Type 3

What is Type 3 Gaucher disease?

In all forms of Gaucher Disease, there is a build-up of glucocerebroside in the liver and spleen. In addition, in patients with types 2 and 3, there is accumulation within the nervous system. This is also seen in type I but does not cause any obvious problems. Certain areas seem to be more affected than others.

Particularly important is the brainstem. This is located just below the cerebral hemispheres. It has many important functions - two particularly so. The vital centres (controlling breathing and heart rate) are located here. Also most of the cranial nerves (the nerves to the face and neck) originate from here. Other areas that seem to be involved are the cerebellum and the basal ganglia, which control balance, posture and movement.

How comon is nGD?

nGD is a very rare condition. By 1998, only 90 patients worldwide had been reported to the International Collaborative Gaucher Registry. This figure is almost certainly an underestimate. Nevertheless, it gives us an idea of the rarity of the condition.

Why does Gaucher disease affect the nervous system in some people but not on others?

There is no clear explanation for this although there are several theories. However, none of them has been proven.

One theory that seems to be fairly plausible has to do with is the origin of glucocerebroside. Most of the glucocerebroside (we will call it GC for short) in our body comes from the membranes of blood cells that have reached the end of their natural lives and have to be broken down. However, the GC in the brain is formed from other compounds called gangliosides. This much is definite. The theory is that in type I Gaucher disease there is enough enzyme to break down this GC and so it protects the brain. However, in types 2 and 3 the enzyme levels are too low to break down the GC. As a result it builds up and that is why neurological problems occur in such patients. This theory has not yet been proven but it seems to make sense.

There has also been a lot of recent interest in the role of calcium. It seems that for the correct functioning of nerve cells, calcium balance is critical. Accumulation of GC seems to upset this balance and cause nerve cells to die. So it looks as though this happens only in NGD. However, why this should be the case, or exactly how calcium and glucocerebroside are related, are questions that remain to be answered.

 Signs and Symptoms of nGD

Symptoms usually develop first in childhood. The initial problems are usually enlargement of the liver and spleen, poor feeding and failure to gain weight adequately. These usually appear in the first year of life, but may appear later. Without treatment, the long-term outlook is poor.

Eye Movements

Imagine you are standing at the side of a road, watching the cars go past. Normally you would fix on a car, follow it until it moved out of your field of vision, then your eyes would flick quickly back and fix on another car, and so on. So your eyes would make a slow movement, followed by a quick movement. You would be able to do this without moving your head. The movements of the eyes are called saccades, and the combination of the quick and slow movements is called nystagmus.

In nGD, the ability to initiate the quick movements is lost. Slow movements are unaffected. So, to use the cars-on-the-road parallel, the eyes follow the first car till it moves out of the field of vision, then stay ‘locked’ in that position. The ability to flick quickly back to fix on the next car is lost.

To compensate for this, sufferers develop a habit of blinking in order to ‘unlock’ and then thrusting their head sideways to look at the next object. This is not seen in young children, who have not developed the habit. Older children and adults become quite expert at this, and as a result, the eye movement problem may be much less obvious. This may give the impression that the eye movements get better as the child gets older. However, there is no evidence that they do actually improve.

There are many terms that have been used for this, such as ‘oculomotor apraxia’, ‘saccade initiation failure’ etc. It is invariably the first visible sign of type 3 nGD. It is therefore very important not to miss it, since the diagnosis of nGD often hinges on it. Sometimes it can appear when a child is as young as six months.

It is usually possible for someone with experience of nGD to pick this up on clinical examination alone, although it can be difficult in certain circumstances. For example:

• In young children, who may not be very co-operative

• Soon after the initial diagnosis of Gaucher Disease is made, when the child may be too ill to co-operate

• In patients with very mild disease, regardless of their age.
  In such situations the use of special equipment may be necessary in order to make the diagnosis. However, such equipment is not widely available.

Horizontal eye movement is always affected first. For some children, vertical eye movements may be affected as well. It is not clear why horizontal movement should be affected before vertical movement.

How does this affect day to day activities?

There are several practical problems that may arise as a result of these abnormal eye movements.

You will be unable to look from side to side quickly, and so are particularly vulnerable in a crowd. This is especially relevant for young children in a crowded playground. He or she may get inadvertently knocked over.

Your ability to cross the road may be severely affected, as you will be unable to look quickly from side to side for approaching vehicles.

There are also significant educational issues for young children. These are discussed more fully in the booklet; Neuronopathic Gaucher Disease; Special Educational Needs.

Audiology

Most people with Type 3 appear to have normal hearing. However, in spite of a normal hearing test, some people with Type 3 do not seem to hear very well. They can take a little longer to respond to questions, although eventually they will give a response. In other words, there seems to be a problem with processing. There also seems to be problems hearing what is said to them against a background noise. This is known as cocktail party syndrome.

Research is under way to find out exactly why this should be the case. One area that is being investigated is the brainstem. The test used is the brainstem auditory evoked response (BAER). There are standardised ways of doing this. Usually, a series of clicks is emitted through headphones placed over the patients ears, and the response is read through special electrodes placed over the scalp. Normally, a trace is obtained showing several waves. These waves have a distinctive shape and occur at certain intervals. Although people initially believed that each step in the hearing pathway is represented by a wave, the real situation is probably far more complex, so interpreting the result can be quite difficult.

What is clear is that these waveforms are more severely affected in Type 2 than Type 3. However, within each group the pattern is not so clear. Also it is not yet clear how useful the test is in monitoring disease progression. Although there is evidence that the waveform may get less distinct as the patient grows older, there is no clear evidence that this means that the disease is progressing.

It should be emphasized that the BAER is not a hearing test. Its function is to test the pathways within the brain. A proper hearing test should always be performed. In fact, if there are any abnormalities in the BAER, they can be interpreted accurately only if a hearing test has been performed.

How does this affect day-to-day activities?

Even if the peripheral hearing is normal, there may be problems. If the patient suffers from cocktail party syndrome, his or her ability to understand what is being said, particularly against a noisy background - for example, in the playground or a noisy classroom - may be affected. This, together with the processing problem mentioned above, may give the impression that he or she is very slow to respond to questions or instructions.

Movement Disorders

Problems with posture and movement can be seen in Gaucher Disease. The most common of these is Parkinson’s disease. It has been thought for some time that Parkinsonian symptoms are more common in people with Gaucher Disease. They are different from those seen in otherwise normal people in that they occur at a younger age, are more severe and are more resistant to therapy. Initially it was thought that they might be part of nGD. However, these symptoms occur in type I sufferers as well. Most people now believe that these symptoms are not true manifestations of nGD, but that Gaucher disease sufferers are more likely to develop Parkinsonian symptoms.

Other movement disorders have been observed as well. Because of this, there has been a lot of recent interest in the basal ganglia. These are the nerve centres in the brain that control posture and movement. If they are affected, potential problems include:

• Changes in tone (floppiness, rigidity)

• Abnormal movements (tics, tremor)

• Problems with balance (ataxia).

Further research is needed to clarify these issues.

How does this affect day-to-day activities?

This will vary depending on the nature and degree of the movement disorder.

Other Problems

NGD sufferers may have quite severe visceral disease (visceral refers to involvement of the viscera or the chest and abdominal organs). Especially in small children, the abdominal distension caused by the enlarged liver and spleen may be so great as to push upwards on the diaphragm. This can cause quite significant breathing difficulties, and may also cause feeding problems.

The spine is invariably involved. A generalized curvature (kyphosis) is seen in nearly all sufferers. The reason for this is not quite clear.

Lung disease is extremely common and may cause breathing problems, a troublesome cough and chest infections. These are thought to be due to the presence of Gaucher cells in the lungs.

Sufferers may feel extremely tired. There may be more than one reason for this, such as lung involvement or spinal involvement. However, in many cases there is no obvious cause. There is no doubt though that it can be quite significant.

Treatment:

Splenectomy

As already mentioned, the spleen may occasionally become so large that it pushes the diaphragm up, making breathing and feeding difficult. When this happens in small children, something may need to be done to reduce the abdominal distension (debulking). Although enzyme replacement therapy does achieve this, it takes time to do so.

In such a situation, it may be necessary to remove part or all of the spleen (a partial or total splenectomy) in order to relieve the pressure quickly. A partial splenectomy is preferable to a total splenectomy for two reasons. Firstly, the spleen protects against certain types of infection, and removal of the entire spleen would increase the risk of such infections. This is especially true for children under the age of five.

Secondly, the neurological problems have been shown to worsen more quickly in patients who have had their entire spleen removed. Keeping at least part of the spleen avoids both of these problems.

Sometimes a total splenectomy is unavoidable and in this case it is important to protect against infection as much as possible. This is done by giving a vaccine and antibiotics. These antibiotics need to be given every day, for the rest of the patient’s life.

Even after a partial splenectomy, the remainder of the spleen may not work very well. So it is sensible to treat such people as though they have had a total splenectomy.

Bone marrow transplantation (BMT)

Bone marrow transplantation was the only specific treatment available before enzyme replacement therapy became available. Approximately 20-25 transplants have been performed on patients with Gaucher Disease, mostly in Sweden and the UK. About half the patients probably had NGD. There is some evidence that their outcome has been better than that of untreated patients. However, at present the procedure is too risky to be recommended.

Enzyme replacement therapy (ERT)

Enzyme replacement therapy (ERT) has been available for the past decade. Even so, it is a relatively new form of treatment. We can, however, say with confidence that it is highly effective in treating many of the complications that arise outside the nervous system (visceral complications). Such problems tend to be more severe in NGD sufferers. In 2003, Cerezyme was licensed for the treatment of such complications.

The question of whether ERT can reverse, halt, or even slow down the neurological problems that are seen in NGD is a very important one. Unfortunately, at present the answers are far from clear. The most important reason for this is that there is insufficient experience of ERT. In addition, the severity of the disease and the doses used vary considerably and it has therefore been very difficult to evaluate the response to ERT. There is no definite evidence that ERT has a beneficial effect on the neurological problems.

For some children, however, ERT does seem to help. For example, ataxia (unsteadiness) definitely seems to improve, as do some forms of fits. However, certain problems do not seem to respond, such as myoclonic fits (short, sharp, jerky movements).

We mentioned earlier that the calcium balance in the nerve cells is upset by the build-up of GC and that this leads to nerve cell damage. However, when nerve cells are incubated with Cerezyme beforehand, they are resistant to this damage.

These experiments have been carried out in a laboratory, so of course we should be cautious in drawing our conclusions. Even so, it looks as though this enzyme has a protective effect on nerve cells if it can somehow reach them. This is the biggest challenge. There is a barrier between the blood and the brain, the blood-brain barrier (BBB). This serves a very important purpose, namely, to protect the brain. Unfortunately, it also means that this barrier prevents many substances from reaching the brain. This means that ERT probably does not cross the BBB, at least not to any great extent.

Several researchers are working in this important area, although it may be a while before significant progress is made.

Long - Term Outlook

Before ERT became available, neurological problems were overshadowed by the visceral complications. The only group for whom reliable long-term follow-up has been reported are the Norbottnian patients from Sweden. The outlook was not good, with the average life expectancy being 11 years. The most serious complications seen were cirrhosis of the liver and lung involvement.

The outlook for most patients has dramatically improved since the onset of enzyme replacement therapy.

Neurologically, many sufferers remain stable for long periods of time. The eye movement abnormality may be the only abnormal sign for many years. In others, increasing spasticity (stiffness), ataxia (unsteadiness) and, eventually, loss of higher function may be seen. The appearance of fits is of particular concern. At present, it is not clear why some people develop problems and others don’t. It would be good to be able to identify such ‘high-risk’ individuals at an early stage. Unfortunately, at present this is not possible.

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