A Guide to Understanding Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III)

Introduction

This information sheet has been developed by the Mucopolysaccharide & Related Diseases Society of Australia (the MPS Society) to provide information about mucopolysaccharidosis type III (MPS III), its clinical presentation and medical management.

The content of the information sheet draws on the experiences of parents and doctors with reference to the medical literature. It is not intended to replace medical advice or care.

For reference purposes, it may be useful to provide a copy of this information sheet to your GP and others who are involved in providing medical or supportive care.

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What is MPS III?

MPS III is an inherited disorder that encompasses a wide spectrum of severity. The brain is the primary site of disease and its function declines with time; physical symptoms may also develop with time, and may include hearing and breathing difficulties. The age of onset of symptoms and rate of disease progression vary considerably, even in affected siblings: in some, disease progress may be rapid with diagnosis in the first few years of life; in others it may be relatively slow and diagnosis may not occur until the third or fourth decade. Generally, if clinical symptoms are apparent early in life, it is more likely that disease progress will be rapid.

 

There are four types of MPS III, known as types A, B, C and D. Recently, type E was described in a mouse but is yet to be reported in humans. MPS III is also referred to Sanfilippo syndrome, so named after the doctor who first described the condition.

 

What causes MPS III?

In common with the other MPS disorders, the characteristic of MPS III is the build up (or ‘storage’) of long chains of sugar molecules called mucopolysaccharides in the body’s cells. ‘Muco’ refers to the thick jelly-like consistency of the molecules, ‘poly’ means many, and ‘saccharide’ is a general term for the sugar part of the molecule. Mucopolysaccharides are also referred to as glycosaminoglycans (or GAGs for short) but for the purpose of this information sheet, the term mucopolysaccharide will be used.

 

Mucopolysaccharides are used by the cells to build connective tissues in the body, such as skin, muscle, cartilage and bone. They also help with many other cellular functions, including growth control, organ development and signalling between cells.

 

The human body is made up of billions of cells. Each cell contains various structures that carry out many functions important to life. One such structure is known as the lysosome [pronounced lie-so-soam]. Mucopolysaccharides carry out their tasks outside the cell. Once their job is complete they are transported


to the lysosomes to be broken down (or degraded) into their basic building blocks. Degradation requires the action of enzymes that are found inside the lysosomes. Once the mucopolysaccharides have been broken down by these enzymes, they are transported out of the lysosomes to be reassembled and re-used to build tissue, etc. Mucopolysaccharides are therefore in a continuous process of being recycled.

 

In people with an MPS disorder one of the lysosomal enzymes that is needed to degrade mucopolysaccharides is either missing or is present at levels that do not allow the recycling process to work properly. This means that the mucopolysaccharides cannot be completely degraded and removed from the lysosomes in the usual way. As a result, partially broken down mucopolysaccharides remain ‘stored’ in the lysosomes: with time, lysosomes increase in size as the amount of storage increases. This interferes with normal cell functioning and causes progressive clinical problems in affected people.

 

These pictures show a normal cell (left)

and a cell that is filled with stored mucopolysaccharides in the lysosomes (right).

 

 

People with MPS III are deficient in one of the four lysosomal enzymes shown below:

 

Disorder

Enzyme Deficiency

MPS type IIIA

Sulphamidase

MPS type IIIB

N-Acetylglucosaminidase

MPS type IIIC

Acetyl-CoA:alpha-glucosaminide-acetyltransferase

MPS type IIID

N-acetylglucosamine 6-sulphatase

 

 

 

Each of these enzymes is essential in breaking down a mucopolysaccharide called heparan sulphate. In all four forms of MPS III, heparan sulphate storage occurs in the brain, leading to its progressive deterioration; the amount of heparan sulphate storage in other tissues influences the extent of physical symptoms.

 

 

 

How common is MPS III?

 

The estimated incidence of MPS III (all four types combined) is 1 in 70,000 births.

 

 

 

The incidence of all MPS disorders combined (of which 11 are currently recognised) is estimated to be 1 in 25,000 births.

 

 

 

The MPS group of disorders belong to a larger group of about 50 inherited disorders collectively known as lysosomal storage disorders, so named because storage of materials that are unable to be properly degraded (mucopolysaccharides in the case of the MPS disorders) occurs in the lysosome. It is estimated that lysosomal storage disorders occur in about 1 in every 5,000 to 7,000 births.

 

 

 

How is MPS III inherited?

 

All four forms of MPS III are inherited in what is known as an autosomal recessive manner. In this form of inheritance both parents must carry a copy of the defective gene and each pass that defective gene to their child. In the case of MPS III, the defect relates specifically to the faulty production of one of the four enzymes shown in the table above.


In autosomal recessive inheritance, in each pregnancy of a carrier couple, there is a:

 

  • 25% (1 in 4) chance of having an affected child;
  • 50% (1 in 2) chance of a child receiving only one copy of the defective gene and therefore being a carrier. A carrier will not be affected but can pass the defective gene to his/her offspring; and a
  • 25% (1 in 4) chance that a child will be neither affected nor a carrier.

 

 

 

The child of an affected person will not have MPS III but they will be a healthy carrier of the defective gene. Only in the rare case that the affected person’s partner is also a carrier is there a chance (50%; 1 in 2) that the child will be affected.

 

 

 

The MPS Society has produced a specialist booklet (The Pattern of Inheritance) that is available.

 

 

 

Genetic Counselling

 

Because MPS III is inherited it is important to seek genetic counselling as there may be implications for other children in the family, future pregnancies and extended family members. Geneticists and/or genetic counsellors will explain the inheritance pattern and help determine who should be tested.

 

 

 

Diagnosis

 

At present, there is no routine newborn screening procedure to diagnose a baby with MPS III. If there is a family history of the disorder, however, prenatal testing can be arranged during the early stages of pregnancy (see below) or soon after birth. MPS III is not well known in the community. As the initial symptoms are variable it is often not easily recognised by doctors, hence (in the absence of a family history) diagnosis is often made after obvious problems have developed.

 

 

 

To diagnose MPS III, mucopolysaccharides are usually first measured in urine, followed by measurement of enzyme activity in blood. Increased heparan sulphate in urine, and a decrease in the activity of any one of the four enzymes (shown in the table above) in blood is usually consistent with a diagnosis of MPS III and will identify the specific form of the disorder (A, B, C or D). To confirm the urine and blood results it is useful to measure enzyme activity in a small piece of skin. Whilst all four forms of MPS III appear clinically similar, it is important to identify the correct form of the disorder to assist with future testing and application of treatments as they are developed.

 

 

 

Diagnosis by mutation testing may also be possible. Mutations are mistakes in the genetic information (DNA) that is inherited by an affected child from their parents. In MPS III, the mutations are present in the gene that codes for any one of the four enzymes shown in the table above, and lead to a defect in its production. If the disease-causing mutations are found (which is not always possible to achieve) testing future pregnancies or other family members may be simplified. Mutation testing can be done using either blood or skin.

 

 

 

It is generally agreed that a comprehensive medical and supportive care plan should be started as early as possible after diagnosis to promote the best quality of life.

 

 

 

Can you test for MPS III in pregnancy?

 

Testing a fetus for an inherited condition whilst it is still in the womb is called prenatal testing and can be performed if there is a family history of the condition.

 

 

 

Prenatal testing is usually done within the first three months of pregnancy. If the parents of an affected child wish to consider prenatal testing, it is important to discuss it with your doctor, a geneticist or genetic counsellor prior to or during the very early stages of pregnancy.

 

 

 

Prenatal testing for carriers of MPS III in the family is not done routinely unless their partner is known to be a carrier. If a partner’s carrier status is not known, it is highly recommended that the advice of a geneticist or genetic counsellor is sought prior to pregnancy.

 

 

 

Disease Progression

 

In common with other MPS disorders, all four forms of MPS III are progressive, meaning that the symptoms worsen with time.

 

 

 

The biological processes that determine the age at which symptoms appear and the rate at which they progress are complex and not all are clearly understood. Storage of mucopolysaccharides begins as a result of mistakes (mutations) in the genetic information (DNA) that code for the production of a specific enzyme that is responsible for breaking down specific mucopolysaccharides. These mutations determine how much active enzyme can be made, which will affect how much mucopolysaccharide can be broken down in the lysosome. As a general rule, if a mutation allows more active enzyme to be made, the mucopolysaccharide can be broken down more efficiently so disease progress is likely to be slower, with less storage occurring; if a mutation allows little or no active enzyme to be made, mucopolysaccharide break down will be much less efficient and more will remain stored, so disease progress is likely to be more rapid.

 

 

 

Whilst mucopolysaccharide storage is a significant cause of symptoms, it is important to understand that it is one part of a complex ‘cascade’ of changes that occur as a result of the reduction in enzyme activity: the mucopolysaccharides cannot be properly broken down in the lysosomes at the correct time and recycled; in turn, this causes abnormal changes to their function as well as to other functions of the cell. The flow-on effects of these changes significantly contribute to clinical outcome and disease progression in addition to the storage itself. Research is continuing to understand this ‘cascade’ of changes to improve diagnosis, predicting the rate of disease progression (prognosis) and treatment options.

 

 

 

Life Expectancy

 

It is difficult to be precise about life expectancy because of variation in severity and age of onset. Some individuals have lived into adulthood but this is usually accompanied by a decline in their quality of life as brain function deteriorates.

 

 

 

Fertility

MPS III does not affect fertility. Teenagers will go through puberty, although it may be delayed.


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