Type 2 Gauchers Disease

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Type 2 Gauchers disease is a very rare, rapidly progressive form of Gauchers disease which affects the brain (central nervous system) as well as the spleen, liver and bones. Formerly called infantile Gauchers disease, it is characterised by severe neurological (brain) involvement in the first year of life. It is also called acute neuronopathic Gauchers disease. Fewer than 1 in 100,000 newborn babies have Type 2 disease and this form of the disease is not concentrated within any particular ethnic group.

Babies usually appear normal at birth but develop neurologic and other symptoms by the age of 3 to 6 months. Type 2 is almost always apparent by 6 months of age. Most children die by the age of one and 90% by the age of two. However in the remaining 10%, the course of the disease may be prolonged over a number of years.

Signs and symptoms include failure to thrive, rigidity of the neck and limbs (hypertonia), head held awkwardly, lockjaw (trismus), squinting (strabismus) and difficulty in swallowing. Other difficulties include throat (laryngeal) spasm, seizures and a failure to shake off colds and virus infections. The spleen and liver often become very enlarged with accompanying low blood counts. The lungs may also be affected and the bones show signs of disease. The baby may eventually 'switch off', not reacting to parents or stimulus, for a period before death.

The Cause of Type 2 Gauchers disease

Gauchers disease is an inherited disorder. Children with Type 2 lack an important enzyme called glucocerebrosidase. This enzyme deficiency results in the accumulation of a fatty substance (glucocerebroside) which is normally produced during the recycling of cells in the body but is then broken down by the enzyme.

The human body contains specialised cells called macrophages. Macrophages contain lysosomes where enzymes degrade worn-out cells into simple molecules for recycling. The enzyme glucocerebrosidase is located within the lysosomes and is responsible for breaking down glucocerebroside into glucose and a fat called ceramide.

Babies with Type 2 Gauchers disease lack the normal form of the glucocerebrosidase enzyme and are unable to break down glucocerebroside. Instead, the glucocerebroside remains stored within the macrophages, preventing them from functioning normally. Enlarged macrophages, containing undigested glucocerebroside, are called Gauchers cells. These cells are the hallmark of the disease and will be found in the bone marrow, spleen, liver and brain.

Type 2 Gauchers disease is quite distinct from the chronic non-neurological Type 1 and once a proper diagnosis has been made, no neurological features will develop in the more usual chronic Type 1.

Treatment for Type 2 disease

No successful treatment for Type 2 Gauchers disease has been available to date. Although enzyme replacement therapy (Ceredase) has been found to be effective for Type 1, the therapy has not worked in treating Type 2 infants.

In the past couple of years, attempts to treat Type 2 babies with Ceredase have been made in one case in America by Prof Gregory Grabowski, Director of Genetics, Children's Hospital, Cincinatti, and in two cases in Italy by Dr Bruno Bembi at the Children's Hospital, Trieste, but without success.

Work is also being carried out in America on a drug called L-cycloserine which is claimed to help Type 2 children. Experiments have taken place on 'mice with Gauchers' and the drug has been in use on humans suffering from other illnesses, such as tuberculosis, for some time. So far it has not been used on Type 2 babies but Dr Meir Lev, Director of Research Services and Development, City University of New York Medical School, believes it could be effective. This drug works by slowing down the accumulation of Gaucher cells in the body rather than supplementing the missing enzyme (which is what Ceredase does). The theory is by preventing new accumulation, any residual enzyme produced in the body will reduce or eventually eliminate the existing Gauchers cells.

Similar research is being carried out with a different substance called NB-DNJ by Dr Terry Butters and Dr Frances Platt at the Glycobiology Institute, University of Oxford. It is hoped that this or a similar substance will also inhibit the accumulation of Gauchers cells.

However most doctors believe that once neurological damage has occurred, this cannot be reversed. Unfortunately damage starts while the baby is within the womb.

Caring treatment

Professional help is available, whether the child is being looked after in hospital or at home: doctors and skilled nursing staff can offer instruction and should be called upon whenever parents feel unable to deal with a particular problem. Anti-convulsant drugs to control fits and antibiotics to treat infection may be prescribed.

With help and support, parents can deal with many unfamiliar situations, in particular nursing techniques. Doctors outline, at the time of diagnosis, how the disease will progress but it may be difficult at that time for parents to fully anticipate the practical difficulties which may arise.

Listed below are the professionals who can help and what advice they can offer:

Paediatricians at local hospitals may be able to give the child open access to the children's ward. Parents can feel confident that if a difficulty arises at home, they can immediately and directly get medical help and admit the child into hospital if necessary. It is also useful to establish a good relationship with hospital nursing staff so queries can be answered over the telephone.

Physiotherapists play an important part in educating parents on how to hold the child correctly and to advise on seating and sleeping arrangements. As the disease progresses, stiffness in the child's neck and limbs may be alleviated by drugs. Special chairs for use at home and adapted pushchairs to help support the child's body are available. Physiotherapists can also advise on special exercises for the child's limbs to lessen the stiffness - the exercises can be incorporated into playtimes with the child.

Nursing staff, either hospital or district nurses, can give practical help on using and maintaining specialist equipment. Swallowing difficulties often arise in the later stages of the disease. Suction machines may be necessary for use at home to clear saliva (secretions) from the child's throat. Nursing staff will instruct parents on how to use this equipment and how to hygienically maintain it. Also because of swallowing difficulties, the child may have to be fed by naso-gastric tube (which passes through the nose into the stomach). Again parents will be instructed on how to use this.

One of the major contributions given by nursing staff is moral and emotional support - this cannot be under-estimated.

Other professionals may be involved in the care of the child; for example, GPs can often give advice on day to day care; and dieticians can advise when the child's diet is restricted. In addition social workers can help by giving advice and information on financial allowances and benefits available for parents.

Relatives and friends can give invaluable support. If possible enlist their help in the everyday caring of the child. They often want to help and this can give parents a much needed break, even if just for the evening, or spending more time with another child.

Contacting parents who are, or have been, in a similar situation can also be useful - they alone can understand the pressures on parents who are caring for a sick child. See the contact list at the end of this leaflet.

Help is available and should be asked for.

Inheritance patterns

Type 2 Gauchers disease is an inherited disorder. Both parents must be carriers of the disease in order for there to be a risk of them having an affected child. For a couple who are both carriers, there is a 1 in 4 (25%) chance with each pregnancy that the child will have the disease, a 1 in 2 (50%) chance the child will be a carrier and a 1 in 4 (25%) chance that the child will neither be a carrier nor have the disease.

Much of a person's makeup is a result of what is inherited from each parent. Many characteristics, such as eye colour, blood groups and genetic conditions, are passed from parents to children through their genes. The genes for these characteristics are organised on 23 pairs of chromosomes, one of each pair coming from the mother and father. Each chromosome carries thousands of genes.

The gene which instructs the body to make the enzyme glucocerebrosidase is also passed on from both parents to children. In Gauchers disease, this gene is defective. As a result, the enzyme produced from the defective pair of genes, one gene inherited from each parent, is unable to perform its normal function.

A person with one normal gene and one defective (Gauchers) gene is a carrier of Gauchers disease. Carriers are perfectly healthy and will not develop any symptoms of Gauchers disease. As long as one of the pair of genes is normal, enough enzyme can be produced to prevent Gauchers cells from accumulating.

If only one parent is a carrier of Gauchers disease, none of the children will have Gauchers disease but there is a 1 in 2 chance (50%) of the child being a carrier.

It must be emphasised that the chances in each pregnancy, of the child inheriting Gauchers disease, are totally independent of whether or not a previous child has the disease. Having had one child with Gauchers disease does not mean that the next three children cannot inherit the disease.

Gauchers disease is an autosomal recessive disorder. Autosomal describes the type of chromosome on which the gene is carried. Recessive refers to the fact that in order to develop the disease, a child must inherit two defective genes, one from each parent.

Genetic counselling

In families where a baby with Gauchers Type 2 has been born, the parents and their close family may wish to be offered genetic counselling. Your paediatrician or GP can arrange this. Pre-natal testing and carrier screening, which are described below, together with individual genetic counselling are available at several centres around Britain. Your GP, hospital, local genetic centre or the Gauchers Association can tell you the nearest one.

Prenatal testing

In families where a Type 2 Gauchers baby has been born, pre-natal testing on subsequent pregnancies is available and should be discussed in advance of starting a pregnancy. A chorionic villus biopsy (CVB) and/or amniocentesis can be performed to diagnose the disease early in pregnancy.

A chorionic villus biopsy (CVB) is carried out at around 10 weeks of pregnancy. A sample of cells is taken from the developing placenta under ultrasound guidance and analysed. Results are usually known within 48 hours with confirmation of the result on cultured cells within 2 weeks.

Amniocentesis is carried out at 14-16 weeks of pregnancy. A needle is inserted through the mother's abdominal wall into the amniotic sac holding the baby. A small amount of the liquid surrounding the baby is removed and cells for testing are grown in the laboratory. The results are known after another 3-4 weeks.

Carrier screening

Close relatives of a family where a baby with Type 2 has been born and who are of reproductive age or younger may wish to be offered genetic counselling in order to discover if they are a carrier. Carrier screening can then be offered.

The chance of other close family members being carriers exists but there is only a risk if their partner is also a carrier of Gauchers disease. The chance of any one person in the general population, outside of an affected family, being a carrier of Type 2 is very small.

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