly seen.

An additional mechanism for these cytopenias is infiltration of the bone marrow by glycosphingol-ipid-laden macrophages, termed ‘Gaucher cells’, resulting in impaired haematopoietic capacity. Skeletal manifestations include osteopenia, avas-cular necrosis and acute episodes of pain (‘bone crises’) likely as a result of acute bone infarction. Patients with Gaucher disease exhibit increased osteoclast activity, enhancing bone resorption, which is thought to arise in part from altered cytokine signalling within the bone marrow microenvironment.

The liver can also be infiltrated by Gaucher cells resulting in hepatomegaly. Altered cytokine secretion and a pro-inflammatory state can lead to the development of cirrhosis in untreated patients and some patients required liver transplantation for end stage cirrhosis before the availability of enzyme replacement therapy. Gaucher disease is associated with a bleeding diathesis, predomi-nately mucocutaneous in nature. A broad range of platelet and coagulation factor abnormalities has been reported in Gaucher disease which may arise from a combination of impaired platelet and coagulation factor synthesis and the effects of an abnormal metabolic profile on platelet function.

Less common manifestations include peripheral neuropathy and lung involvement. Patients with type 1 Gaucher disease have an increased risk of developing haematological malignancies, espe-cially plasma cell dyscrasias (Thomas et al, 2014). Glycosphingolipid-driven alterations in the bone marrow microenvironment have been proposed as the underlying mechanism. Both patients with type 1 Gaucher disease and carriers of glucocer-ebrosidase mutations have an increased incidence of Parkinson’s disease; the mechanisms underlying this are an area of active research.

Type 3, or subacute neuronopathic, Gaucher disease shares the systemic manifestations of type 1 Gaucher disease but the CNS is also involved.

Figure 2. Clinical manifestations of Gaucher disease.

Pulmonary hypertension

HepatomegalyAbnormal liver function testsCirrhosisGallstones

Bone pain and infarcts

Neurodegeneration (II/III) Supranuclear

gaze palsy (III)

Splenomegaly

Gammopathies

Avascular necrosis

ThrombocytopeniaAnaemia

Bleeding diathesis

Symptomatic presentation usually occurs in childhood or adolescence with survival reduced to the fourth or fifth decade of life. The main CNS manifestations are a supranuclear gaze palsy and slowly progressive cognitive decline; some patients may develop cardiac valve disease or myoclonic seizures.

Type 2, or acute neuronopathic, Gaucher dis-ease presents in early infancy with severe neurolog-ical involvement and death usually occurs within the first 2 years of life. It may also present as non-immune hydrops fetalis or congenital ichthyosis.

Diagnosing Gaucher diseaseDiagnosis of Gaucher disease requires the dem-onstration of reduced glucocerebrosidase activity at acid pH (Charrow et al, 1998). While enzyme activity can be measured in cultured skin fibrob-lasts, it is most commonly measured in peripheral blood leukocytes. The diagnosis may initially be suggested by the finding of Gaucher cells in bone marrow biopsies performed for the investiga-tion of splenomegaly or cytopenias; however, Gaucher-like cells can be seen in disorders includ-ing chronic myeloid leukaemia, tuberculosis and haemoglobinopathies, so their presence is not sufficient for diagnosis.

Diagnostic difficultiesIn common with many rare disorders, patients with Gaucher disease often experience long delays between symptom onset and eventual diagnosis with an average time of 4 years (Mistry et al, 2007). Presenting symptoms often evolve slowly over time and may initially be wrongly attributed to commoner conditions. It is not uncommon for patients to present to multiple specialities along their diagnostic journey including haematology, hepatology, rheumatology and orthopaedics. The presence of splenomegaly and/or an abnormal full blood count leads to frequent presentation to haematologists where subsequent bone mar-row examination, often performed for suspected haematological malignancy, is usually the prequel to making the correct diagnosis (Thomas et al,

2013). The presence of bleeding symptoms with thrombocytopenia or abnormal coagulation tests can lead to erroneous diagnoses of congenital bleeding disorders or primary immune thrombo-cytopenia.

The goals of timely diagnosis are to provide patients with an explanation of their symptoms and to be able to institute treatment before the development of irreversible complications. There is some evidence to suggest that a delay in initia-tion of therapy results in increased risk of irrevers-ible complications such as growth retardation in children or avascular necrosis of the hips (Mistry et al, 2009), adding impetus to make a timely diagnosis.

ManagementFollowing diagnosis, patients should undergo a comprehensive evaluation including assessment of liver and spleen size, X-ray and magnetic reso-nance imaging of the skeleton and, in types 2 and 3, neurological referral. In many countries special-ist centres oversee the management of patients with Gaucher disease, including the appropriate use and monitoring of high cost therapies.

Historically the mainstay of therapy was sup-portive care with blood transfusions, splenectomy and orthopaedic surgery. However, the advent of targeted therapy has dramatically altered the goals of treatment (Pastores et al, 2004). Therapies aim to restore the balance within cells of the amount of substrate to be degraded and the capacity of enzyme to degrade it. This can be achieved either by increasing the enzyme activity or reducing the amount of substrate; both strategies have been used in Gaucher disease (Figure 3). The earliest effective strategy for increasing enzyme activity was through allogeneic bone marrow transplanta-tion in the 1980s; the main therapeutic strategy is now the administration of exogenous enzyme (enzyme replacement therapy).

Enzyme replacement therapyThe identification of the deficient enzyme in the 1960s raised the conceptual possibility of replace-

ment of glucocerebrosidase. In-vitro experiments demonstrated that cells were able to take up exog-enously administered enzyme and modifications to the mannose residues of infused glucocerebrosi-dase enabled targeting of the enzyme to cells of the monocyte-macrophage system. Tolerability and efficacy of placental-derived glucocerebrosidase in type 1 Gaucher disease was demonstrated in an initial study of 12 patients which showed improve-ment in haemoglobin, platelet count and spleen size over a 9-month period (Barton et al, 1991).

Advances in cellular therapeutics and recom-binant technology, assisted by the development of orphan drug legislation, have led to the subse-quent development of recombinant enzyme prepa-rations. Three preparations are currently licensed worldwide (two for type 1 and one for types 1 and 3, of which one for type 1 and one for types 1 and 3 are licensed in the UK). Clinical trials of all three products have demonstrated their efficacy in treating the haematological and visceral param-eters of disease (Grabowski et al, 1995; Zimran et al, 2011; Gonzalez et al, 2013).

The main side effect of all three products is immunogenicity; documented rates of antibody formation vary between products but differences in assay design make direct comparisons difficult (Thomas et al, 2014). Anaphylaxis and other infusion reactions are rare and antibody formation does not appear to impact therapeutic response.

Substrate reduction therapySynthesis of glycosphingolipids can also be reduced by reversibly inhibiting glucosylceramide synthase (Platt et al, 1994). Clinical trials demonstrated

improvements in haematological parameters and liver and spleen size in treatment-naïve patients and those who had received enzyme replacement therapy for >6 months; however, switching directly from enzyme replacement therapy to substrate reduction therapy was associated with a deteriora-tion in haematological parameters in some patients (Cox et al, 2012). This substrate reduction therapy is licensed for those in whom enzyme replacement therapy is not suitable or an option. Significant side effects include diarrhoea and peripheral neu-ropathy. This is a small molecule (219 Da) so is able to cross the blood–brain barrier, although evidence of its effect on CNS manifestations is to date disappointing (Schiffmann et al, 2008).

A second, more specific glucosylceramide syn-thase inhibitor has recently been developed. It has demonstrated efficacy for haematological and visceral manifestations both in treatment-naïve patients (Mistry et al, 2015) and in those previous-ly treated with enzyme replacement therapy (Cox et al, 2015). The incidence of diarrhoea is less than that reported with the previous glucosylceramide synthase inhibitor and peripheral neuropathy has not been reported to date. It has recently received marketing approvals in the USA and Europe. It is a substrate for the MDR1 transporter and is therefore unable to penetrate the CNS, despite its small size.

Future directionsThough efficacious for many systemic manifesta-tions of Gaucher disease, neither enzyme replace-ment therapy nor substrate reduction therapy is effective against the CNS manifestations of

Figure 3. Therapeutic strategies to restore the balance between glycosphingolipid production and degradation.

Glucocerebrosidase activity Glycosphingolipid production

Enzyme replacement therapyBone marrow transplantationGene therapy

Substrate reduction therapy

Gaucher disease, nor are they curative. The development of self-inactivating viral vectors has proved a great step forward in the pathway to achieving cure for a wide range of inherited disorders. Pre-clinical data using lentiviral vec-tors to drive expression of glucocerebrosidase in mouse models shows promise for this approach in Gaucher disease (Dahl et al, 2015). The devel-opment of therapeutic strategies that ameliorate CNS manifestations of neuronopathic forms of Gaucher disease remains a significant challenge and arguably the greatest unmet therapeutic need in Gaucher disease.

ConclusionsGaucher disease is a rare multi-system disorder caused by autosomal recessive inheritance of pathogenic mutations in the glucocerebrosidase gene. The manifestations of peripheral blood cytopenias and splenomegaly result in patients with type 1 Gaucher disease frequently present-ing to hospital doctors including haematologists, among whom greater awareness of Gaucher dis-ease is essential. Treatment with enzyme replace-ment therapy results in significant improvements, particularly in haematological and visceral param-eters, but no effective therapy is yet available for CNS manifestations.

Cover image: Very high magnification micrograph of Gaucher disease and necrotic bone reproduced from Wikimedia Commons ©Nephron / Wikimedia Commons / CC-BY-SA-3.0 / GFDL

Barton NW, Brady RO, Dambrosia JM et al (1991) Replacement therapy for inherited enzyme deficiency-macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324: 1464–70

Charrow J, Esplin JA, Gribble TJ et al (1998) Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med 158: 1754–60

Charrow J, Andersson HC, Kaplan P et al (2000) The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 160: 2835–43

Cox TM, Amato D, Hollak CE, Luzy C, Silkey M, Giorgino R, Steiner RD (2012) Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective, open-label non-inferiority study. Orphanet J Rare Dis 7: 102

Cox TM, Drelichman G, Cravo R et al (2015) Eliglustat

compared with imiglucerase in patients with Gaucher’s disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet 385: 2355–62

Dahl M, Doyle A, Olsson K et al (2015) Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice. Mol Ther 23: 835–44

Gonzalez DE, Turkia HB, Lukina EA et al (2013) Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double-blind, multinational, Phase 3 study. Am J Hematol 88: 166–71

Grabowski GA, Barton NW, Pastores G et al (1995) Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources. Ann Intern Med 122: 33–9

Maor G, Rencus-Lazar S, Filocamo M, Steller H, Segal D, Horowitz M (2013) Unfolded protein response in Gaucher disease: from human to Drosophila. Orphanet J Rare Dis 8: 140

Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281: 249–54

Mistry PK, Sadan S, Yang R, Yee J, Yang M (2007) Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention. Am J Hematol 82: 697–701

Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ (2009) Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol 147: 561–70

Mistry PK, Lukina E, Ben TH et al (2015) Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA 313: 695–706

Pastores GM, Weinreb NJ, Aerts H et al (2004) Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 41: 4–14

Platt FM, Neises GR, Dwek RA, Butters TD (1994) N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem 269: 8362–5

Poupětová H, Ledvinová J, Berná L, Dvořáková L, Kožich V, Elleder M (2010) The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations. J Inherit Metab Dis 33(4): 387–96

Schiffmann R, Fitzgibbon EJ, Harris C et al (2008) Randomized, controlled trial of miglustat in Gaucher’s disease type 3. Ann Neurol 64: 514–22

Taddei TH, Kacena KA, Yang M et al (2009) The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients. Am J Hematol 84: 208–14

Thomas AS, Mehta AB, Hughes DA (2013) Diagnosing Gaucher disease: an on-going need for increased awareness amongst haematologists. Blood Cells Mol Dis 50: 212–17

Thomas AS, Mehta A, Hughes DA (2014) Gaucher disease: haematological presentations and complications. Br J Haematol 165(4): 427–40

Zimran A, Brill-Almon E, Chertkoff R et al (2011) Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood 118: 5767–73

UK/C-ANPROM/GAU/15/0001. Date of preparation February 2016