What is Sanfilippo Syndrome?
Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is an autosomal recessive lysosomal storage disorder (LSD). Sanfilippo Syndrome is caused by the buildup of glycosaminoglycans (GAGs or mucopolysaccharides) in the lysosomes which prevent the cellular machinery from working properly. GAGs are sugar chain molecules stored in lysosome and are degraded by enzymes such as sulfamidases and sulfatases. The lack or deficiency of these enzymes can lead to MPS III. There are four subtypes of the Sanfilippo syndrome corresponding to the particular deficient enzyme in the pathway of heparan sulfate breakdown. Type A is the most common and severe type of Sanfilippo syndrome and is caused by the accumulation of heparan sulfate GAGs. [1,2]
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Symptoms and DiagnosisChildren affected don’t usually show any symptoms until early childhood, ages 2-6, where they start to lose their previously learned skills and show signs of developmental disability. Some infants show mild facial dysmorphisms, such as larger head size than usual. Additional somatic symptoms can include coarse facial features with broad eyebrows, rough hair and skeletal pathology, affecting growth or causing degenerative joint disease.
Most affected children also experience speech delay and hyperactivity. Slowed development is followed by progressive intellectual decline, and severe dementia. Some develop seizures and movement disorders at the later stages of the disease. Patients usually become immobile and unresponsive at the final phase. [2,4] All four types of Sanfilippo syndrome show high levels of GAGs in the urine. Enzyme assay of cultured skin fibroblasts and white blood cells is the best way to detect the presence or absence of enzymes breaking down heparan sulfate. Gene sequencing is another diagnostic tool to detect the genetic mutations causing Sanfilippo syndrome. [4] |
Sanfilippo Syndrome and SGSH Gene
Each type of Sanfilippo syndrome is known to be caused by a different gene mutation. Sanfilippo Syndrome type A is caused by a mutation in the gene encoding N-sulfoglucosamine sulfohydrolase (SGSH). SGSH encodes enzyme sulfamidase which is involved in the breakdown of GAGs. Over 80 mutations in the SGSH have been linked to Sanfilippo syndrome. Most of these mutations are point mutation and they all negatively affect the function of sulfamidase. [2,3]
Treatments
At this time, there is no approved treatment for Sanfilippo Syndrome. Treatment is limited to supportive or palliative care to reduce the severity of the symptoms and improve quality of life. Bone marrow transplants and enzyme replacement therapy (ERT) have not been successful yet in showing improvement. There is, however, ongoing research on the effect of different types of therapies. [2,5]
Enzyme replacement therapy
The basic idea of enzyme replacement therapy is to gain the ability for sulfamidase to be secreted and taken up by lysosomes in the cells. The obstacle of establishing an effective enzyme replacement therapy is the proteins’ inability to cross the blood brain barrier (BBB). Injection of sulfamidase into the brain or cerebrospinal fluid is another potential treatment, but crossing the BBB remains an issue. [2] |
Gene therapy
The hope of gene therapy is that by introducing the coding sequence of the protein of interest into the cells using a viral vector, the cells will posses enzymatic activity and secrete it into circulation. This strategy is currently at the stage of human clinical trial. [2]
The hope of gene therapy is that by introducing the coding sequence of the protein of interest into the cells using a viral vector, the cells will posses enzymatic activity and secrete it into circulation. This strategy is currently at the stage of human clinical trial. [2]
Genistein
Genistein is an isoflavone from soy that has shown the ability to reduce GAG levels and increase the expression of CLEAR-containing lysosomal genes. A pilot study including five Sanfilippo patients who were administered with genistein-enriched soy for a year showed reduction in GAG levels and improved behavior. [2] |
Gap in Knowledge
Despite the extensive research being done on this disease, it is still unclear why the GAGs accumulation mostly affects the central nervous system in Sanfilippo syndrome patients.
Organizations
References
[1] Cure Sanfilippo Syndrome Foundation. Retrieved from: https://curesanfilippofoundation.org/what-is-sanfilippo/
[2] Fedele A. O. (2015). Sanfilippo syndrome: causes, consequences, and treatments. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664539/
[3] Genetics Home Reference. Retrieved from: https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-iii?_ga=2.266501518.1071217777.1580939228-804763989.1579724316#statistics
[4] Gilkes JA, Heldermon CD. Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies. (2014). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/25345095
[5] National MPS Society. Retrieved from: https://mpssociety.org/learn/diseases/mps-iii/
[6] de Ruijter, J. (2013). Sanfilippo disease (mucopolysaccharidosis type III): Early diagnosis and treatment. Retrieved from: https://pure.uva.nl/ws/files/2234091/126751_thesis.pdf
[7] Pena, A. (2018). Advances in Substrate Reduction Therapy Show Promise for Sanfilippo Syndrome. Retrieved from: https://sanfilipponews.com/2018/05/15/advances-substrate-reduction-therapy-show-promise-sanfilippo-syndrome/
Figures
[1] Cure Sanfilippo Foundation. Retrieved from: https://curesanfilippofoundation.org/what-is-sanfilippo/
[2] SGSH Gene. Genetics Home Reference-NIH.(2008). Retrieved from https://ghr.nlm.nih.gov/gene/SGSH#sourcesforpage
Images
Header: https://www.perlara.com/blog/sanfilippo-syndrome-perlquest/
Lysosome: https://www.sciencemedia.com/l/Lysosomal_Storage_Disorders_Sanfilippo_Syndrome/
Patient: https://researchaustralia.org/corporate-giving-goes-beyond-dollar/
ERT: https://www.nature.com/articles/s10038-019-0662-9#citeas
Gene therapy: https://ib.bioninja.com.au/options/untitled/b4-medicine/gene-therapy.html
Genistein: https://www.douglaslabs.com/isoflavone-250-with-genistein.html
[2] Fedele A. O. (2015). Sanfilippo syndrome: causes, consequences, and treatments. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664539/
[3] Genetics Home Reference. Retrieved from: https://ghr.nlm.nih.gov/condition/mucopolysaccharidosis-type-iii?_ga=2.266501518.1071217777.1580939228-804763989.1579724316#statistics
[4] Gilkes JA, Heldermon CD. Mucopolysaccharidosis III (Sanfilippo Syndrome)- disease presentation and experimental therapies. (2014). Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/25345095
[5] National MPS Society. Retrieved from: https://mpssociety.org/learn/diseases/mps-iii/
[6] de Ruijter, J. (2013). Sanfilippo disease (mucopolysaccharidosis type III): Early diagnosis and treatment. Retrieved from: https://pure.uva.nl/ws/files/2234091/126751_thesis.pdf
[7] Pena, A. (2018). Advances in Substrate Reduction Therapy Show Promise for Sanfilippo Syndrome. Retrieved from: https://sanfilipponews.com/2018/05/15/advances-substrate-reduction-therapy-show-promise-sanfilippo-syndrome/
Figures
[1] Cure Sanfilippo Foundation. Retrieved from: https://curesanfilippofoundation.org/what-is-sanfilippo/
[2] SGSH Gene. Genetics Home Reference-NIH.(2008). Retrieved from https://ghr.nlm.nih.gov/gene/SGSH#sourcesforpage
Images
Header: https://www.perlara.com/blog/sanfilippo-syndrome-perlquest/
Lysosome: https://www.sciencemedia.com/l/Lysosomal_Storage_Disorders_Sanfilippo_Syndrome/
Patient: https://researchaustralia.org/corporate-giving-goes-beyond-dollar/
ERT: https://www.nature.com/articles/s10038-019-0662-9#citeas
Gene therapy: https://ib.bioninja.com.au/options/untitled/b4-medicine/gene-therapy.html
Genistein: https://www.douglaslabs.com/isoflavone-250-with-genistein.html
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Sheida Pourdashti
[email protected]
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
Last updated: 5/1/20
[email protected]
This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison.
Last updated: 5/1/20