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Mucopolysaccharidosis type III (Sanfilippo)
Sanfilippo syndrome is a rare inherited condition where the body cannot properly break down certain complex sugars. This leads to a build-up of these sugars, primarily affecting the brain and nervous system, causing progressive developmental delay and cognitive decline.
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Overview
Sanfilippo syndrome, also known as Mucopolysaccharidosis type III (MPS III), is a rare inherited metabolic disorder. It belongs to a group of conditions called lysosomal storage disorders. In Sanfilippo syndrome, the body lacks or has insufficient amounts of specific enzymes needed to break down a complex sugar molecule called heparan sulphate [PMID:33671181].
This inability to break down heparan sulphate leads to its accumulation within cells, particularly in the brain and nervous system. The build-up of these sugar molecules is toxic to cells, causing progressive damage over time. Sanfilippo syndrome is typically characterised by neurodevelopmental delay, behaviour changes, and eventually severe cognitive decline.
Symptoms & clinical features
The symptoms of Sanfilippo syndrome usually become noticeable in early childhood, typically between the ages of 2 and 6 years. Initial signs may include developmental delays, particularly in speech, and behavioural issues such as hyperactivity, anxiety, and sleep disturbances [PMID:33671181].
As the condition progresses, affected individuals may experience a decline in cognitive abilities, loss of acquired skills, and increasing behavioural difficulties. Physical features can vary but may include coarse facial features, joint stiffness, and frequent ear infections. The rate and severity of progression can differ between individuals, as Sanfilippo syndrome is categorised into types A, B, C, and D, each caused by a different enzyme deficiency.
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Affected organs
Sanfilippo syndrome primarily affects the central nervous system, including the brain and spinal cord. The accumulation of heparan sulphate in these areas leads to neurodegeneration, which is the underlying cause of the neurological and cognitive decline seen in the condition.
While the brain is most significantly impacted, other organs can also be affected, though typically to a lesser degree than in some other MPS disorders. These can include the liver and spleen, leading to mild enlargement, and the skeletal system, which may show some joint stiffness. The heart can also be affected in some individuals, but severe cardiac issues are less common than neurological symptoms.
Risks & severity
Sanfilippo syndrome is a progressive condition, meaning symptoms worsen over time. The severity and rate of progression can vary depending on the specific type of Sanfilippo syndrome (A, B, C, or D) and the particular genetic changes involved. Generally, type A is considered the most severe form, often with an earlier onset and more rapid progression [PMID:20301777].
The condition typically leads to significant developmental regression and profound intellectual disability. Life expectancy is reduced, with many affected individuals not living beyond adolescence or early adulthood. Exact prevalence figures suggest Sanfilippo syndrome affects approximately 1 in 70,000 live births globally, but this can vary by population.
Genetic causes
Sanfilippo syndrome is caused by genetic changes in one of four different genes: SGSH, NAGLU, HGSNAT, or GNS. Each of these genes provides instructions for making an enzyme essential for breaking down heparan sulphate, a type of complex sugar molecule, within lysosomes - the 'recycling centres' of cells.
* **SGSH** (N-sulfoglucosamine sulfohydrolase): Changes in SGSH cause Sanfilippo type A. * **NAGLU** (N-acetyl-alpha-glucosaminidase): Changes in NAGLU cause Sanfilippo type B. * **HGSNAT** (heparan-alpha-glucosaminide N-acetyltransferase): Changes in HGSNAT cause Sanfilippo type C. * **GNS** (glucosamine (N-acetyl)-6-sulfatase): Changes in GNS cause Sanfilippo type D.
When one of these genes has a pathogenic variant, the corresponding enzyme is either missing or non-functional. This prevents the proper breakdown of heparan sulphate, leading to its accumulation in lysosomes and causing the cellular damage characteristic of the syndrome.
- GNS glucosamine (N-acetyl)-6-sulfataseThe GNS gene provides instructions for an enzyme called N-acetylglucosamine-6-sulfatase, which is vital for the proper breakdown of complex sugar molecules within cells.
- HGSNAT heparan-alpha-glucosaminide N-acetyltransferaseThe HGSNAT gene provides instructions for an enzyme called heparan-alpha-glucosaminide N-acetyltransferase, which plays a crucial role in the breakdown of specific molecules within cellular lysosomes.
- NAGLU N-acetyl-alpha-glucosaminidaseThe NAGLU gene provides instructions for an enzyme essential for breaking down complex sugar molecules within cellular compartments called lysosomes, and pathogenic variants are associated with Mucopolysaccharidosis type III (Sanfilippo syndrome).
- SGSH N-sulfoglucosamine sulfohydrolaseThe SGSH gene provides instructions for producing the sulfamidase enzyme, which is vital for the proper breakdown of complex sugar molecules called glycosaminoglycans within cells.
Inheritance pattern
Sanfilippo syndrome has an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the same gene - one from each parent - to develop the condition. People who carry one altered copy of the gene and one functional copy are known as 'carriers'.
Carriers typically do not show symptoms of Sanfilippo syndrome. If both parents are carriers of a pathogenic variant in the same gene, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop the condition. There is also a 2 in 4 (50%) chance that their child will be a carrier, and a 1 in 4 (25%) chance that their child will inherit two functional copies and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
A diagnosis of Sanfilippo syndrome is typically suspected based on a child's developmental regression and behavioural changes. Initial investigations may involve urine tests to detect elevated levels of heparan sulphate. This finding suggests a lysosomal storage disorder, but further testing is needed to confirm Sanfilippo syndrome and its specific type.
Definitive diagnosis is confirmed through enzyme assays, which measure the activity of the specific enzymes involved in heparan sulphate breakdown, usually performed on blood samples or skin biopsies. Genetic testing, analysing the SGSH, NAGLU, HGSNAT, or GNS genes, can then confirm the diagnosis and identify the specific pathogenic variants, which is increasingly part of the NHS Genomic Medicine Service. Referral to a clinical geneticist for these tests is the typical pathway, which can be initiated by a paediatrician or other specialist clinician.
Management & lifestyle
Currently, there is no cure for Sanfilippo syndrome, and management focuses on providing supportive care to alleviate symptoms and improve the quality of life for affected individuals and their families. This often involves a multidisciplinary team approach.
Supportive care may include therapies such as physiotherapy, occupational therapy, and speech and language therapy to help manage developmental and physical challenges. Medications may be used to address specific symptoms like seizures, hyperactivity, or sleep disturbances. Regular monitoring by specialists, including neurologists and paediatricians, is essential. Research into potential treatments, such as gene therapy and enzyme replacement therapy, is ongoing.
UK care pathway
In the UK, suspected cases of Sanfilippo syndrome are generally referred to a paediatrician or a clinical genetics service. The NHS Genomic Medicine Service (GMS) provides a national framework for genomic testing, with specific R-codes for lysosomal storage disorders that encompass Sanfilippo syndrome. Genetic testing, often guided by enzyme assay results, is typically arranged by a clinical geneticist or specialist paediatrician.
Genetic counsellors play a vital role in supporting families, explaining the inheritance pattern, discussing the implications of a diagnosis, and offering information about family planning options and support networks. Care is then coordinated by a multidisciplinary team, often within specialist NHS centres, to address the complex and progressive nature of the condition.
Frequently asked questions
What does 'lysosomal storage disorder' mean?
Lysosomes are like the recycling centres within our cells, breaking down waste products. In a lysosomal storage disorder, an enzyme needed for this process is missing or not working properly, leading to a build-up of waste materials that can damage cells and organs over time.
Can Sanfilippo syndrome be detected before birth?
Yes, if the genetic changes causing Sanfilippo syndrome are known in the family, prenatal diagnosis is possible through chorionic villus sampling (CVS) or amniocentesis. This involves testing cells from the pregnancy for the specific genetic alterations.
Are there different types of Sanfilippo syndrome?
Yes, there are four main types of Sanfilippo syndrome: type A, B, C, and D. Each type is caused by a genetic change in a different gene (SGSH, NAGLU, HGSNAT, or GNS) leading to a deficiency in a specific enzyme involved in heparan sulphate breakdown.
What support is available for families affected by Sanfilippo syndrome?
Families can access support through clinical genetics services, genetic counsellors, and patient advocacy groups in the UK. These organisations provide information, emotional support, and connect families with others facing similar challenges. Multidisciplinary care teams also offer ongoing medical and therapeutic support.
Is there a cure for Sanfilippo syndrome?
Currently, there is no cure for Sanfilippo syndrome. Management focuses on supportive care to manage symptoms and improve quality of life. However, research into potential new treatments, including gene therapy and enzyme replacement therapy, is actively ongoing.