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MPS Reference
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MPS III: an overview

Patients with mucopolysaccharidosis (MPS) III are at elevated risk for severe morbidity and early mortality1

MPS III, also known as Sanfilippo syndrome, is caused by a deficiency of 1 of 4 enzymes—heparan N-sulfatase, α-N-acetylglucosaminidase, acetyl CoA:α-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase—which correlate with the disease’s 4 subtypes, MPS IIIA, IIIB, IIIC and IIID, respectively. The resulting intracellular accumulation of the glycosaminoglycan (GAG) heparan sulfate leads to progressive multisystemic disease, of which central nervous system degeneration is a hallmark feature.1,2

Observed presentation

  • Symptoms appear at varying ages depending on the specific enzyme deficiency and rate of disease progression1: MPS IIIA and IIIB typically appear between ages 1 and 4, while MPS IIIC and IIID typically appear by 7 years of age.1
  • A clinical pattern that includes progressive cognitive decline including speech delay, behavioural problems including aggressiveness, hyperactivity, sleep disorders and defiant behaviour, accompanied by dysmorphic features, cardiomegaly, epilepsy, and/or orthopaedic malformations should prompt testing for MPS III.1
  • Prevalence:
    • MPS IIIA is more prevalent in Northern Europe.1
    • MPS IIIB is more prevalent in Southern Europe1 and was also found to have increased prevalence among a Turkish population in Germany.3

Disease progression

  • Overall disease burden:
    • Patients typically experience severe central nervous system deterioration, with slow loss of skills and development of gait disorder, and eventually reach a vegetative state.1
    • Patients have severe behavioural problems between the ages of 3 and 10 years but are physically quite strong and mobile, often making it difficult for caregivers to manage these patients.2
    • This progressive, debilitating disease places high psychological and financial burdens on patients and their families.1,4
  • General disease progression:
    • Developmental delay typically occurs between the ages of 1 and 4.2
    • Affected patients between the ages of 3 and 10 have severe temper tantrums, hyperactivity, sleep disturbances, aggression and attention deficit.2
    • During the later stages of disease, patients typically have impaired mobility due to joint disease and experience seizures, which can lead to a vegetative state.1,2
  • Patients with the most rapidly progressing form of disease often die in the mid-to-late teenage years because of respiratory infection and neurological disease, while other patients may live until their late 30s.1,2,5
  • Patients with MPS III have mild musculoskeletal abnormalities and therefore require fewer surgical interventions than do patients with other MPS subtypes. Patients may undergo the following1:
    • Myringotomies
    • Hernia surgery
    • Carpal tunnel surgery

Genetic information

  • MPS III is a polygenic disease, with each subtype associated with a different gene1,2:
    • MPS IIIA is caused by mutations in the heparan N-sulfatase gene, SGSH.
    • MPS IIIB is caused by mutations in the α-N-acetylglucosaminidase gene, NAGLU.
    • MPS IIIC is caused by mutations in the acetyl CoA: α-glucosaminide N-acetyltransferase gene, HGSNAT.
    • MPS IIID is caused by mutations in the N-acetylglucosamine-6-sulfatase gene, GNS.
  • These genetic mutations lead to enzyme deficiency and accumulation of the GAG heparan sulfate.2

Key management considerations

  • There are currently no approved drugs for MPS III; however, clinical trials investigating novel therapeutic approaches are ongoing.
  • Available treatment and management recommendations:
    • Delaney KA, Rudser KR, Yund BD, Whitley CB, Haslett PA, Shapiro EG. Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome. JIMD Rep. 2014;13:129-137. doi:10.1007/8904_2013_269.
    • de Ruijter J, Broere L, Mulder MF, et al. Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). J Inherit Metab Dis. 2014;37(3):447-454. doi:10.1007/s10545-013-9658-3.
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References:  1. Andrade F, Aldámiz-Echevarría L, Llarena M, Couce ML. Sanfilippo syndrome: overall review. Pediatr Int. 2015;57(3):331-338. doi:10.1111/ped.12636.  2. Yogalingam G, Hopwood JJ. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: diagnostic, clinical, and biological implications. Hum Mutat. 2001;18(4):264-281. doi:10.1002/humu.1189.  3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28(6):1011-1017. doi:10.1007/s10545-005-0112-z.  4. Grant S, Cross E, Wraith JE, et al. Parental social support, coping strategies, resilience factors, stress, anxiety and depression levels in parents of children with MPS III (Sanfilippo syndrome) or children with intellectual disabilities (ID). J Inherit Metab Dis. 2013;36(2):281-291. doi:10.1007/s10545-012-9558-y.  5. Tomatsu S, Montaño AM, Oikawa H, et al. Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment: a special review. Curr Pharm Biotechnol. 2011;12(6):931-945. doi:1389-2010/11.  6. Online Mendelian Inheritance in Man, OMIM. Baltimore, MD: Johns Hopkins University Press. http://www.ncbi.nlm.nih.gov/omim. Updated December 20, 2015. Accessed December 21, 2015.