Also known as: Glucocerebrosidase Deficiency, Glucosylceramidase Deficiency
Gaucher disease (GD) is an autosomal recessive, lysosomal storage disease, resulting from a deficiency of the lysosomal enzyme acid beta glucosidase (glucocerebrosidase). This deficiency leads to the accumulation of glycolipids in macrophages, particularly those in the bone marrow, liver, spleen and lungs.
There are 3 clinical subtypes of GD, with different manifestations. Type 1 is the most common form.
GD type 1 (adult/non-neuropathic form) may present in childhood, although symptoms may manifest in individual of all ages. The severity of GD type 1 is extremely variable.
Clinical features of GD type 1 may include:
- Anaemia and thrombocytopaenia.
- Bone manifestations including osteopenia, lytic lesions, pathological fractures, chronic bone pain, bone infarcts, osteonecrosis and skeletal deformities.
- Lung involvement which is rare includes interstitial lung disease and occasionally pulmonary hypertension.
- Although individuals with GD type 1 do not have primary central nervous system disease, neurological complications (spinal cord or nerve root compression) may occur secondary to bone disease or coagulopathy.
- Peripheral neuropathy and Parkinsons disease have also been described.
Clinical features of GD type 2 and 3:
- Type 2 (infantile form – acute neuropathic) is extremely rare and the most severe type of GD. It is characterized by neurological impairment in addition to visceral symptoms. GD type 2 patients rarely survive past 2-3 years of life.
- Type 3 (juvenile, chronic or subacute neuropathic) is a less rapidly progressive neurovisceral storage disease. GD type 3 patients tend to survive into their third or fourth decade.
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- As a result of the lysosomal enzyme acid beta glucosidase deficiency found in GD, glucosylceramide is degraded much more slowly than in normal cells and accumulates intracellularly, primarily in the cells of mononuclear phagocyte origin.
- These glucosylceramide laden macrophages are known as ‘Gaucher cells’ and are the classical hallmark of the disease.
- As glucosylceramide is an important constituent of biological membranes and is a key intermediate in the biosynthetic and degradative pathways of complex glycosphingolipids, its accumulation in Gaucher disease (GD) has severe pathological consequences.
- The liver and spleen often increase greatly in size, however, the amount of pathological lipid stored in the affected macrophages (Gaucher cells) accounts for less than 2% of the additional tissue mass. Implying that other biochemical pathways (such as an inflammatory response) must be activated in GD and contribute to changes in tissue mass and development of pathology.
- Factors released by Gaucher cells, including pro-inflammatory cytokines provide a link between lysosomal storage and the diverse clinical manifestations of GD.
- Approximately 1:12 Ashkenazi Jews (AJ) are carriers of GD type 1 with a disease frequency in the region of 1:500 to 1:800.
- Disease frequency in the general population is estimated at 1:50,000.
- The most common mutation accounts for 70% of mutant alleles in Ashkenazi Jews and 25% in non-Jewish patients.
- Testing for acid beta-glucosidase activity would be the first-line diagnostic test. This can be measured in peripheral blood leukocytes or cultured skin fibroblasts. Heterozygotes have half normal enzyme activity, but there is an overlap with non-affected controls and enzyme activity should not be used for diagnosis of carrier status.
- Clinical diagnosis can be confirmed by genetic testing for mutations in the acid beta-glucosidase gene. This is useful for genetic counselling, classification and in some cases prognosis.
Other supporting evidence:
- Full blood count – to assess anaemia and thrombocytopenia.
- Clotting tests- to evaluate a coagulation abnormality.
- Liver function tests –minor elevations of liver enzymes are common, but jaundice is a poor prognostic indicator.
- Protein electrophoresis to evaluate the presence of a serum paraprotein.
- MRI axial skeleton – to detect and evaluate skeletal manifestations of Gaucher disease.
- MRI or Ultrasound Scan of the abdomen – to assess the extent of organomegaly
- Patients with neuropathic forms also need MRI brain, EEG and diagnostic brain stem evoked responses.
- DEXA scanning – for evaluation of osteopenia.
- Chest x-ray if symptomatic – to evaluate pulmonary manifestations.
Some individuals with GD type 1 are largely unaffected throughout their lives and have no need for medical intervention, however the following treatments are available for those that do experience symptoms.
- Enzyme replacement therapy (ERT) with macrophage targeted recombinant human glucocerebrosidase (imiglucerase, Velaglucarase or taliglucerase (US)) can be administered.
- ERT is very effective in reversing the visceral and haematological manifestations of Gaucher disease, but skeletal disease is slow to respond.
- Miglustat, an inhibitor of glucosylceramide synthase, is an alternative in patients for whom imiglucerase is unsuitable. It has been shown to help with the symptoms of mild-to-moderate type 1 disease.
- Eliglustat a newly developed oral substrate reduction therapy has recently received marketing approval in the US and EU.
- Family members should be referred for further investigation as appropriate.
- The severity of GD type 1 is very variable.
- Avascular necrosis of the hip and bone crises (secondary to infarcts).
- Splenic rupture – from trauma.
- Cirrhosis – rarely.
- Haematological abnormalities – anaemia, thrombocytopenia are common. Leucopenia is found on occasions.
- Immunological abnormalities such as hypergammaglobulinaemia.
- The incidence of haematological malignancy especially myeloma is elevated in patients with GD.
- The incidence of Parkinson’s disease is elevated in both patients and carriers of GD type 1.
- For children exhibiting features of GD, initial referral would usually be to a specialist metabolic paediatrician. For adults initial specialist referral will usually depend on presenting symptoms.
- For Jewish patients, it is important to note the individual’s ancestry and higher prevalence of GD in the Jewish population.
- For patients who receive a positive GD diagnosis:
- On-going management is under the care of specialist Lysosomal Storage Disorder centres in the UK (click here for information about the different centres).
- Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
This Association provides information about all types of Gaucher Disease (GD); keeps families and medical advisers up to date with research developments; offers a support network for affected families; encourages the availability of treatment and provides details on how treatment can be accessed; and actively promotes medical research.
Tel/Fax: 01453 549 231
The site also provides details of the specialist Lysosomal Storage Disorder centres in the UK in their links section.
A closed support group on Facebook for people with Gaucher disease.
This Alliance, which now has a membership of 27 countries, facilitates the collaboration of Gaucher patient groups across Europe. It aims to: collect and disseminate information on new developments about GD; provide guidance and encourage GD patient groups; represent GD patient interests internationally; encourage and promote research; provide a forum to address ethical issues relating to GD, and ensure that suitable treatment is available to all GD patients.
This American organisation offers a wide range of programs and resources for the benefit of the Gaucher community. It funds research, offers financial assistance, promotes education and awareness, supports legislative issues and provides outreach programs vital to the Gaucher community in the USA
Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Dr Derralynn Hughes, Consultant Haematologist and Senior Lecturer in Haematology at the Royal Free London NHS Foundation Trust and University College London
Last review: 06.07.2018