NORD gratefully acknowledges Kristina Elvidge, PhD, Research Manager, Sanfilippo Children's Foundation, Australia, for assistance in the preparation of this report.
The Mucopolysaccharidoses (MPS disorders) are a group of seven rare genetic disorders caused by the deficiency of one of the enzymes needed to break down complex sugar molecules called mucopolysaccharides. Mucopolysaccharides are also sometimes called GAGs (glycoaminoglycans) and are naturally produced by the body and used in the building of bones, cartilage, skin, and tissues. Mucopolysaccharides get their name from their thick jelly-like consistency (‘muco’), ‘poly’ meaning many and ‘saccharide’ meaning sugar. High concentrations of mucopolysaccharides in the cells of the central nervous system, including the brain, cause the neurological and developmental problems that accompany these disorders. MPS disorders are part of a larger group of disorders known as “lysosomal storage disorders” because the enzymes that break down mucopolysccharides are found within a compartment of the cell called the lysosome. The lysosome is often called the "waste disposal plant" of the cell. There are more than 50 lysosomal storage disorders. MPS III (Sanfilippo syndrome) is caused by a lack of enzymes to break down a particular mucopolysaccharide called heparan sulfate. There are four subtypes of MPSIII: types A, B, C and D. Each type is caused by a mistake in a different gene (see below). All types of MPS III are associated with some degree of mental deterioration, but the severity and rate of progression depends on the particular type of MPS lll and there is also variability in severity within the sub-types, and even between affected siblings.
Patients with Sanfilippo syndrome (MPS Type III) usually appear normal at birth, but developmental delay is usually evident by age 2-5 years. Mental and motor development reach a peak by 3-6 years of age after which behavioral disturbances and intellectual decline usually occur. However, behavioral problems such as hyperactivity and irritability may become obvious earlier. Severe behavioral disturbance is a very common feature of Sanfilippo syndrome, and one of the more difficult aspects of the disorder to manage.
Other symptoms can be coarse hair, excess hair growth (hirsutism), slightly coarse facial features, sleeping problems, mildly enlarged liver and/or spleen, speech delay, respiratory and ear infections, diarrhea, hernias, seizures, and a wobbly and erratic walk. Hearing loss and vision impairment may develop in some children.
Children with Sanfilippo syndrome usually start to lose their intellectual functions, especially speech before their motor function declines. There is great variability in the rate of regression, even among siblings, with some showing rapid loss of function and others who exhibit a much slower progression of the disease. Death can occur from before the age of 10 until the third or fourth decades of life, with the average being around 15 to 20 years of age.
All four types of MPS III are caused by changes (mutations) in different genes that contain the instructions for making enzymes that break down heparan sulfate.
MPS IIIA……..SGSH…………heparan N-sulfatase
MPS IIIC……..HGSNAT……..heparan-alpha-glucosaminide N-Acetyltransferase
MPS IIID……..GNS………….N-acetylglucosamine 6-sulfatase
MPS III is inherited in an autosomal recessive manner. This means that both parents have one copy of the altered gene and one normal copy – they are known as carriers and do not show signs of the condition. A child with MPS III inherits two copies of the altered gene, one from each parent.
In autosomal recessive inheritance, in each pregnancy of a couple who are both carriers, 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 altered gene and therefore being a carrier
– 25% (1 in 4) chance that a child will be neither affected nor a carrier.
The risk is the same for males and females.
MPS III is classified as a rare disease with incidence reported to be between 0.28 and 4.1 cases per 100,000 births. MPS IIIA is the most common subtype affecting around 1 in 100 000 births, closely followed by type B at 1 in 200,000. In some countries in Southern Europe, type B has been reported to be more common than A. MPS IIIC and IIID are rarer with reported incidences of approximately 1 in 1.5 million and 1 in 1 million births respectively.
To diagnose MPS III, mucopolysaccharides (GAGs) are usually first measured in urine, followed by measurement of enzyme activity in blood or a small skin sample. Increased heparan sulfate in urine, and a decrease in the activity of any one of the four enzymes (shown in the table above) is usually consistent with a diagnosis of MPS III and will identify the MPS III type (A, B, C or D). It is important to know the MPS III type as this will make genetic testing easier and importantly, many of the treatments being developed are only for specific types.
Genetic testing of a blood sample will allow the identification of the exact changes in the DNA. It is important to attend genetic counseling to learn the implications for other children in the family, future pregnancies and extended family members. The counselor will explain the inheritance pattern and help advise who should be tested.
If the genetic diagnosis is known, this information can be used to test other at risk members of the family. It can also be used for prenatal testing of future pregnancies (testing a fetus while still in the womb) and/or preimplantation diagnosis (testing of embryos created through IVF to select those that do not carry the relevant gene mutation).
Treatment of Sanfilippo syndrome is symptomatic and supportive. It is important for children with MPS III to be managed by a multidisciplinary team of specialists to give these children the best quality of life. At different stages this could include a combination of the following: a neurologist, developmental pediatrician, metabolic/genetics specialist, orthopedics, gastroenterologist, ophthalmologist, cardiologist, endocrinologist, allied health (e.g. physiotherapy, OT, behavioral therapists) and an ENT (ear, nose and throat) specialist.
Clinical trials designed to gauge the safety and efficacy of several different approaches are under way. Therapeutic approaches include:
– Gene therapy which involves using a harmless virus to deliver a functional copy of the altered gene into the body
– Enzyme replacement therapy, where the missing enzyme is administered
– Substrate reduction therapy: researchers are searching for drugs which could reduce the amount of mucopolysaccharides produced by the body
– Stem cell therapy, which although promising is in the early stages of lab based research
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
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