Type 3

What is Type 3 Gaucher disease?

In type 3 Gaucher disease there is neurological involvement but it is not as severe as that seen in type 2.

How common is Type 3 GD?
nGD is a very rare condition. By 2011, only 334 children (<18 years) 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.

Signs and Symptoms of Type 3 GD
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.
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 type 3 GD, 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 ability to do this. 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 3GD. It is therefore very important not to miss it, since the diagnosis often hinges on it. Sometimes it can be seen in the first few months of life.

It is usually possible for someone with experience of type 3 GD 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. In some children, vertical eye movements may be affected as well. It is not clear why horizontal movement should be affected before vertical movement. The two are controlled by different areas of the brain and this may account for it.
It should be emphasised that eye movements are also abnormal in type 2 GD. However, they are usually not obvious as the other neurological features are so severe. In addition these children usually have a squint which masks the eye movements.

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 GD 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. They understand the question perfectly well, and know the answer, but take a bit longer to respond. We now know that they have a problem with auditory processing.
There also seems to be problems hearing what is said against a background noise. This is commonly known as “cocktail party syndrome”. Normally one is able to suppress such noise and “filter” the important sounds. However, people with type 3 have difficulty in doing this.

How does this affect day-to-day activities?
Even if the peripheral hearing is normal, there may be problems. If someone cannot suppress background noise, their ability to understand what is being said, particularly against a noisy background - for example, in a noisy classroom - may be affected. When a teacher is talking, their voice appears louder to those children sitting at the front of the class than at the back. If the loudness (or decibel level) falls below the level of the background noise then the teacher’s voice cannot be heard. Normally, children will suppress the background noise and so be able to hear the teacher’s voice. A child with type 3 may not be able to do this.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.
Seizures
There is a higher risk of seizures in type 3 GD. In the majority this is a late manifestation. Different types of seizures may be seen. Most can be controlled fairly easily. However, they do of course have implications for day to day activity, education, driving etc. A detailed description is beyond the scope of this article. However, one type of seizure is particularly important; myoclonic seizures.The word myoclonic comes from ‘myo’ meaning muscle, and ‘clonus’ meaning jerk. So in a myoclonic seizure the muscles jerk. Myoclonic seizures can sometimes cause the whole body to jerk. More usually, they only cause jerking in one or both arms and sometimes the head. Although it may not be obvious, during the seizure, consciousness is lost for a very brief time. In type 3 GD, myoclonic seizures are usually very difficult to treat and nearly always signify disease progression.
Behavioural Problems
It is well known that children with chronic disorders can suffer from a variety of behavioural problems. Therefore it would not be surprising to find such problems in type 3 GD. However, results of a recent study have shown that the incidence is probably higher in such children. Particular problems identified included anxiety, depression and low mood. Conclusions must be drawn with caution as the study was performed in a very small cohort. It is planned to extend the study to larger numbers eventually.

Other Problems
Type 3 GD 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 problemsin young children.

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.

Clinical Course and Spectrum
It will be clear from the above descriptions that there is a spectrum of clinical involvement in type 3 Gaucher disease. The majority of patients have very mild symptoms throughout childhood. A small number will have more severe symptoms, though not as severe as in type 2, with significant neurodisability appearing before the age of 10. It is usually possible to identify such children at an early age.

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 Type 3 GD. 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 type 3 GD sufferers. In 2003, Cerezyme was licensed for the treatment of such complications. In 2010 VPRIV ® was licensed for type I Gaucher disease and is prescribed for type 3 patients by physicians on a named patient basis.

The questions of whether ERT can reverse halt, or even slow down the neurological problems that are seen in type 3 GD is a very important one. Unfortunately, at present there is no evidence that it does so.

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 significant 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.