Mucopolysaccharidosis type III

Mucopolysaccharidosis type III
Other names: Sanfilippo syndrome
12-year-old girl with MPS III type A
Pronunciation
  • /ˌsanfɪˈliːpəʊz/
SymptomsIntellectual disability , delayed speech, behavior problems, poor social interaction, sleep problems[1]
ComplicationsSeizures, movement disorders[1]
Usual onsetBirth; symptom onset early childhood[1]
TypesType A, B, C, D[2]
CausesGenetic disease[1]
Diagnostic methodMPS urine, blood enzyme activity, genetic testing[3]
Differential diagnosisBatten disease, mucolipidoses, mannosidosis[3]
TreatmentSupportive care[3]
PrognosisLife expectancy 15 to 20 yr old[3]
Frequency1 in 70,000[1]

Mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome, is a progressive disorder that primarily affects the brain and spinal cord.[1] There are generally no signs at birth, with onset beginning in early childhood.[1] Initial symptoms include speech and behavior problems followed by worsening intellectual disability .[1] Sleep problems also often occur.[1] In later stages, seizures and movement disorders may occur.[1]

It occurs due to mutations in specific genes for enzymes involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs), specifically heparan sulfate.[1] This results in the build up of these molecules inside lysosomes.[1] It is inherited from a persons parents in an autosomal recessive manner.[1] It is a type of mucopolysaccharidoses and a type of lysosomal storage disorder.[1][3] Diagnosis is by detecting mucopolysaccharides in the urine, blood enzyme activity, and genetic testing.[3]

Treatment is supportive care.[3] A number of measures are being studied including gene therapy, stem cell therapy, and enzyme replacement therapy.[3] Life expectancy is around 15 to 20 years old.[3] MPS III affects about 1 in 70,000 newborns.[1] The disease was first described in 1963 by Sylvester Sanfilippo.[4]

Signs and symptoms

The disease manifests in young children. Symptoms usually begin to appear between two and six years of age.[5] Affected infants appear normal, although some mild facial dysmorphism may be noticeable. Of all of the MPS diseases, Sanfilippo syndrome produces the fewest physical abnormalities. 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.[6] Acquisition of speech is often slow and incomplete.

The disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructiveness, aggressive behavior, pica, difficulties with toilet training, and sleep disturbance. As affected children initially have normal muscle strength and mobility, the behavioral disturbances may be 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 Type III tend to have mild skeletal abnormalities; osteonecrosis of the femoral head may be present in patients with the severe form. Optic nerve atrophy, deafness, and otitis can be seen in moderate to severe individuals. Other characteristics include coarse facial features, thick lips, synophrys, and stiff joints.

It is difficult to distinguish differences among the four types based on symptoms. However, type A is usually the most severe, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival.[7] The median age of death with type A is 15.4 ± 4.1 years.[8]

It is important 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 type 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 type III. Some children with MPS type III may have a blood-clotting problem during and after surgery.[5]

Genetics

Mutations in four different genes can lead to Sanfilippo syndrome. This disorder is inherited in an autosomal recessive pattern. People with two working copies of the gene are unaffected. People with one working copy are genetic carriers of Sanfilippo syndrome. They have no symptoms but may pass down the defective gene to their children. People with two defective copies will suffer from Sanfilippo syndrome.[9]

Genetics of MPS-III
TypeGeneEnzymeChromosomal regionNumber of known mutations causing this type
Type A SGSHheparan N-sulfatase[9]17q25.3137
Type B NAGLUAlpha-N-acetylglucosaminidase[9]17q21.2152
Type C HGSNATacetyl-CoA:alpha-glucosaminide N-acetyltransferase[9]8p11.2164
Type D GNSN-acetylglucosamine-6-sulfatase[9]12q14.323

Mechanism

Structure of heparan sulfate, one of the molecules that builds up in the tissues of people with Sanfilippo syndrome

Glycosaminoglycans (GAGs) are chains of sugar molecules. They are found in the extracellular matrix and the cell membrane, or stored in the secretory granules. GAGs are stored in the cell lysosome, and are degraded by enzymes such as glycosidases, sulfatases, and acetyltransferases. Deficiency in these enzymes lead to the four subtypes of MPS III.[7]

Diagnosis

Sanfilippo syndrome Types 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.

A urinalysis can show elevated levels of heparan sulfate in the urine.[9] All four types of Sanfilippo syndrome show increased levels of GAGs in the urine; however, this is less true of Sanfilippo syndrome than other MPS disorders. Additionally, urinary GAG levels are higher in infants and toddlers than in older children. In order to avoid a false negative urine test due to dilution, it is important that a urine sample be taken first thing in the morning.

The diagnosis may be confirmed by enzyme assay of skin fibroblasts and white blood cells. The enzyme assay is considered to be the most credible diagnostic tool because it detects whether or not the enzymes that are normally present in the cellular pathway that is responsible for breaking down heparan sulfate are present or not, thereby providing a definitive answer. This test is also ideal for younger patients in which collecting a viable urine sample is difficult or impossible. Another diagnostic tool can be gene sequencing. However, if the genetic mutation they carry has never been seen or recorded, the patient would receive a false negative.

Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis.[10]

Treatments

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. The French company Lysogene is conducting a Phase II/III clinical trial of a gene therapy based treatment.[11][12] 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 accumulation of GAGs.[13] In vitro, animal studies and clinical experiments suggest that the symptoms of the disease may be alleviated by an adequate dose of genistein.[14] Despite its reported beneficial properties, genistein also has toxic side effects.[15]

Caregiver impact

Caregivers face challenges because of the disease's complex nature. There is little understanding among clinicians of the family experience of caring for patients with Sanfilippo and how a caregiver's experiences change and evolve as patients age. The burden and impact on caregivers' quality of life is poorly defined and best-practice guidance for clinicians is lacking.[16]

Guidance to help clinicians understand the challenges caregivers face was published in 2019 in the Orphanet Journal of Rare Diseases.[16] Recommendations include: "Providing care for patients with Sanfilippo B impinges on all aspects of family life, evolving as the patient ages and the disease progresses. Important factors contributing toward caregiver burden include sleep disturbances, impulsive and hyperactive behavior, and communication difficulties ... Caregiver burden remained high throughout the life of the patient and, coupled with the physical burden of daily care, had a cumulative impact that generated significant psychological stress."[16] Additionally, the authors call for changing the narrative associated with Sanfilippo: "The panel agreed that the perceived aggressive behavior of the child may be better described as 'physical impulsiveness' and is often misunderstood by the general public. Importantly, the lack of intentionality of the child’s behavior is recognized and shared by parents and panel members ... Parents may seek to protect their child from public scrutiny and avoid situations that many engender criticism of their parenting skills."[16]

Prognosis

The median life expectancy varies depending on the subtype. In Sanfilippo syndrome type A, the mean age at death (± standard deviation) was 15.22 ± 4.22 years. For Type B, it was 18.91 ± 7.33 years, and for Type C it was 23.43 ± 9.47 years. The mean life expectancy for Type A has increased since the 1970s.[17]

Epidemiology

Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland,[18] 1 per 66,000 in Australia,[19] and 1 per 50,000 in the Netherlands.[20]

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

TypeApproximate incidenceProportion of casesAge of onset
A 1 in 100,000[19]60%1.5–4
B 1 in 200,000[19]30%1–4
C 1 in 1,500,000[19]4%3–7
D 1 in 1,000,000[19]6%2–6

History

The condition is named after Sylvester Sanfilippo, the pediatrician who first described the disease in 1963.[5][10][21]

Society and culture

The community have listed November 16 as World Sanfilippo Awareness Day.[22][23] This was done as an effort to spread awareness and to honor people living with the condition, aswell as those who have died. It also honors the families of the children with Sanfilippo syndrome. 2019, was the first year it was observed.

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Mucopolysaccharidosis type III: MedlinePlus Genetics". medlineplus.gov. Archived from the original on 17 May 2022. Retrieved 25 July 2022.
  2. ↑ "Mucopolysaccharidoses Fact Sheet | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Archived from the original on 4 June 2022. Retrieved 25 July 2022.
  3. 1 2 3 4 5 6 7 8 9 Sencen, Lisa. "Mucopolysaccharidosis Type III". NORD (National Organization for Rare Disorders). Archived from the original on 4 May 2022. Retrieved 25 July 2022.
  4. ↑ Boelens, Jaap Jan; Wynn, Robert (10 October 2013). Stem Cell Therapy in Lysosomal Storage Diseases. Springer Science & Business Media. p. 44. ISBN 978-1-4614-8357-1. Archived from the original on 2 August 2022. Retrieved 25 July 2022.
  5. 1 2 3 "A Guide to Understanding MPS III" (PDF). web.archive.org. Archived from the original (PDF) on 8 July 2011. Retrieved 13 March 2019.
  6. ↑ 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". Inherit Metab Dis. 10.1007/s10545-010-9199-y (6): 759–767. doi:10.1007/s10545-010-9199-y. PMC 2992652. PMID 20852935.
  7. 1 2 Andrade, F.; Aldámiz-Echevarría, L.; Llarena, M.; Couce, M.L. (2015). "Sanfilippo syndrome: Overall review". Pediatrics International. 57 (3): 331–8. doi:10.1111/ped.12636. PMID 25851924. S2CID 24663642.
  8. ↑ 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): 506–516. doi:10.1089/hum.2013.238.
  9. 1 2 3 4 5 6 Edens Hurst, Anna C.; Zieve, David; Conaway, Brenda (1 May 2017). "Mucopolysaccharidosis type III". United States National Library of Medicine. Archived from the original on 27 September 2019. Retrieved 20 June 2019.
  10. 1 2 Defendi, Germaine L. (23 May 2018). "Sanfilippo Syndrome (Mucopolysaccharidosis Type III)". Medscape. Archived from the original on 5 October 2008. Retrieved 20 June 2019.
  11. ↑ Koberstein, Wayne (November 7, 2018). "Lysogene: Mother of Invention". Life Science Leader. United States: VertMarkets. Archived from the original on August 5, 2021. Retrieved June 10, 2022.
  12. ↑ Intracerebral Gene Therapy for Sanfilippo Type A Syndrome Archived 2012-03-18 at the Wayback Machine on clinicaltrials.gov
  13. ↑ "Archived copy". Archived from the original on 2013-06-21. Retrieved 2014-01-07.{{cite web}}: CS1 maint: archived copy as title (link)
  14. ↑ 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.
  15. ↑ 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.
  16. 1 2 3 4 Shapiro, Elsa; Lourenço, Charles Marques; Mungan, Neslihan Onenli; Muschol, Nicole; O’Neill, Cara; Vijayaraghavan, Suresh (8 July 2019). "Analysis of the caregiver burden associated with Sanfilippo syndrome type B: panel recommendations based on qualitative and quantitative data". Orphanet Journal of Rare Diseases. 14 (1): 168. doi:10.1186/s13023-019-1150-1. ISSN 1750-1172. PMC 6615275. PMID 31287005. Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License Archived 2017-10-16 at the Wayback Machine.
  17. ↑ Lavery, Christine; Hendriksz, Chris J.; Jones, Simon A. (23 Oct 2017). "Mortality in patients with Sanfilippo syndrome". Orphanet Journal of Rare Diseases. 12 (1): 168. doi:10.1186/s13023-017-0717-y. PMC 5654004. PMID 29061114.
  18. ↑ Nelson J (December 1997). "Incidence of the mucopolysaccharidoses in Northern Ireland". Hum. Genet. 101 (3): 355–8. doi:10.1007/s004390050641. PMID 9439667. S2CID 23099247.
  19. 1 2 3 4 5 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ [Awareness Days - International Calendar] https://www.awarenessdays.com/awareness-days-calendar/world-sanfilippo-awareness-day-2019/ Archived 2020-10-25 at the Wayback Machine
  23. ↑ [World Sanfilippo Awareness Day] https://curesanfilippofoundation.org/worldsanfilippoawarenessday/ Archived 2022-01-25 at the Wayback Machine
Classification
External resources
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.