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Sanfilippo syndrome

This is part of Rare diseases.

Diagnosis: Sanfilippo syndrome

Synonyms: Mucopolysaccharidosis type III, MPS III


Date of publication: 2012-08-20
Version: 1.0

The disease

Sanfilippo syndrome (MPS III) is an inherited disease and one of the mucopolysaccharidoses (MPS diseases). They are rare metabolic disorders caused by deficiencies in various lysosomal enzymes which normally help to break down different substances in the body. The disease causes an accumulation of a substance normally broken down by the enzyme, leading to organ damage. Sanfilippo syndrome was described for the first time in 1961 by RC Harris, but was named after American paediatrician, Sylvester Sanfilippo, in 1963. Four forms of Sanfilippo syndrome have been identified, A, B, C and D. They are the result of four different enzyme deficiencies.

In total, there are seven known MPS diseases. They are named after the physicians who first described the disease, or the missing enzyme. Names are often followed by a figure. Currently, it is becoming more common to denote the diseases with a figure, such as MPS III, or with the name of the deficient enzyme.

In the Swedish Board of Health and Welfare’s Database of Rare Diseases, apart from this information material, there is information on the following MPS diseases and syndromes: Hunter (MPS II), Hurler, Hurler-Scheie and Scheie (MPS IH, IH/S, IS), Maroteaux-Lamy (MPS VI), Morquio (MPS IV) and Sly (MPS VII).

Occurrence

Occurrence figures vary between countries. In the Netherlands, for example, the disease is approximately three times more common than in Sweden. In Sweden, fewer than one child per year is born with Sanfilippo syndrome. It is estimated that there are approximately ten individuals with the disease in Sweden.

It is possible that there are people with Sanfilippo syndrome who have not received a diagnosis, as symptoms vary.

Cause

Sanfilippo syndrome is caused by a mutation in one of the genes controlling the production of (codes for) various enzymes which help break down heparan sulphate. Heparan sulphate is a mucopolysaccharide (or a glycosaminoglycan), a substance containing, among other things, long chains of carbohydrates which are a component of different tissues in the body.

Sanfilippo syndrome Chromosome Gene Enzyme
type A 17q25.3 SGSH N-sulfoglucosamine sulfohydrolase
type B 17q21.2 NAGLU N-acetyl-alpha-D-glucosaminidase
type C 8p11.21 HGSNAT acetyl-CoA, alpha-glucosaminide-N-acetyltransferase
type D 12q14.3 GNS N-acetylglucosamine-6-sulfatase

Table: The different forms of Sanfilippo syndrome

Lysosomes are small units found in all the cells of the body except the red blood cells, and it is in these lysosomes that substances are broken down. The role of lysosomes is to manage and break down different substances. It does this with the help of enzymes, types of protein which contribute to chemical processes without themselves being broken down. In Sanfilippo syndrome, there is a deficiency in one of the four enzymes named above, which means that mucopolysaccharides are not broken down so they accumulate in cells. This in turn causes progressive damage to different tissues and organs.

Heredity

In Sanfilippo syndrome the pattern of inheritance is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one single copy of the mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

In Sanfilippo syndrome the mucopolysaccharides are stored primarily in the nervous system, while other organs are far less affected. This is significantly different from the other MPS diseases. Unlike children with other MPS diseases (Hurler, Hunter, Morquios and Maroteaux-Lamy), children with Sanfilippo syndrome do not necessarily have a characteristic appearance.

There is a wide variation in symptoms among people with disease types A to D. In Sweden, type A is most common. Type D is extremely rare, having been identified in approximately ten people in the world, none of them Swedish.

Children with Sanfilippo syndrome are born healthy and develop normally between the ages of two to six. At this time, developmental abnormalities begin to manifest in the form of delayed speech development or autistic behaviour patterns. Developmental delay becomes more pronounced in the first years after symptoms have manifested. Children with Sanfilippo syndrome are often described as having coarse hair, heavy eyebrows and increased hirsuteness (body hair) but many children with the syndrome do not develop these characteristics.

After some years, usually at pre-school age for children with type A and later for children with another type of the disease, there is a progressive deterioration. Behavioural abnormality in the form of severe hyperactivity can create many problems for people close to the child. Speech and comprehension skills that the child has acquired are lost and an intellectual disability manifests. Sleep patterns are often severely disrupted. The children may have problems chewing and may easily choke on their food.

In the last phase of the disease, balance deteriorates and the child loses the ability to walk. Intellectual ability continues to deteriorate. Epilepsy is common. In the final stages of the disease, there is a great need of medical care.

The skeleton may be affected in the form of slight or moderate spinal abnormalities (kyphosis, scoliosis). Height is usually normal. One or both hip joints may be underdeveloped, leading to pain and difficulties walking. X-rays reveal a condition similar to Perthes disease, an orthopaedic condition. Other joints may also become stiff although this does not usually affect mobility until later. Stiffness in the joints of the feet may affect the child’s gait and surgical intervention may be discussed, but experience shows that effects are short-lived with a major risk of the condition recurring.

Infections of the upper respiratory tract, pneumonia and ear infections are common problems. Hearing may be impaired as a result of recurrent ear infections, with fluid building up behind the eardrums.

Gastrointestinal problems with bouts of diarrhoea are common and some children develop gallstones. However, the heart and eyes are not affected, which is the case in several other MPS diseases.

The lifespans of children with Sanfilippo syndrome vary greatly and there is also a variation between types A, B, C and D. Individuals with the more severe form of the disease do not usually live beyond the age of twenty, while people with a milder form may live considerably longer.

Diagnosis

MPS diseases are identified by testing for elevated levels of mucopolysaccharides (glycosaminoglycans) in urine. After this, the exact nature of the enzyme deficiency is identified in a blood test. Diagnosis can be definite when levels of one of the four enzymes is low while levels of heparan sulphate in the urine are elevated.

It is possible to make a diagnosis based on DNA testing. At the same time that the diagnosis is made, the family should be offered genetic counselling. Carrier diagnosis, pre-natal diagnosis and embryo diagnosis are possible if the mutation in the family has been identified.

Treatment/interventions

There is currently no cure for Sanfilippo syndrome. Instead, treatment focuses on trying to prevent medical complications and attempting to ease everyday tasks so that the quality of life of the child and the family is as good as possible. A soya protein supplement (genistein) has been studied to see whether it has any effect on the disease. Some of the results are contradictory and the protein does not appear to affect the brain’s development.

Upper respiratory infections, pneumonia and ear infections are treated with antibiotics and it may sometimes be necessary to insert grommets (plastic tubes) through the eardrums to drain fluid.

Many children have periodic bouts of diarrhoea which may be difficult to treat. A lactose-free diet has been shown to have some positive effect. If the child has problems chewing and chokes easily, food should be finely chopped. If the child refuses to eat, or there is a problem with feeding, a PEG may be necessary. In PEG, (percutaneous endoscopic gastrostomy) a surgical procedure creates a direct connection through the abdominal wall and into the stomach. It is important that the family has contact with a dietician from an early stage.

Epilepsy is common and treated with anti-epileptic medication.

Behavioural abnormalities including hyperactivity, disturbed sleep patterns, screaming and destructive tendencies can be difficult to control with medication. Children with the syndrome do not usually find it difficult to go to sleep but their sleeping patterns are extremely irregular and some medications used to aid sleep are not effective. Sleep disturbance is believed to become worse with age. In recent years the naturally-occurring hormone, melatonin, has been found to function well as a treatment for disturbed sleep if combined with regular routines and fixed times for going to bed and getting up.

A hematopoietic stem cell transplant is a form of treatment used to replace missing enzymes in certain enzyme deficiency diseases, including other MPS diseases such as Hurler syndrome. Long term monitoring of children with Sanfilippo syndrome who have undergone such transplantations reveals that this procedure has no effect on the accumulation of heparan sulphate in the brain, which causes the primary symptoms. For this reason, this treatment is no longer recommended for Sanfilippo syndrome.

Children with Sanfilippo syndrome have a blood-clotting impairment (caused by the elevated levels of heparan sulphate in the blood) and should therefore be examined, and if necessary treated for this, before any operation.

Children with Sanfilippo syndrome should, like those with the other MPS syndromes, be examined by a team with specialist knowledge of the disease. Examinations of the hearing, as well as the eyes, heart and skeleton are carried out and a neurological assessment is made.

Habilitation

The child and his/her family require early contact with a habilitation team made up of professionals with special expertise in how disability affects everyday life, health and development.

Support and treatment are given within the medical, educational, psychological, social and technical fields. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings can also receive support. The family may also require help in coordinating different forms of help.

Habilitation is planned on the basis of the child’s special needs and problems. Habilitation varies over time but always takes place in collaboration with those close to the child or young person.

For advice on feeding difficulties, contact with a speech therapist is necessary from an early stage. It is important to stimulate speech development from a young age by means including augmentative and alternative communication (AAC), so that the child develops communication skills.

It is also essential to adapt accommodation so that children do not harm themselves or those around them. Pre-schools and schools should also be adapted to the child’s needs. Structured activities and fixed routines can help children who are hyperactive.

As the disease progresses, a physiotherapist can help by teaching breathing techniques which make it easier for the child to cough up phlegm from the lungs.

It is important that the psychological and social needs of the whole family are met.

The local authority can offer different forms of support to facilitate the family’s everyday life. Respite care can, for example, take the form of a contact family or short-term accommodation outside the home. Special assistance can help the family lead an active life despite the child’s disabilities.

Adults with Sanfilippo syndrome require continued, individually-designed habilition and support in their daily lives. This may take for the form of special accommodation offering assistance in managing daily life.

Practical advice

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National and regional resources in Sweden

Paediatricians and paediatric neurologists at Swedish regional and county hospitals can make the diagnosis with the help of laboratory tests.

Two laboratories specialising in metabolic diseases have resources to make clinical chemical diagnoses. The Department of Clinical Chemistry and Neurochemistry, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, and the Centre for Congenital Metabolic Diseases, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden.

DNA-based diagnosis is carried out at the Department of Clinical Genetics, Rudbeck Laboratory, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.

Resource personnel

Specialist teams with knowledge of, and interest in, MPS diseases are located at:

Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Acting Senior Physician Karin Naess, tel: +46 8 585 800 00.

Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Associate Professor Ulrika von Döbeln, Centre for Congenital Metabolic Diseases, tel: +46 8 517 700 00.

Skåne University Hospital, SE-221 85 Lund, Sweden: Specialist Physician Domniki Papadopoulou, Children’s Hospital, tel: +46 46 17 10 00.

Sahlgrenska University Hospital in Gothenburg: Professor Paul Uvebrant and Associate Professor Niklas Darin, Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden, tel: +46 31 343 40 00. Also, Professor Jan-Erik Månsson, Clinical Chemistry and Neurochemistry, Sahlgrenska University Hospital /Mölndal, SE-431 80 Mölndal, Sweden, tel: +46 31 343 10 00.

Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Professor Niklas Dahl, Clinical Genetics, Rudbeck Laboratory, tel: +46 18 611 10 00.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visits Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Stockholm County Council Habilitation Services’ section for rare diseases arranges training days on MPS diseases for parents and personnel. Contact Kristina Gustafsson Bonnier, tel: +46 8 123 350 23, email: kristina.gustafsson-bonnier@sll.se, www.habilitering.nu/forumfunktionshinder.

Organizations for the disabled/patient associations

The Swedish MPS association, email: mps.foreningen@gmail.com, www.mpsforeningen.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: www.sallsyntadiagnoser.se, info@sallsyntadiagnoser.se.

Rare Diseases Sweden is a federation of rare disease organizations, serving the interests of people with rare disorders and varied disabilities.

FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities. Gävlegatan 18 C, Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.

The Society for Mucopolysaccharide Diseases is a UK organisation, email: mps@mpssociety.co.uk, www.mpssociety.co.uk.

The National MPS Society is a US organisation, email: info@mpssociety.org, www.mpssociety.org.

Courses, exchanges of experience for personnel

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children and young people who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Stockholm County Council Habilitation Services’ section for rare diseases arranges training days on MPS diseases for parents and personnel. Contact Kristina Gustafsson Bonnier, tel: +46 8 123 350 23, email: kristina.gustafsson-bonnier@sll.se, www.habilitering.nu/forumfunktionshinder.

Research and development (R&D)

Studies are under way to map the molecular mutations causing different MPS syndromes. It is hoped that in future it will be possible to relate specific genetic molecular changes to symptoms and remaining enzyme activity. This will give more accurate prognoses in individual cases.

Animal experiments for all sub-groups of Sanfilippo syndrome have been developed, facilitating research into future methods of treatment. In other mucopolysaccharidoses (MPS I, MPS II och MPS VI), enzyme-based medication has been developed which may be administered intravenously. Research is under way into developing enzyme-based medication for Sanfilippo syndrome. The disease primarily affects the brain, which is where symptoms originate, and as it is not believed that the enzyme can travel from the blood to the brain, it is not known if enzyme-based medication has any effect. Attempts are being made to bridge the blood-brain barrier by modifying the enzyme.

Attempts are also being made to inhibit the production of substances which damage the brain (substitution therapy). Gene therapy trials using animal models are being developed.

Information material

An information leaflet on Sanfilippo syndrome that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-11-33). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The Swedish MPS Association has produced a brochure on Sanfilippo syndrome (2007). In Swedish only. It can be ordered from the association, email: mps.foreningen@gmail.com, www.mpsforeningen.se or downloaded in pdf format from its home page, www.mpsforeningen.se/documents/Sanfilippobroshyren.pdf.

Newsletter from Ågrenska on mucopolysaccharidoses, number 224 (2003). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

Information in English on the different MPS diseases/syndromes is produced by the British association, the Society for Mucopolysaccharide Diseases, and the American association, National MPS Society. (See addresses under Organizations for the disabled/patient associations etc.)

Literature

Cleary MA, Wraith JE. Management of mucopolysaccharidoses type III. Arch Dis Child 1993; 69: 403-406.

Coville GA, Watters JP, Yule W, Baxd MC. Sleep problems in children with Sanfilippo syndrome. Dev Med Child Neurol 1996; 38: 538-544.

Delgadillo V, Mar O’Callaghan M, Artuch R, Montero R, Pineda M. Genistein supplementation in patients affected by Sanfilippo disease. J Inherit Metab Dis 2011; 34: 1039-1044.

Harris RC. Mucopolysaccaride disorder: a possible new genotype of Hurler’s syndrome. Am J Dis Child 1961; 102: 741.

Héron B, Mikaeloff, Y, Froissart R, Caricade G, Maire I, Caillaud C et al. Incidence and natural history of mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am J Med Genet A 2011; 155A: 58-68.

Malm G, Månsson JE. Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: clinical presentation of 22 children diagnosed during a 30-year period. Acta Paediatr 2010; 99: 1253-1257.

Malm G, von Döbeln U, Naess K, Ringden O. Lysosomala sjukdomar - forskning och framsteg ger hopp om bot och bättring. Läkartidningen 2008; 105: 3731-3735.

Malm G, Lund Melgard A, Månsson J-E, Heiberg A. Mucopolysaccharidoses in the Scandinavian countries: incidence and prevalence. Acta Paediatrica 2008; 97: 1577-1581.

Neufeld EF, Muenzer J. The mucopolysaccharidoses. In Scriver CS, Beaudet AL, Sly WS, Valle eds: The metabolic and molecular bases of inherited disease. New York: McGraw-Hill 2001, 8th edition; 3421-3452.

Ruijter GJ, Valstar MJ, van der Kamp JM, van der Helm RM, Durand S, van Diggelen OP et al. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol Genet Metab 2008; 93: 104-111.

Valstar MJ, Ruijter GJ, van Diggelen OP, Poorthuis BJ, Wijburg FA. Sanfilippo syndrome: a mini review. J Inherit Metab Dis 2008; 31: 240-252.

van de Kamp JJ, Niermeijer MF, von Figura K, Giesberts MA. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clin Genet 1981; 20: 152-60.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: mucopolysaccharidosis type III A, mucopolysaccharidosis type III B, mucopolysaccharidosis type III C, mucopolysaccharidosis type III D

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Gunilla Malm, Karolinska University Hospital, Huddinge/Stockholm,Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2012-08-20
Version: 1.0
Publication date of the Swedish version: 2012-02-27

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.