Gaucher Disease

What is Gaucher Disease?

Gaucher is a genetic lipid storage disorder, in which lipids (fatty substances) build up in certain cells in the body (called macrophages). It is caused by a missing or deficient enzyme called ‘glucocerebrosidase’, which normally breaks down these lipids. Accumulation of lipids in cells in the liver, spleen and bones can interfere with some of the normal processes of the body.

Gaucher belongs to a group of conditions called Iysosomal storage disorders (LSDs). There are 3 main types of Gaucher disease:

  • Type 1 (Non-neuronopathic) – the most common type with variable symptoms and progression
  • Type 2 (Acute neuronopathic) – an acute, severe form affecting the central nervous system in babies and infants
  • Type 3 (Chronic neuronopathic) – a chronic form affecting the central nervous system, that progresses over time

What are the signs and symptoms of Gaucher Disease?

Gaucher is different for everyone, with symptoms varying considerably from person to person. Some people experience severe symptoms in childhood, while some people have no symptoms or only mild symptoms and are diagnosed later in life.

The most common clinical symptoms of Type 1 Gaucher are:

  • Tiredness
  • Bone pain
  • Tendency to bruise
  • Enlarged liver
  • Enlarged spleen

In Type 3 Gaucher, the nervous system is also affected and additional symptoms
may include:

  • Abnormal eye movements
  • Loss of muscle coordination
  • Learning difficulties
  • Seizures
  • Dementia

What are the causes of Gaucher Disease?

Gaucher disease results from abnormal deposits of a fatty substance, known as glucocerebroside or glucosylceramide. Normally, glucocerebrosidase is metabolised (broken down) by an enzyme called glucocerebrosidase (acid β-glucosylceramidase). In people with Gaucher disease, the gene that would normally tell the body to produce this enzyme is altered (often called a gene mutation). This alteration means that the enzyme does not work properly or is completely absent. This in turn leads to a build-up of glucocerebroside in cells. It is because of this build-up that Gaucher disease is referred to as a storage disorder, and because the build-up happens in a part of the cell called the lysosome it is called a lysosomal storage disorder (also known as lysosomal storage disease). 

Who is likely to be at risk of Gaucher Disease?

Gaucher is a rare genetic disorder affecting around 1 in 100,000 of the population. Most people (over 90%) have Type 1 Gaucher. It affects males and females equally. Gaucher is more common within the Ashkenazi Jewish population, with approximately 1 in 1000 having Type 1 Gaucher.

Gaucher is an inherited disorder that is said to be ‘recessive’. This means that a child needs to inherit a copy of the faulty gene from both parents to have Gaucher.

How is Gaucher Disease diagnosed?

Patients who present with the above signs and symptoms may have the diagnosis confirmed by the following methods;

Enzyme assay
The most reliable method of diagnosing Gaucher disease is to test the activity of the glucocerebrosidase enzyme. This is carried out using a fluorometric assay with the substrate 4-methylumbelliferyl-ß-D-glucopyranoside. In affected individuals, glucocerebrosidase enzyme activity in peripheral blood leukocytes is 0-15% of normal activity.

DNA test
DNA testing may be carried out to identify the mutation of the Gaucher gene. More than 200 different mutant GBA alleles have been identified in patients with Gaucher disease. Some genotypes have been associated with different disease characteristics. For example, patients with type 1 Gaucher disease who are homozygous for the N370S mutation tend to have a later onset and a milder form of the disease.

Histological findings
Histological tests, such as bone marrow aspirates and liver biopsies, may help to diagnose identify Gaucher cells, but they should not be used as a first-line diagnostic tool, as enzyme testing is more specific and other patients may exhibit pseudo-Gaucher cells.

What are the treatments for Gaucher Disease?

Treatment of Gaucher disease consists of two components; symptom management and replacement of the deficient or dysfunctional enzyme with enzyme replacement therapy (ERT), or by use of Substrate Reduction Therapy (SRT, licensed for use in patients unsuitable for ERT). Treatment needs to be tailored to the individual. Because it is quite a rare condition, most people with Gaucher disease are treated at specialist centres by doctors and nurses who are experts in treating lysosomal storage disorders like Gaucher Disease. At these centres the patient and their family can be assessed by a range of medical specialists and advised on a specific treatment programme.