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Sanfilippo syndrome

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Sanfilippo Syndrome (MPS III)
Other namesMucopolysaccharidosis III; MPS III
12-year-old girl with Sanfilippo Syndrome Type A
Pronunciation
  • /ˌsanfɪˈliːpəʊz/
SpecialtyMedical genetics Edit this on Wikidata
SymptomsProgressive intellectual disability; hyperactivity; dementia; loss of mobility
Usual onsetBirth; symptoms usually become apparent between ages 1-4
DurationLifelong
TypesSanfilippo Syndrome Types A, B, C, and D
CausesInherited enzyme deficiency
Diagnostic methodMPS urine screen (initial test), confirmed by blood test
PrognosisLifespan is reduced; most patients survive until the early teenage years, but some may reach their 30s
Frequency1 in 70,000[1]

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare genetic disease that mainly affects the brain and spinal cord. It is caused by a problem with how the body breaks down certain large sugar molecules called glycosaminoglycans (also known as GAGs or mucopolysaccharides). In people with this condition, these sugar molecules build up in the cell's lysosomes, which act like the cell's recycling centers. The buildup of GAGs leads to damage and problems in the central nervous system.[2]

Children with Sanfilippo syndrome do not usually show any problems at birth. As they grow, they may begin having trouble learning new things and might lose previously learned skills. As the disease progresses, they may develop seizures and movement disorders. Most people with Sanfilippo syndrome live into adolescence or early adulthood.[3]

Signs and symptoms

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The age of onset can vary greatly between patients with different subtypes and within the same subtype. Typical disease usually manifests between 1 and 4 years of age.[4] 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, symptoms may arise during the early years of development, from the age of one to three.[5] Patients usually present with delayed cognitive 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.

Between the ages of three to five, the disease progresses to increasing behavioral disturbance including temper tantrums, hyperactivity, destructive behavior, 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.[7] People with this disorder may stay in this phase for five to ten year.[5] After that, their behavior returns to normal.

In the final phase of the illness, children become increasingly immobile and unresponsive, often require wheelchairs, and develop swallowing difficulties and seizures. Patients with Sanfilippo Syndrome tend to regress to an unresponsive or vegetative state until they pass away, which can occur as early as the anywhere early teen years to their seventies.[5] The life-span of a severely affected patient does not usually extend beyond late teens to early twenties.[8] However, patients with less severe phenotypes of the disease have varied life spans, some cases surviving into their seventies.[7]

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 clinically distinguish differences among the four types of Sanfilippo syndrome. However, type A is usually the most severe subtype, characterized by earliest onset, rapid clinical progression with severe symptoms, and short survival.[9] The median age of death for children afflicted with type A is 15.4 years, ±4.1 years.[10]

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.[4]

Genetics

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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.[11]

Genetics of MPS-III
Sanfilippo syndrome type Gene Enzyme Chromosomal region Number of known mutations causing this type
Type A SGSH heparan N-sulfatase[11] 17q25.3 155[12]
Type B NAGLU Alpha-N-acetylglucosaminidase[11] 17q21.2 229[12]
Type C HGSNAT acetyl-CoA:alpha-glucosaminide N-acetyltransferase[11] 8p11.21 77[12]
Type D GNS N-acetylglucosamine-6-sulfatase[11] 12q14.3 25[12]

Mechanism

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Symptoms due to Sanfilippo Syndrome arise because of incomplete lysosomal degradation of the glycosaminoglycan (GAG), heparan sulfate.[5] GAGs are chains of sugar molecules found in the extracellular matrix and the cell membrane, or stored in the secretory granules (which are small particles). They are degraded by enzymes such as glycosidases, sulfases, and acetyltransferases. Deficiency in these enzymes lead to the four subtypes of MPS III, which causes a buildup of GAGs.[9][13] This is because a buildup of GAG tends to occur in the blood, brain, spinal cord, and other connective tissue to cause local cell damage to have the neurological symptoms present in Sanfilippo syndrome.[14]

Diagnosis

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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. Diagnosing individuals with Sanfilippo syndrome can be challenging because of the rarity of the disease and variability of the presentation in early symptoms. Additionally, screening for Sanfilippo syndrome is not a routine procedure, which can also delay a proper diagnosis to have the best possible management.[15] Thus, there are 2 main ways that can be used to confirm if an individual has Sanfilippo syndrome: a urinalysis and genetic testing.[15]

A urinalysis can show elevated levels of heparan sulfate in the urine.[11] All four types of Sanfilippo syndrome show increased levels of GAGs in the urine, so there is no distinction between the Sanfilippo syndrome subtypes based on a urinalysis alone. 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, as well as gene sequencing. Through gene sequencing, known genetic defects can be detected in order to identify the disease.[15] Aside from confirming diagnosis, genetic testing is also recommended to determine carriers and to understand development of the disease.[7]

There are various stages in a child's life in which they can be diagnosed with Sanfilippo syndrome. Diagnosing a child prior to presentation of symptoms is integral for experimental treatments to be beneficial.[16] Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis.[17] Newborn diagnosis is also a possibility; however no country has mandated testing for this specific disease. Testing for newborns includes examining their blood to locate the mutation.[16]

Treatment

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While treatment remains largely supportive, research advancements are being made in the fields of pharmacology, stem cell, and genetics to address the disease.[18][19]

The behavioral disturbances of MPS-III respond poorly to medication, as each individual may respond differently to the medications that are intended to treat the individual's mental state.[15] 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.[15]

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.[20][21] 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.

Several support and research groups have been established to speed the development of new treatments for Sanfilippo syndrome.[22][23][24][25][26]

Prognosis

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According to a study of patients with Sanfilippo syndrome, 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.[27]

Epidemiology

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Incidence of Sanfilippo syndrome varies geographically, with approximately 1 case per 280,000 live births in Northern Ireland,[28] 1 per 66,000 in Australia,[29] and 1 per 50,000 in the Netherlands.[30] Globally, there are an estimated 12,000 to 19,000 individuals living with types A, B, and C.[31]

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[29] 60% 1.5-4
B 1 in 200,000[29] 30% 1–4
C 1 in 1,500,000[29] 4% 3–7
D 1 in 1,000,000[29] 6% 2–6

History

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The condition is named after Sylvester Sanfilippo, the pediatrician who first described the disease in 1963.[4][17][32]

Caregiver impact

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Caregivers for children with Sanfilippo syndrome face a unique set of 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.[8]

A best-practice guidance to help clinicians understand the challenges caregivers face was published July 2019 in the Orphanet Journal of Rare Diseases by a group of international clinical advisors with expertise in the care of pediatric patients with Sanfilippo, lysosomal storage disorders, and life as a caregiver to a child with Sanfilippo.[8]

The group reviewed key aspects of caregiver burden associated with Sanfilippo B by identifying and quantifying the nature and impact of the disease on patients and caregivers. Recommendations were based on findings from qualitative and quantitative research.[8]

The article's authors reported that: "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."[8]

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."[8]

See also

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References

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  1. ^ "Mucopolysaccharidoses Fact Sheet". National Institute of Neurological Disorders and Stroke. 15 Nov 2017. Retrieved 25 May 2018.
  2. ^ "Mucopolysaccharidosis Type III". europepmc.org. Europe PMC. 2019. PMID 31536183. Retrieved 2024-07-26.
  3. ^ "Mucopolysaccharidosis type III". Genetics Home Reference. March 2017. Retrieved 22 July 2018.
  4. ^ a b c "A Guide to Understanding MPS III" (PDF). web.archive.org. Archived from the original (PDF) on 8 July 2011. Retrieved 13 March 2019.
  5. ^ a b c d Fedele AO (2015-11-25). "Sanfilippo syndrome: causes, consequences, and treatments". The Application of Clinical Genetics. 8: 269–281. doi:10.2147/TACG.S57672. PMC 4664539. PMID 26648750.
  6. ^ Valstar MJ, Bruggenwirth HT, Olmer R, Wevers RA, Verheijen FW, Poorthuis BJ, et al. (December 2010). "Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype". Journal of Inherited Metabolic Disease. 33 (6): 759–767. doi:10.1007/s10545-010-9199-y. PMC 2992652. PMID 20852935.
  7. ^ a b c Muschol N, Giugliani R, Jones SA, Muenzer J, Smith NJ, Whitley CB, et al. (October 2022). "Sanfilippo syndrome: consensus guidelines for clinical care". Orphanet Journal of Rare Diseases. 17 (1): 391. doi:10.1186/s13023-022-02484-6. PMC 9612603. PMID 36303195.
  8. ^ a b c d e f Shapiro E, Lourenço CM, Mungan NO, Muschol N, O'Neill C, Vijayaraghavan S (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. PMC 6615275. PMID 31287005. Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  9. ^ a b Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML (June 2015). "Sanfilippo syndrome: Overall review". Pediatrics International. 57 (3): 331–338. doi:10.1111/ped.12636. PMID 25851924.
  10. ^ Tardieu M, Zérah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, et al. (June 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. PMID 24524415.
  11. ^ a b c d e f Edens Hurst AC, Zieve D, Conaway B (1 May 2017). "Mucopolysaccharidosis type III". United States National Library of Medicine. Retrieved 20 June 2019.
  12. ^ a b c d Alyazidi AS, Muthaffar OY, Baaishrah LS, Shawli MK, Jambi AT, Aljezani MA, et al. (April 2024). "Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review". Cureus. 16 (4): e58023. doi:10.7759/cureus.58023. PMC 11087936. PMID 38738088.
  13. ^ Zhou J, Lin J, Leung WT, Wang L (February 2020). "A basic understanding of mucopolysaccharidosis: Incidence, clinical features, diagnosis, and management". Intractable & Rare Diseases Research. 9 (1): 1–9. doi:10.5582/irdr.2020.01011. PMC 7062595. PMID 32201668.
  14. ^ Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, et al. (September 2021). "Mucopolysaccharidosis III: Molecular basis and treatment". Pediatric Endocrinology, Diabetes, and Metabolism. 27 (3): 201–208. doi:10.5114/pedm.2021.109270. PMC 10228206. PMID 34743503.
  15. ^ a b c d e Cyske Z, Anikiej-Wiczenbach P, Wisniewska K, Gaffke L, Pierzynowska K, Mański A, et al. (2022-09-19). "Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach". Journal of Multidisciplinary Healthcare. 15: 2097–2110. doi:10.2147/JMDH.S362994. PMC 9505362. PMID 36158637.
  16. ^ a b Winner LK, Rogers ML, Snel MF, Hemsley KM (August 2023). "Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia". Journal of Neurochemistry. 166 (3): 481–496. doi:10.1111/jnc.15891. PMID 37357981.
  17. ^ a b Defendi GL (23 May 2018). "Sanfilippo Syndrome (Mucopolysaccharidosis Type III)". Medscape. Retrieved 20 June 2019.
  18. ^ Spahiu L, Behluli E, Peterlin B, Nefic H, Hadziselimovic R, Liehr T, et al. (2021). "Mucopolysaccharidosis III: Molecular basis and treatment". Pediatric Endocrinology, Diabetes, and Metabolism. 27 (3): 201–208. doi:10.5114/pedm.2021.109270. PMC 10228206. PMID 34743503.
  19. ^ Seker Yilmaz B, Davison J, Jones SA, Baruteau J (January 2021). "Novel therapies for mucopolysaccharidosis type III". Journal of Inherited Metabolic Disease. 44 (1): 129–147. doi:10.1002/jimd.12316. PMC 8436764. PMID 32944950.
  20. ^ Koberstein W (November 7, 2018). "Lysogene: Mother of Invention". Life Science Leader. United States: VertMarkets.
  21. ^ Intracerebral Gene Therapy for Sanfilippo Type A Syndrome on clinicaltrials.gov
  22. ^ Cure Sanfilippo Foundation, funding research to accelerate discovery of a cure to Sanfilippo Syndrome
  23. ^ Jonah's Just Begun - Foundation to Cure Sanfilippo, Inc.
  24. ^ Phoenix Nest, Inc., a biotech company seeking treatments and cures for Sanfilippo Syndrome
  25. ^ Phunk Phenomenon HipHop For Hope, a dance crew in Boston raising awareness for Sanfilippo Syndrome
  26. ^ Team Sanfilippo Foundation, a medical research foundation created by parents of children with Sanfilippo Syndrome
  27. ^ Lavery C, Hendriksz CJ, Jones SA (October 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.
  28. ^ Nelson J (December 1997). "Incidence of the mucopolysaccharidoses in Northern Ireland". Human Genetics. 101 (3): 355–358. doi:10.1007/s004390050641. PMID 9439667.
  29. ^ a b c d e Meikle PJ, Hopwood JJ, Clague AE, Carey WF (January 1999). "Prevalence of lysosomal storage disorders". Jama. 281 (3): 249–254. doi:10.1001/jama.281.3.249. PMID 9918480.
  30. ^ Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, et al. (1999). "The frequency of lysosomal storage diseases in The Netherlands". Human Genetics. 105 (1–2): 151–156. doi:10.1007/s004390051078. PMID 10480370.
  31. ^ Kong W, Wu S, Zhang J, Lu C, Ding Y, Meng Y (October 2021). "Global epidemiology of mucopolysaccharidosis type III (Sanfilippo syndrome): an updated systematic review and meta-analysis". Journal of Pediatric Endocrinology & Metabolism. 34 (10): 1225–1235. doi:10.1515/jpem-2020-0742. PMID 34271605.
  32. ^ Sanfilippo SJ, Podosin R, Langer L, Good RA (October 1963). "Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type)". The Journal of Pediatrics. 63 (4): 837–838.
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