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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-sulphatase, α-N-acetylglucosaminidase, acetyl CoA:α-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulphatase—which correlate with the disease’s 4 subtypes, MPS IIIA, IIIB, IIIC, and IIID, respectively. The resulting intracellular accumulation of the glycosaminoglycan (GAG) heparan sulphate 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 age1
  • A clinical pattern that includes progressive cognitive decline including speech delay, behavioral problems including aggressiveness, hyperactivity, sleep disorders, and defiant behavior, accompanied by dysmorphic features, cardiomegaly, epilepsy, and/or orthopedic malformations should prompt testing for MPS III1
  • Prevalence:
    • MPS IIIA is more prevalent in Northern Europe1
    • MPS IIIB is more prevalent in Southern Europe1 and was also found to have increased prevalence among a Turkish population in Germany3
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 state1
    • 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 them2
    • This progressive, debilitating disease places high psychological and financial burdens on patients and their families1,4
  • General disease progression:
    • Developmental delay typically occurs between the ages of 1 and 42
    • Affected patients between the ages of 3 and 10 have severe temper tantrums, hyperactivity, sleep disturbances, aggression, and attention deficit2
    • During the later stages of disease, patients typically have impaired mobility due to joint disease and experience seizures, which can lead to a vegetative state1,2
  • 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 30s1,2
  • Patients with MPS III have mild musculoskeletal abnormalities and therefore require fewer surgical interventions than patients with other MPS subtypes. Patients may undergo:1
    • 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-sulphatase 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-sulphatase gene, GNS
  • These genetic mutations lead to enzyme deficiency and accumulation of the GAG heparan sulphate2
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, et al. Methods of neurodevelopmental assessment in children with neurodegenerative disease: Sanfilippo syndrome. JIMD Rep. 2014;13:129–137.
    • de Ruijter J, et al. Growth in patients with mucopolysaccharidosis type III (Sanfilippo disease). J Inherit Metab Dis. 2014;37(3):447–454.

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References:  1. Andrade F et al. Sanfilippo syndrome: overall review. Pediatr Int 2015;57(3):331–338.   2. Yogalingam G et al. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: diagnostic, clinical, and biological implications. Hum Mutat 2001;18(4):264–281.   3. Baehner F et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28(6):1011–1017.   4. Grant S 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.