Sanfilippo syndrome

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Sanfilippo syndrome
Heparan sulfate.png
Structure of heparan sulfate, one of the molecules that builds up in the tissues of people with Sanfilippo syndrome
Specialty Endocrinology Edit this on Wikidata
Symptoms Deafness; intellectual disability; dementia; loss of mobility
Prognosis Lifespan is reduced; most patients survive until the teenage years, but some may reach their 30s
Frequency 1 in 70,000[1]

Sanfilippo syndrome, or mucopolysaccharidosis III (MPS-III) is a rare autosomal recessive lysosomal storage disease. It is caused by a deficiency in one of the enzymes needed to break down the glycosaminoglycan (GAG) heparan sulfate (which is found in the extra-cellular matrix and on cell surface glycoproteins).

Affected children generally do not show any signs or symptoms at birth. In early childhood, they begin to develop developmental disability and loss of previously learned skills. In later stages of the disorder, they may develop seizures and movement disorders. Patients with Sanfilippo syndrome usually live into adolescence or early adulthood.[2]

History[edit]

The condition is named after Sylvester Sanfilippo, the pediatrician who first described the disease.[3][4]

Signs and Symptoms[edit]

The disease manifests in young children. Affected infants are apparently normal, although some mild facial dysmorphism may be noticeable. The stiff joints, hirsuteness and coarse hair typical of other mucopolysaccharidoses are usually not present until late in the disease. After an initial symptom-free interval, patients usually present with a slowing of development and/or behavioral problems, followed by progressive intellectual decline resulting in severe dementia and progressive motor disease.[5] Acquisition of speech is often slow and incomplete. The disease progresses to increasing behavioural disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behaviour, pica and sleep disturbance. As affected children have normal muscle strength and mobility, the behavioural disturbances are very difficult to manage. The disordered sleep in particular presents a significant problem to care providers. In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. The life-span of an affected child does not usually extend beyond late teens to early twenties.

Individuals with MPS III tend to have mild skeletal abnormalities; osteonecrosis of the femoral head may be present in patients with the severe form. Optical nerve atrophy, deafness, otitis can be seen in moderate to severe individuals. Other characteristics include coarse facial features, thick lips, synophrys, and stiff joints. Chronic diarrhea, enlarged liver and spleen are also common. It is difficult to clinically distinguish differences among the four types of Sanflippo syndrome. However, MPS IIIA is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival.[6] The median age of death for children afflicted with MPS III-A is 15.4 years, +-4.1 years. [7]

Of all the MPS diseases, MPS III produces the mildest physical abnormalities. It is important, however, that simple and treatable conditions such as ear infections and toothaches not be overlooked because of behavior problems that make examination difficult. Children with MPS III often have an increased tolerance to pain. Bumps, bruises, or ear infections that would be painful for other children often go unnoticed in children with MPS III. Some children with MPS III may have a blood-clotting problem during and after surgery. [1]

Pathophysiology and genetics[edit]

Glycosaminoglycans (GAGs) are polysaccharides that contain repeating disaccharides and sulfate groups. GAGs are attached to serine and threonine at the surface of proteoglycans, which are found in the extracellular matrix and the cell membrane, or stored in the secretory granules. GAGs are stored in the cell lysosome, and degraded by glycosidases, sulfatases and acetyltransferases. Deficiency in these enzyme leads to the four subtypes of MPS III.

All four subtypes of Sanfilippo syndrome have autosomal recessive inheritance. Impaired enzymatic activities are due to multiple mutations. The SGSH gene, which is located on chromosome 17q25.3, encodes heparan-N-sulfatase; deficiency of the enzyme is responsible for MPS IIIA. A total of 137 mutations that causes this form of Sanfilippo syndrome have been found so far. MPS IIIA is more common in Northern Europe. The NAGLU gene, located on chromosome 17q21.2, encodes alpha-N-acetylglucosaminidase, deficiency of which results in MPS IIIB. To date, 152 mutations were identified to cause MPS IIIB. This form of the syndrome is more common in Southern Europe. The HGSNAT gene which encodes CoA:alpha-glucosaminidase N-acetyltransferase is located on chromosome 8p11.21, causing MPS IIIC. 64 mutations associated with this form have been described so far. Deficiency of N-acetylglucosamine 6-sulfatase that leads to MPS IIID is due to mutations in the GNS gene, which is located on chromosome 12q14.3. 23 mutations have been identified. In general, MPS IIIA and B are the most common form of Sanfilippo syndrome.[8]

Genetics of MPS-III
MPS-III type gene enzyme chromosomal region
MPS-III A SGSH heparan N-sulfatase 17q25.3
MPS-III B NAGLU N-acetyl-alpha-D-glucosaminidase 17q21.2
MPS-III C HGSNAT acetyl-CoA:alpha-glucosaminide N-acetyltransferase 8p11.21
MPS-III D GNS N-acetylglucosamine-6-sulfatase 12q14.3

Diagnosis[edit]

MPS-III A, B, C and D are considered to be clinically indistinguishable, although mutations in different genes are responsible for each disease. The following discussion is therefore applicable to all four conditions.

The diagnosis may be confirmed by assay of enzyme levels in tissue samples and gene sequencing. Prenatal diagnosis is possible.

Treatment[edit]

Treatment remains largely supportive. The behavioral disturbances of MPS-III respond poorly to medication. If an early diagnosis is made, bone marrow replacement may be beneficial. Although the missing enzyme can be manufactured and given intravenously, it cannot penetrate the blood–brain barrier and therefore cannot treat the neurological manifestations of the disease. Along with many other lysosomal storage diseases, MPS-III exists as a model of a monogenetic disease involving the central nervous system.

Several promising therapies are in development. Gene therapy in particular is under Phase I/II clinical trial in France since October 2011 under the leadership of Paris-based biotechnology company Lysogene. [9] Other potential therapies include chemical modification of deficient enzymes to allow them to penetrate the blood–brain barrier, stabilisation of abnormal but active enzyme to prevent its degradation, and implantation of stem cells strongly expressing the missing enzyme. For any future treatment to be successful, it must be administered as early as possible. Currently MPS-III is mainly diagnosed clinically, by which stage it is probably too late for any treatment to be very effective. Neonatal screening programs would provide the earliest possible diagnosis.

The flavonoid genistein decreases the pathological accumulation of glycosaminoglycans in Sanfilippo syndrome.[10] In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein.[11] Despite its reported beneficial properties, genistein also has toxic side effects.[12]

Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.[13][14][15]

Incidence[edit]

Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland,[16] 1 per 66,000 in Australia,[17] and 1 per 50,000 in the Netherlands.[18]

The Australian study estimated the following incidences for each subtype of Sanfilippo syndrome:

Sanfilippo syndrome type Approximate incidence Percentage of cases Age of onset
A 1 in 100,000[17] 60% 1.5-4
B 1 in 200,000[17] 30% 1-4
C 1 in 1,500,000[17] 4% 3-7
D 1 in 1,000,000[17] 6% 2-6

See also[edit]

References[edit]

  1. ^ "Mucopolysaccharidoses Fact Sheet". National Institute of Neurological Disorders and Stroke. 15 Nov 2017. Retrieved 25 May 2018. 
  2. ^ "Mucopolysaccharidosis type III". Genetics Home Reference. March 2017. Retrieved 22 July 2018. 
  3. ^ "eMedicine - Mucopolysaccharidosis Type III : Article by Germaine L Defendi". 
  4. ^ Sanfilippo, S. J.; Podosin, R.; Langer, L. O., Jr.; Good, R. A. : Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type). J. Pediat. 63: 837-838, 1963.
  5. ^ Marlies J. Valstar; Hennie T. Bruggenwirth; Renske Olmer; Ron A. Wevers; Frans W. Verheijen; et al. (September 2010). "Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype" (PDF). Inherit Metab Dis. 10.1007/s10545-010-9199-y. 
  6. ^ Andrade, F., Aldámiz-Echevarría, L., Llarena, M., & Couce, M. L. (2015). Sanfilippo syndrome: Overall review. Pediatrics International, 57(3), 331-338. doi:10.1111/ped.12636
  7. ^ Tardieu, Marc (February 2014). "Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial". Human Gene Therapy. 25 (6). p. 506-516. Retrieved 25 May 2018. 
  8. ^ Andrade, F., Aldámiz-Echevarría, L., Llarena, M., & Couce, M. L. (2015). Sanfilippo syndrome: Overall review. Pediatrics International, 57(3), 331-338. doi:10.1111/ped.12636
  9. ^ Intracerebral Gene Therapy for Sanfilippo Type A Syndrome on clinicaltrials.gov
  10. ^ http://www.bgo.ug.gda.pl/kbm/dmb/staff/gw.htm
  11. ^ Piotrowska, E.; Jakóbkiewicz-Banecka, J.; Barańska, S.; Tylki-Szymańska, A.; Czartoryska, B.; Wegrzyn, A.; Wegrzyn, G. (Jul 2006). "Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses". European Journal of Human Genetics. 14 (7): 846–52. doi:10.1038/sj.ejhg.5201623. PMID 16670689. 
  12. ^ Jin, Y.; Wu, H.; Cohen, EM.; Wei, J.; Jin, H.; Prentice, H.; Wu, JY. (Mar 2007). "Genistein and daidzein induce neurotoxicity at high concentrations in primary rat neuronal cultures". J Biomed Sci. 14 (2): 275–84. doi:10.1007/s11373-006-9142-2. PMID 17245525. 
  13. ^ Jonah's Just Begun - Foundation to Cure Sanfilippo, Inc.
  14. ^ Phoenix Nest, Inc., a biotech company seeking treatments and cures for Sanfilippo Syndrome
  15. ^ Phunk Phenomenon HipHop For Hope, a dance crew in Boston raising awareness for Sanfilippo Syndrome
  16. ^ Nelson J (December 1997). "Incidence of the mucopolysaccharidoses in Northern Ireland". Hum. Genet. 101 (3): 355–8. doi:10.1007/s004390050641. PMID 9439667. 
  17. ^ a b c d e Meikle PJ, Hopwood JJ, Clague AE, Carey WF (January 1999). "Prevalence of lysosomal storage disorders". JAMA. 281 (3): 249–54. doi:10.1001/jama.281.3.249. PMID 9918480. 
  18. ^ Poorthuis BJ, Wevers RA, Kleijer WJ, et al. (1999). "The frequency of lysosomal storage diseases in The Netherlands". Hum. Genet. 105 (1–2): 151–6. doi:10.1007/s004390051078. PMID 10480370. 

External links[edit]

Classification
External resources