Synonyms: glucocerebrosidase deficiency, acid beta-glucosidase deficiency

Gaucher's disease is the most common lysosomal storage disease and is caused by insufficient activity of the lysosomal enzyme acid beta glucosidase (glucocerebrosidase), leading to the deposition of glucocerebroside in cells of the macrophage-monocyte system.¹

• Deficiency of acid beta-glucocerebrosidase causes widespread accumulation of glucosylceramide-laden macrophages.
• Glucosylceramide accumulation is widespread, including the bone marrow, liver, spleen and lungs. Central nervous system involvement only occurs in patients with disease type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) Gaucher's disease.² There are three clinical subtypes:
  • Type 1: adult or non-neuronopathic form.
    • Often presents in childhood with hepatosplenomegaly, pancytopenia and skeletal disease.
    • The severity of type 1 Gaucher's disease is extremely variable; some patients present in childhood with virtually all the complications of Gaucher's disease, while others are asymptomatic into the eighth decade.
    • Patients diagnosed in the first five years of life are frequently non-Jewish and typically have a more malignant disease course.²
  • Type 2 (rare): infantile form (acute neuronopathic). This causes rapidly progressive neurovisceral storage disease and death during infancy.³
  • Type 3: juvenile or Norrbottnian form (chronic or subacute neuronopathic). This is less rapidly progressive neurovisceral storage disease, causing death in childhood or early adulthood.⁴

Epidemiology

• All three subtypes are inherited as autosomal recessive traits.
• The overall frequency of Gaucher's disease variants is about 1 in 40,000 to 1 in 50,000 live births.¹
• Type 1 Gaucher's disease is frequent among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 in 15, whereas the disease frequency is as high as 1 in 855.⁵
• Many type 1 affected individuals never come to medical attention, contributing to an underestimation of frequency.
• Neuronopathic forms (types 2 and 3) are the rarest variants of Gaucher's disease, with an estimated incidence of fewer than 1 in 100,000 live births.⁶

Presentation

Type 1 Gaucher's disease

• May present with chronic fatigue, hepatomegaly, splenomegaly (may become massive), bone involvement (bone pain due to bone infarcts or pathological fractures due to osteopenia) and may bruise easily or present with nose bleeds, bruising and petechiae (because of thrombocytopenia).
• Short stature and wasting occasionally are found in patients with massive organomegaly.
• Occasionally present with pulmonary infiltration or portal hypertension.

Type 2 Gaucher's disease

• Presents in infancy with increased tone, strabismus, and organomegaly. Failure to thrive and stridor (due to laryngospasm) are also common.
• Rapid neurodegenerative course with extensive visceral involvement and death (usually caused by respiratory problems) within the first two years of life.

Type 3 Gaucher's disease

• Presents in infancy or childhood. In addition to organomegaly and bony involvement, neurological involvement is present, including developmental delay and abnormal neurological findings, e.g. increased tendon reflexes.
• Has been further classified as type 3a (with progressive myotonia and dementia) and type 3b (with isolated supranuclear gaze palsy) based on the extent of neurological involvement.

Differential diagnosis

• Any other cause of hepatosplenomegaly, thrombocytopenia, bone pain and osteopenia (type 1).
• Any other cause of neurodevelopmental delay (types 2 and 3).

Investigations

General assessment

• FBC and differential (assess the degree of pancytopenia); LFTs (minor elevations of liver enzymes are common but jaundice is a poor prognostic indicator).
• Skeletal radiography can detect and evaluate skeletal manifestations of Gaucher's disease. CXR to evaluate pulmonary manifestations.
• Ultrasonography of the abdomen: determine extent of organomegaly.
• MRI scanning is more accurate in determining organ size and involvement.
• Patients with neuronopathic forms also need MRI scan of the brain, electroencephalogram (EEG) and diagnostic brain stem evoked responses.⁶
• Dual-energy X-ray absorptiometry (DEXA) scanning: evaluation of osteopenia.

Diagnosis

• Acid beta-glucosidase activity: this can be measured in peripheral blood leukocytes or cultured skin fibroblasts to confirm diagnosis.¹ Heterozygotes have half-normal enzyme activity, but there is an overlap with non-affected controls.
• Acid beta-glucosidase genotyping: molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom four mutations (N370S, 84GG, L444P, IVS2+1) in the acid beta-glucosidase gene account for nearly 97% of disease alleles.
• Bone marrow aspiration: diagnosis may be suggested by the finding of classic glycolipid-laden macrophages (Gaucher cells). Not now the initial diagnostic test, as the blood enzyme test is sensitive, specific, and much less invasive.⁷

Prenatal diagnosis

• There is carrier-screening for individuals of Ashkenazi Jewish descent to identify couples at risk of having a child affected with Gaucher's disease.

Management

• Enzyme replacement therapy (ERT) with macrophage-targeted recombinant human glucocerebrosidase (imiglucerase) is administered as enzyme replacement therapy for non-neurological manifestations of type I or type III Gaucher's disease.⁶ This has been given as intravenous therapy to more than 5,000 patients (worldwide) for more than 18 years.
• ERT is very effective in reversing the visceral and haematological manifestations of Gaucher's disease, but skeletal disease is slow to respond. In patients with established acute neuronopathic disease, ERT has had little effect on the progressively downhill course, as it unable to cross the blood brain barrier.
• Miglustat, an inhibitor of glucosylceramide synthase, is licensed for the treatment of mild-to-moderate type I Gaucher's disease in patients for whom imiglucerase is unsuitable. It has been shown to help with the symptoms of mild-to-moderate type 1 Gaucher's disease.⁸ Other new enzymatic preparations such as velaglucerase alfa (VPRIV®) and taliglucerase alfa (UPLYSO®) are now available, as well as alternatives like substrate reduction and pharmacological chaperones.⁹ Work is also underway to produce oral preparations that are more acceptable to patients requiring lifelong therapy.¹⁰
• Responses to miglustat are slower and less robust than those observed with ERT, and miglustat may produce significant side-effects. Miglustat is currently in trials in combination with ERT to assess whether it will help to reduce some of the neurological deterioration in type 3 Gaucher's disease.¹¹
• Bone marrow transplantation may be an effective treatment for neurological progression in this disorder. However, there is significant morbidity and mortality, and therefore it is not currently recommended in the management of neuronopathic Gaucher's disease.⁶
• Gene therapy may offer the possibility of definitive therapy in the future.^1,12
• Supportive treatment for specific organ involvement.
• There is evidence that, in neuronopathic Gaucher's disease, complete or partial splenectomy is associated with increased severity and rate of progression of neurological and bone involvement and increased risk of infection.⁶

Complications

• Avascular necrosis of the hip and bone crises (secondary to infarcts).
• Splenic rupture (from trauma).
• Cirrhosis - rare.
• Rarely, pulmonary infiltration by Gaucher cells may lead to overt lung disease.
• Haematological abnormalities, e.g. anaemia, thrombocytopenia, and leukopenia are common.
• Immunological abnormalities, e.g. hypergammaglobulinaemia, T-lymphocyte deficiency in the spleen and impaired neutrophil chemotaxis are also common.

Prognosis

• Type 1: very variable disease severity.
• Type 2 (acute neuronopathic): rapidly progressive with death during infancy.
• Type 3 (subacute neuronopathic): less rapidly progressive neurovisceral involvement, causing death in childhood or early adulthood.

Document references

1. Grabowski GA; Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. 2008 Oct 4;372(9645):1263-71. [abstract]
2. Gaucher disease, Type I, Online Mendelian Inheritance in Man (OMIM)
3. Gaucher disease, Type II, Online Mendelian Inheritance in Man (OMIM)
4. Gaucher disease, Type III, Online Mendelian Inheritance in Man (OMIM)
5. Fuller M, Meikle PJ, Hopwood JJ; Epidemiology of lysosomal storage diseases: an overview [abstract]
6. Neuronopathic Gaucher Disease Task Force of the European Working Group on Gaucher Disease; Management of neuronopathic Gaucher disease: A European consensus. J. Inherit. Metab. Dis.;24 (2001); 319-327.
7. Ierardi-Curto L; Lipid Storage Disorders, Medscape, Sep 2010
8. Cox TM, Aerts JM, Andria G, et al; The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis. 2003;26(6):513-26. [abstract]
9. Elstein D; Recent advances in treatment approaches to Gaucher disease. Curr Pharm Biotechnol. 2011 Jun 1;12(6):854-60. [abstract]
10. Cox TM; Gaucher disease: clinical profile and therapeutic developments. Biologics. 2010 Dec 6;4:299-313. [abstract]
11. Weinreb NJ, Barranger JA, Charrow J, et al; Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol. 2005 Nov;80(3):223-9. [abstract]
12. Karlsson S, Correll PH, Xu L; Gene transfer and bone marrow transplantation with special reference to Gaucher's disease. Bone Marrow Transplant. 1993;11 Suppl 1:124-7. [abstract]