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Last updated:
August 13, 2020
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NORD gratefully acknowledges Kristina Elvidge, PhD, Head of Research, Sanfilippo Children’s Foundation, Australia, for assistance in the preparation of this report.
Summary
Mucopolysaccaridosis type III (MPS III) is a rare genetic condition that causes fatal brain damage. It is also known as Sanfilippo syndrome and is a type of childhood dementia.
MPS III is caused by a lack of an enzyme that normally breaks down and recycles a large, complex sugar molecule called ‘heparan sulphate’. This heparan sulphate accumulates and causes damage to the cells of the central nervous system, including the brain. Sanfilippo belongs to a group of disorders known as the “mucopolysaccharidoses” (MPS), which are part of a larger group of disorders known as “lysosomal storage disorders”.
There are four subtypes of MPS III: types A, B, C and D. Each type is caused by a change (mutation) in a different gene (see below). All types of MPS III are associated with mental deterioration, but the severity and rate of progression depends on the particular type of MPS lll. There is also variability in severity within the sub-types and even between affected siblings.
Children with MPS III usually appear healthy at birth, but developmental delay is usually evident by age 2-5 years. Mental and motor development peak by 3-6 years of age, after which intellectual decline usually occurs. 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 include 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. Children with MPS III also often experience hearing loss and vision impairment.
Children with Sanfilippo syndrome usually start to lose their intellectual functions, especially speech, before their motor function declines. Death can occur from before the age of 10 or not until the third or fourth decades of life, with the average being around 15 to 20 years of age. Children with MPS IIIC have a longer life expectancy into the mid-twenties on average. There are attenuated forms of MPS III which result in slower progression and a longer life expectancy.
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.
TYPE..……….GENE…………ENZYME
MPS IIIA……..SGSH…………heparan N-sulfatase
MPS IIIB……..NAGLU……….alpha-N-acetylglucosaminidase
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 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 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
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, speech therapist) 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 in clinical trial include:
– Gene therapy which involves using a harmless virus to deliver a functional copy of the altered gene into the body
– Gene modified stem cell therapy, where stem cells are removed from the body, the genetic error corrected and the stem cells transplanted back into the body
– Enzyme replacement therapy, where the missing enzyme is administered
Laboratory based research is also searching for drugs to help slow disease progression and improve quality of life. It is thought that a combination of treatments will be required to give the best outcome.
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
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Fuller M, Meikle PJ, Hopwood JJ. Epidemiology of lysosomal storage diseases: an overview. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006;Chapter 2.
Clarke JTR. The Mucopolysaccharide Storage (MPS) Diseases. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:474-79.
Neufeld EF, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:3421-41.
REVIEW ARTICLES
Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML. Sanfilippo syndrome: Overall review. Pediatr Int. 2015 Jun;57(3):331-8.
Fedele AO. Sanfilippo syndrome: causes, consequences, and treatments. Appl Clin Genet. 2015;8:269-81.
Hemsley KM, Hopwood JJ. Emerging therapies for neurodegenerative lysosomal storage disorders – from concept to reality. J Inherit Metab Dis. 2011 Oct;34(5):1003-12.
INTERNET
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIA. Entry Number; 252900: Last Edit Date; 05/29/2018.Available at https://www.omim.org/entry/252900?search=252900&highlight=252900 Accessed August 13, 2020.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIB. Entry Number; 252920: Last Edit Date; 02/12/2014. Available at: https://www.omim.org/entry/252920?search=252920&highlight=252920 Accessed August 13, 2020.
McKusick VA, Ed. Online Mendelian Inheritance in Man(OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIIC. Entry Number; 252930: Last Edit Date; 02/12/2014. Available at: https://www.omim.org/entry/252930?search=252930&highlight=252930 Accessed August 13, 2020.
McKusick VA, Ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Mucopolysaccharidosis Type IIID. Entry Number; 252940: Last Edit Date; 02/12/2014. Available at: https://www.omim.org/entry/252940?search=252940&highlight=252940 Accessed August 13, 2020.
Defendi GL. Genetics of Mucopolysaccharidosis Type III. Medscape.Updated: May 23, 2018. www.emedicine.com/ped/topic2040.htm Accessed August 13, 2020.
A Guide to Understanding Sanfilippo syndrome (mucopolysaccharidosis type III; MPS III). MPS Australia. https://www.mpssociety.org.au/about-the-mps-and-related-diseases/mps-iii/ Accessed August 13, 2020.
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