GM1 Gangliosidosis

In the course of normal life there is a continuous recycling process of building new molecules and breaking down old ones. The breakdown and recycling process requires a series of special biochemical tools called enzymes. Beta-galactosidase breaks down several molecules, including a substance called GM1 ganglioside. People with GM1 gangliosidosis cannot make enough beta-galactosidase, without sufficient levels of beta-galactosidase the normal functioning of nerve cells in the brain is affected. Build-up of GM1 ganglioside can lead to harmful levels in many tissues and organs and results in progressive damage causing many of the signs and symptoms of GM1 gangliosidosis.

In general, the severity of GM1 gangliosidosis is related to the level of beta-galactosidase activity. People with higher enzyme activity levels usually have milder signs and symptoms than those with lower activity levels because they have less accumulation of GM1 ganglioside within the body.

The disease has traditionally been classified into three major types based on the age at which signs and symptoms first appear.

• Type I, where signs and symptoms become apparent by 6 months and this is the most severe form.

• Type II, where signs and symptoms become apparent from 18 months to around 5 years as is the intermediate form of the disease.

• Type III, the mildest and chronic form seen during adulthood.

GM1 gangliosidosis represents a continuous spectrum of symptoms and significant overlapping features from type I to type III differing in severity.

GM1 gangliosidosis is an autosomal recessive disease this means that both parents must carry the same affected gene and each pass this same affected gene to their child.

People probably carry from 5 to 10 genes with mutations in each of their cells. Problems happen when the particular gene is dominant or when a mutation is present in both copies of a recessive gene pair. Genes are the unique set of instructions inside our bodies that make each of us an individual. They are the blueprint for our growth and development, as well as controlling how our bodies function.

Genes are carried on structures called chromosomes and it is usual to have 23 pairs. A child will inherit half of the chromosomes from the mother and the other half from the father resulting in 23 pairs. 22 of these pairs look the same in both males and females. Pair 23 are the sex chromosomes, and this is the pair that differ between females and males. The X chromosome is inherited from the mother and the Y chromosome is inherited from the father. More information about inheritance is available in our publication.

All parents of children with GM1 gangliosidosis can benefit from genetic counselling, the counsellor can provide advice on the risk to close relatives and to suggest whether the wider family should be informed. To find out during a pregnancy, if the baby is affected by GM1 gangliosidosis, screening tests can be arranged early on during a pregnancy for those families who already have a child with GM1 gangliosidosis. Where only one parent is a carrier, they can opt for carrier screening but it is not 100% reliable or accurate and is not possible in all cases. Amniocentesis and chorionic villus sampling are both available during the pregnancy to find out if the baby is affected by GM1 gangliosidosis.

It might also be possible to have Pre-implantation genetic diagnosis (PGD) screening to avoid passing GM1 gangliosidosis to the baby. PGD is an assisted fertility treatment that involves checking the chromosomes of embryos before they are transferred in the womb using IVF techniques.

It is estimated that nearly 6% of the UK population (around 3.5million people) will be affected by a rare disease at some point in their lives. A single rare disease may affect up to about 30,000 people however the vast majority of rare diseases affect far fewer than this.

GM1 gangliosidosis is estimated to occur in 1 in 100,000 to 200,000 new-borns. Type I is reported more frequently than the other forms of this disease. GM1 gangliosidosis is more common in those of Japanese descent than other ethnicities.

People with GM1 gangliosidosis can experience some or many symptoms from a wide spectrum which range from severe to very mild.

Generally, infants with the severe form type I have progressive developmental delay, severe progressive physical problems and early advancement of the disease which usually become apparent by the age of 6 months. Life expectancy is rarely beyond 3-4 years of age.

People with type III do not have progressive developmental delay and their physical problems advance more slowly with life expectancy close to normal. People with type II will fall between the two ends of the spectrum and typically life expectancy can be early adulthood. It is important to note that people with GM1 gangliosidosis will not all experience all the symptoms.

Appearance

Infants with type I can look quite similar to other children who are also affected, distinctive facial features include enlarged gums. Children with type II do not have distinctive facial features.

Brain

Infants with type I appear normal until their development slows and their muscles weaken. They can experience seizures, profound intellectual disability and can appear ‘floppy’. Infants eventually lose the skills they had previously acquired and may develop an exaggerated startle reaction to loud noises. In children with type II the first signs and symptoms of the disease tend to be developmental regression, loss of skill and muscle weakness.

Heart

Cardiac problems are also known to be common in children with GM1 gangliosidosis. An enlarged and weakened heart muscle is common. This needs to be carefully managed by a cardiologist; and some children may require medication to support the function of their heart. Children with type II can also present with cardiac problems although these tend to occur a little later in life than the problems observed in children with type I. Despite the later onset of these symptoms, the cardiac problems seen in children with type II can be very serious and may require medical intervention. Regular review by a cardiologist is important in managing the condition.

Liver, Spleen and Abdomen

Infants with type I develop an enlarged liver and spleen and experience gastrointestinal problems, whereas enlarged organs are not a symptom in type II and III.

Bones and joints

Infants with type I experience skeletal abnormalities, and to a degree some skeletal problems are evident in people with type II and type III.

Eyes

Infants with type I can develop clouding of the cornea and loss of vision occurs as the back of the eye gradually deteriorates. An eye abnormality called a cherry-red spot is characteristic of this disease and is often key to making a correct diagnosis, although this sign is not always present. In contrast, children with type II do not have cherry-red spots.

At present there is treatment for symptoms as they arise, but no cure for the underlying disease. More information on supportive care treatments for people with MPS and related diseases can be found in the treatments section.

For an up-to-date list of current UK based trials taking place visit Be Part of Research (resource provided by the National Institute for Health Research). For an international search visit Clinical Trials (resource provided by the U.S. National Library of Medicine).

This resource provides information on trial status including recruiting, completed or withdrawn and worldwide trial locations. To find out more about past or current trials speak to your doctor and learn about the risks and potential benefits.

The MPS Society is the only UK charity at the forefront of supporting people and families affected by MPS and related diseases. Our extensive support services offer you a wide range of support and resources.

The team can advise and sign post you to adequate needs-led support and services in your local area as well as social care, home adaptions, education and much more.

The support team can visit you in your home and provide you with vital support.

Get involved and support us in the community, volunteer or support fundraising; we are a small charity but with your support we can continue to offer a highly valued and essential service.