This Gaucher Disease Platform is committed to bringing you the most up-to-date information about your Gaucher Disease. We know how important it is for you to understand your diagnosis, treatment and support options. With this knowledge, you can work with members of your healthcare team to move forward with the hope of better disease control.
Our vision is that one day the great majority of people who have been diagnosed with Gaucher Disease (GD) will be cured or will be able to manage their disease and have a good quality of life. Personalised therapeutic goals and a monitoring strategy that includes quality of life measures are important in effective management of the disease.
Our patient information is for you and for those close to you. It has been developed for and with patients and by specialists. It is based on International Guidelines and an expert consensus document from the European working group on Gaucher disease. Our aim is to provide a trusted online resource for GD patients, their family, friends and carers, and GD patient advocacy groups.
This online platform contains general information and should help answer many of your questions. However, because every person is different, please always listen to the advice of your GD specialist about your individual treatment.
What is GD (Gaucher Disease)?
Gaucher Disease (pronounced “go-SHAY”) is the most common lysosomal storage disease. Lysosomal storage diseases are rare inherited disorders. They occur due to genes, which encode enzyme proteins and related cofactors, being mutated and causing deficiencies of lysosomal enzymes.
Lysosomes are one of the specialised structures found within our cells. They normally act to digest (remove) old cell parts; macromolecules, such as proteins; and microorganisms, such as viruses, from our body. The enzymes which they use to do this are affected by a genetic mutation, in Gaucher Disease patients, meaning that the enzyme cannot properly do its job. There is insufficient activity of the lysosomal enzyme ‘b-glucocerebrosidase’ (acid beta-glucosidase or GCase) and this allows a macromolecule lipid (fatty substance) called glucocerebroside (also called glucosylceramide, which is a glycosphingolipid) to accumulate within the cell. This then results in the cells swelling, in disturbance of normal cellular activities and the clinical signs and symptoms that patients experience.
In Gaucher Disease the enlarged cells (mostly cells called macrophages) containing undigested glucocerebroside are called Gaucher cells. They are most often found in the bone marrow, liver and spleen but can be found in many other areas of the body such as the lungs, heart, kidney, the lymphatic system and in Type 2 and Type 3 they can be found in the nervous system. There is variation between patients regarding the level of b-glucocerebrosidase enzyme which they have. As a result, the severity of symptoms, the location of symptoms and the timing of first experiencing symptoms differs greatly.
Currently there are three types (Type 1, Type 2 and Type 3) of Gaucher Disease advised by specialists and the disease is classified according to the course of the disease and particular symptoms which a patient may experience. However, it is generally agreed that if symptoms appear later in a person’s life, the less severe the disease is likely to be. Gaucher Disease affects around 1 in 50,000 to 1 in 100,000 people in the general population; with Type 1 being the most common form of the disease. However, this form of the disease is found to be even more common (1 in 500 to 1 in 1000) in people with Jewish (Ashkenazi) descent. Type 1 is a non-neuronopathic form as usually it does not affect the brain or nervous system causing neurological issues.
Type 2 and Type 3 are neuronopathic forms of the disease, meaning that damage to the neurons (a nerve cell which sends messages to and from the brain by an electrical impulse) in the nervous systems occurs, particularly in the brainstem, the basal ganglia and the cerebellum. These are areas which are involved in controlling heart rate and breathing (brainstem) and movement, balance and posture (the basal ganglia and the cerebellum).
There is currently not a clear explanation for why Gaucher Disease affects the nervous system in some patients but not others. One suggestion relates to the location of the glucocerebroside. Most comes from the membranes of old blood cells but in the brain, it comes from different compounds known as gangliosides. The suggestion is that in Type 1 Gaucher Disease there is enough of the enzyme, b-glucocerebrosidase, to breakdown glucocerebroside (formed from gangliosides) and protect the brain, but in Type 2 and Type 3 there is not enough of the enzyme and as a result glucocerebroside builds up and neurological issues occur. This has not been proven at this stage.
Another theory relates to the amounts of calcium present. It is important that the amount of calcium is well balanced to make sure that nerve cells function correctly in normal circumstances. In Gaucher Disease patients, the calcium balance is affected when glucocerebroside accumulates and this can cause neurons to die. This seems to only occur in the neuronopathic Type 2 and Type 3 forms of the disease, but it is not understood at this stage, why that is, or the detail behind the relationship of glucocerebroside and calcium.
Signs & Symptoms
The signs and symptoms of Type 1 Gaucher Disease are wide-ranging, and the course of the disease varies from patient to patient. Some patients with Type 1 Gaucher Disease may lead normal lives with virtually no symptoms, experiencing a mild form of the disease. For others, they may experience a severe and even life-threatening form of the disease. It can present at any point from childhood through to adulthood.
The more common signs and symptoms include an enlargement (or swelling) of the liver (hepatomegaly) or of the spleen (splenomegaly) due to a build-up of the Gaucher cells, causing the stomach/abdomen to become painful and swollen. Another sign occurs due to the enlargement of the spleen, which normally gets rid of old blood cells. In Gaucher Disease the spleen overacts and destroys blood cells, including platelets which help slow and control bleeding by clotting, too quickly. This can then result in having too few platelets (thrombocytopenia) with symptoms showing as frequent nosebleeds, bruising more easily or even serious bleeding issues after dental treatment or surgery.
When Gaucher cells build in the bone marrow this can cause a reduction in the amount of red and white blood cells, as well as platelets, being produced. When there is a reduction of red blood cells being produced, often along with the quicker than normal destruction of them by the spleen, there is less oxygen able to be transported through the body by haemoglobin (found in red blood cells). This can result in some of the symptoms of anaemia such as increased fatigue, loss of energy, difficulty concentrating, dizziness, a rapid heartrate and shortness of breath.
Other signs and symptoms can occur due to a reduction in the flow of oxygen-rich red blood to the bones themselves. Patients can experience bone pain or a severe episode of bone pain, known as a bone crisis, which can be accompanied by redness, swelling, tenderness and warmth at the area involved. A further complication of this can be what is known as a bone infarct, where not enough oxygen-rich blood is supplied and so part of the bone tissue can weaken and die. This can result in an increased risk of bone breaks (or fractures) or conditions such as arthritis.
As mentioned previously there seems to be a link between Gaucher Disease and calcium and calcium is not only important for neurons to function correctly in the nervous system, but it is also important, along with other minerals, for healthy bones. In Gaucher Disease patients can develop lower than normal bone density (osteopenia or osteoporosis) due to the calcium disruption. This also adds to the risk of bone breaks and the development of arthritis. If these signs and symptoms happen in childhood, it can result in a shortened height and build due to an obstruction to their normal growth.
Other signs and symptoms which tend to be less common, include lung diseases such as pulmonary infiltration; when a substance denser than air (e.g., blood, pus, proteins, or the fatty substance known as glucocerebroside, in the case of Gaucher Disease) stays within the area of the lung which is involved in the movement of oxygen and carbon dioxide in and out of the lungs. This can cause symptoms such as breathlessness and fatigue. Gaucher Disease can also present as portal hypertension; an increase in the blood pressure in the system of veins in the abdomen called the portal venous system (the portal vein and its branches, which carries blood from the stomach, intestines and spleen towards the liver). The symptoms in this case may be gastrointestinal bleeding, presenting as blood in the stools or in vomit or simply gastrointestinal discomfort and loss of appetite.
Type 2 Gaucher Disease is a neuronopathic form of the disease. As mentioned earlier, that means it affects neurons and results in neurological problems, as well as having the potential to show the signs and symptoms listed above for Type 1. It usually presents in the first three to six months of life, the earliest onset of the various types and is even more rare and severe than Type 1. It is a fatal form of the disease, usually resulting in death before the age of two years. This means however, that in many cases other typical symptoms, such as bone problems, do not develop; the patients do not live long enough for symptoms to occur.
Signs and symptoms which may be observed include severe brain damage which quickly worsens, poor development and a failure to thrive, seizures, squints (strabismus), abnormal eye movements, spasticity (stiffness or tightness of muscles which affects normal movement) and an increase in muscle tone (hypertonia), especially at the neck and at the limbs. Problems with swallowing and vocal cord (laryngeal) spasms such as stridor (a high-pitched breath sound due to the narrowed airway) and an increased tendency to lung infections along with an enlarged spleen and/or liver may also be apparent.
Type 3 Gaucher Disease is another neuronopathic form of the disease but develops more slowly than Type 2 and tends to be less severe. It is also very rare; according to the Gauchers Association, between 1991 and 2011 only 334 children, under 18 years of age, had been added to the International Collaborative Gaucher Registry, from around the world. It is considered that this figure is likely to be underestimated but highlights how rare Type 3 Gaucher Disease is. However, it may be a more common form of the disease than Type 1 in the Middle East, India, China and the Pacific Rim.
Type 3 Gaucher Disease patients usually show symptoms such as enlarged spleen (splenomegaly) and/or liver (hepatomegaly), poor feeding and low weight gain within the first year of life. Another common sign, that is important for diagnosis, is issues with eye movements, particularly the ability to initiate a “quick” eye movement. For example, in normal eye movements, when following cars along a road, your eye may follow a car along the road – a “slow movement” – and then “flick back” – a “quick movement” – to see another car, without moving the head. The issues can be more apparent in younger children as older children and adults can learn techniques so that issues are less obvious. This sign, which is known as ‘oculomotor apraxia’ or ‘saccade initiation failure’ is one of the first visible signs of Type 3 Gaucher Disease. Horizontal eye movements will be affected first, and, in some children, vertical eye movements may also be affected.
Other signs and symptoms may be developmental delay and cognitive problems; abnormal neurological findings such as increased tendon reflexes; poor coordination; and there is a higher risk of different types of seizures occurring. There may be bony involvement causing skeletal irregularities such as curvature (kyphosis) of the spine; lung problems such as a cough and chest infections, likely due to the presence of Gaucher cells in the lungs; blood disorders; movement disorders such as Parkinson’s Disease which are often seen earlier in life, with more severe symptoms and more resistant to treatment therapies. Additionally, patients can also have an issue with auditory processing, so in spite of a normal hearing test, some people may appear to not hear very well and in particular, some patients cannot suppress background noise – this can be seen in children at school who may struggle to respond quickly to questions or instructions i.e. if they sit at the back of a noisy classroom.
The wide variety of signs and symptoms, the variation in age of onset and the progression of the disease for the three types of Gaucher Disease contributes to why accurate diagnosis can be challenging. As it can resemble some other diseases and as it is a rare disease, doctors may not consider testing for it.
One of the most logical therapeutic approaches to treat Gaucher Disease is to use Enzyme Replacement Therapy (ERT) to replace or supplement the missing enzyme b-glucocerebrosidase in these patients. When the treatment was first developed, it was found that when the natural enzyme was given by infusion it was not very effective, as the majority of the enzyme did not reach the Gaucher cells within the body. Instead a modified version of the normal human enzyme which aims to increase targeting and uptake in the cells where the enzyme is required – the macrophages – was developed.
Clinical trials such as that carried out by Barton et al. (Replacement Therapy for Inherited Enzyme Deficiency – Macrophage-Targeted Glucocerebrosidase for Gaucher’s Disease, New England Journal of Medicine 1991; 324:1464-1470) showed that in Type 1 Gaucher Disease patients, objective clinical improvements could be seen following intravenous (IV) infusion of the modified, macrophage-targeted glucocerebrosidase enzyme. Patients had reversals of their disease progression and reduced signs and symptoms of the disease; with visceral (relating to the organs) and hematologic (relating to the blood) responses developing faster to ERT than skeletal (relating to the bones) responses.
The modified, macrophage-targeted glucocerebrosidase ERT is required to be administered regularly as an infusion (the therapeutic introduction of a fluid solution into a vein); usually around every two weeks, but this is assessed on an individual basis. In the USA there are currently three drugs approved by the FDA (Food and Drug Administration): Cerezyme® (imiglucerase), VPRIV® (velaglucerase alfa) and Elelyso® (taliglucerase alfa). In the UK and the European Union, the ERT medications which are licensed for use are Cerezyme® (imiglucerase) and VPRIV® (velaglucerase alfa).
An alternative therapeutic approach is to use Substrate Reduction Therapy (SRT). This works differently to ERT in that it reduces the quantity of glucocerebroside which is produced by the body rather than restoring levels of the enzyme b-glucocerebrosidase. This means that there is less glucocerebroside to break down, so the work required by the body’s supply of b-glucocerebrosidase is reduced.
Only certain patients receive SRT as the medications are not approved for use in women who are pregnant, breastfeeding or trying to become pregnant; in those patients under the age of 18 years; in the very elderly; or in patients with severe kidney or liver disease. This is because the medication works in a uniquely different way within the body.
SRT is taken as an oral medication – in the form of a capsule – and works by partially blocking the production of glucocerebroside by blocking the action of an enzyme which is involved in the production of one of its precursors called glucosylceramide. It therefore helps to prevent a build-up of glucocerebroside and reduces the symptoms of Type 1 Gaucher Disease and can help the affected organs to function better. To be suitable to use SRT the rate at which your body breaks down the drug must fall within a certain range and this can be tested by specialists/the drug manufacturer.
ERT vs SRT
Some of the advantages of taking SRT instead of ERT are that a more consistent dose can be achieved over time rather than a ‘large dose’, as occurs at the time of infusion, which reduces over a 2-week period to become a small residual amount prior to the next infusion. Patients report that with ERT infusions they feel their best immediately after the infusion, as they have a larger ‘dose’ within their body, but as the 2 weeks progresses, they feel more fatigued as the ‘dose’ reduces. Another advantage is that SRT is less invasive as no IV’s (Intravenous (drip) – a thin bendable tube that slides into one of your veins) or Ports (a small medical device that is implanted below the skin and which is attached to a catheter typically inserted into a blood vessel, and which has a small opening through which a needle can be inserted to administer medications, fluids or draw blood) are required. This helps to reduce the chance of infection and is less invasive. The other advantage is quite simple in that many patients find it more convenient: to take an oral capsule rather than [attend a centre to] receive an infusion which takes more time.
Some of the disadvantages associated with SRT can be issues relating to drug compliance – patients may forget to take their medication as they feel better or may stop or reduce their dosage due to another disadvantage – side effects such as stomach problems, diarrhoea or neuropathy (weakness, numbness and pain in the hands and feet and other areas of the body). A further disadvantage is that some SRT medications are known to interact with other drugs such as antidepressants, cardiac medications and antibiotics. In the case of antibiotics, SRT medications can be temporarily stopped during a course of antibiotic treatment; but overall it is important for patients, in order to stop permanent damage being done to their bodies, to take their medications as advised.
Rarely gene therapy (a technique designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein; if a mutated gene causes a necessary protein to be faulty or missing, gene therapy may be able to introduce a normal copy of the gene to restore the function of the protein) and bone marrow transplantation have been used as alternative treatments to ERT or SRT. Other treatments to target the complications and symptoms associated with Gaucher Disease may include prescription medications for osteoporosis and joint/bone pain, orthopaedic surgery for damaged joints i.e. joint replacements, or blood transfusions to combat anaemia or bleeding.
Living with Gaucher Disease
As Gaucher Disease can have a wide variety of symptoms and different patients experience different levels of severity of symptoms, from very mild to severe, the experience of living with the disease will be different for many people. Some people may experience the onset of symptoms early in life whilst others may not experience them until adulthood or at all. However, it is recognised that many patients, their family and friends may experience social and emotional challenges alongside complications or physical limitations presented by the disease itself.
Commonly, uncertainty is an emotional aspect of the disease which is experienced; regarding how the disease will affect or impact a person, their daily and longer-term plans, their goals and the life decisions they may need to make regarding, for example, having children or getting married. Feelings of isolation and ignorance about this rare disease are other emotional concerns.
A major challenge for patients with Gaucher Disease is the pain which is associated with the disease. It can range from mild to severe, with the pain affecting the bones or organs and episodes of pain can last a week or two but can last longer. Some patients can experience periods of severe skeletal pain, known as “bone crises”, where the joints become red, swollen, warm to the touch and painful. This can make it difficult for patients to sleep or move about.
Another challenge, which occurs due to anaemia, is fatigue. Paediatric patients may struggle to play with other children, as they lack energy and stamina or may find concentrating in classes at school difficult. Even if patients manage to have a full night’s sleep, a significant symptom of severe anaemia can be tiredness. Many patients find it beneficial to schedule naps into their daily routine to help deal with fatigue and to pace themselves to allow them to do the activities which they wish to manage.
For some people their mobility can be impacted – due to fatigue or due to bone crises or fractures – making walking or using stairs difficult. Walking aids can be of use but sometimes mobility is impacted to such a degree that bedrest or hospitalisation is needed. This can obviously affect the patients’ everyday life at work or school, so life-style changes can sometimes help to limit the impact of the strain felt on bones and joints and help to conserve energy.
Frequently, patients who experience liver or spleen enlargement may find their appetite affected due to the pressure of the enlarged organs on the stomach. They may report that after only a few bites of food they feel full and they may take a longer time to eat a meal as their stomach fills much quicker due to a reduced abdominal cavity size. This can in turn cause some distress to a patients’ family and the patient themselves. Patients who do have digestive issues will tend to work out particular eating habits or foods to avoid, to limit any negative symptoms. The enlargement of these organs can also have an impact on body image, particularly in children. Wearing loose fitting, comfortable clothing or stretchy fabrics can help to minimise discomfort and also help to address any issues related to their appearance/body image.
For children and teenagers some challenges are that, more of the child’s energy is used to cope with the disease, so less is available for the growth process, so they may be shorter and grow more slowly. The may appear to have poor balance or be clumsy due to enlargement of their organs. Teenagers often face a delay to the start of puberty, although by their late teens they usually “catch-up” with the rest of their peers. However, the delay may have a psychological effect in adolescence. Children may be advised not to participate in contact sports if they have signs and symptoms which are more severe; such as an enlarged spleen, a tendency towards bone fractures or bleeding or poor agility; although children with less severe symptoms can potentially participate in all but the most aggressive contact sports. Non-contact activities such as cycling, dancing or swimming may be encouraged as being more suitable in children with more severe symptoms. Children who are particularly interested in sports and who are strong enough should be encouraged to learn their bodies’ limitations and to participate as they are able. Other activities should be encouraged if children cannot participate in sports to allow them to develop social skills and other interests.
When the disease onset occurs in adulthood the psychological impact can be significant. Activities, social events or work which the patient used to manage may require more effort, now that they seem to have less stamina. A sudden onset of severe symptoms can particularly impact on life and career plans, especially if they affect mobility and the patients’ independence. Conversely, other adults may experience only a minor impact on their lives if their symptoms are mild and may even forget about the Disease. Recent research suggests that there may also be a link between GD and Parkinson’s Disease, although clinical experience has shown that the vast majority of Gaucher patients never develop Parkinson’s disease.