An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA

Frits A. Wijburg, Karen Aiach, Anupam Chakrapani, Julie B. Eisengart, Roberto Giugliani, Bénédicte Héron, Nicole Muschol, Cara O'Neill, Sophie Olivier, Samantha Parker

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1 Scopus citations


Mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo syndrome) is a rare genetic lysosomal storage disease characterized by early and progressive neurodegeneration resulting in a rapid decline in cognitive function affecting speech and language, adaptive behavior, and motor skills. We carried out a prospective observational study to assess the natural history of patients with MPS IIIA, using both standardized tests and patient-centric measures to determine the course of disease progression over a 2-year period. A cohort of 23 patients (7 girls, 16 boys; mean age 28–105 months at baseline) with a confirmed diagnosis of MPS IIIA were assessed and followed up at intervals of 3–6 months; cognitive function was measured using Bayley Scales of Infant and Toddler Development 3rd edition (BSID-III) to derive cognitive development quotients (DQ). Daily living, speech/language development and motor skills were measured using the Vineland Adaptive Behavior Scale (VABS-II). Sleep–wake patterns, behavior and quality-of-life questionnaires were also reported at each visit using parent/caregiver reported outcome tools. All patients had early onset severe MPS IIIA, were diagnosed before 74 months of age, and had cognitive scores below normal developmental levels at baseline. Patients less than 40 months of age at baseline were more likely to continue developing new skills over the first 6–12 months of follow-up. There was a high variability in cognitive developmental age (DA) in patients between 40 and 70 months of age; two-thirds of these patients already had profound cognitive decline, with a DA ≤10 months. The highest cognitive DA achieved in the full study cohort was 34 months. Post hoc, patients were divided into two groups based on baseline cognitive DQ (DQ ≥50 or <50). Cognitive DQ decreased linearly over time, with a decrease from baseline of 30.1 and 9.0 points in patients with cognitive DQ ≥50 at baseline and cognitive DQ <50 at baseline, respectively. Over the 2-year study, VABS-II language scores declined progressively. Motor skills, including walking, declined over time, although significantly later than cognitive decline. No clear pattern of sleep disturbance was observed, but night waking was common in younger patients. Pain scores, as measured on the quality-of-life questionnaire, increased over the study period. The findings of this study strengthen the natural history data on cognitive decline in MPS IIIA and importantly provide additional data on endpoints, validated by the patient community as important to treat, that may form the basis of a multidomain endpoint capturing the disease complexity.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalMolecular Genetics and Metabolism
Issue number2
StatePublished - Feb 2022

Bibliographical note

Funding Information:
Frits A. Wijburg has served as a consultant for Orchard Therapeutics and Lysogene. Anupam Chakrapani declares institutionally funded research from Actelion, Aegela, Biomarin, Lysogene, Malinckrodt, Sanofi, and Takeda; consulting fees, travel grants, and honoraria from Actelion, Biomarin, Lysogene, Orchard Therapeutics, Recordati, Sanofi, and Takeda. Julie B. Eisengart has received research support from Lysogene, Sangamo and Shire/Takeda; consulting fees from ArmaGen, Denali Therapeutics, JCR Pharmaceutical, Orchard Therapeutics, ReGenXBio, and Shire/Takeda; and honoraria from Amicus Therapeutics, bluebird bio, Orchard Therapeutics, ReGenXBio, Sanofi Genzyme, and Shire/Takeda. Roberto Giugliani has served as speaker, consultant, and advisory board member for Abeona Therapeutics, Amicus Therapeutics, BioMarin, Inventiva, Janssen, JCR Pharmaceuticals, Lysogene, PTC Therapeutics, ReGenXBio, Sanofi Genzyme, Sobi, Takeda, and Ultragenyx; research grants from Allievex, Amicus Therapeutics, Armagen, BioMarin, GC Pharma, JCR Pharmaceuticals, Lysogene, ReGenXBio, Sanofi Genzyme, and Takeda; and travel expenses to attend scientific meetings from Amicus Therapeutics, BioMarin, JCR Pharmaceuticals, Sanofi Genzyme, Takeda, and Ultragenyx. Bénédicte Héron has received honoraria for advisory boards from Actelion, Orchard Therapeutics, Orphazyme, and Shire/Takeda; honoraria/travel support from Actelion, BioMarin, and Shire/Takeda; and is principal investigator for Abeona, Chiesi, Lysogene, Idorsia, Mallinckrodt, and Orphazyme studies. Nicole Muschol has received consulting fees from Amicus, BioMarin, Chiesi, JCR Pharmaceuticals, Lysogene, Sanofi Genzyme, Shire/Takeda, and Sobi; grant/research support from BioMarin, Sanofi Genzyme, and Shire/Takeda; and honoraria/travel support from Actelion, Amicus Therapeutics, BioMarin, Sanofi Genzyme, and Shire/Takeda. Cara O'Neill has received consulting fees from Lysogene and JCR Pharmaceuticals. Karen Aiach, Sophie Olivier, and Samantha Parker are, or were, employees of Lysogene, at the time of writing this paper.

Publisher Copyright:
© 2021 The Authors


  • Cognitive development
  • Mucopolysaccharidosis type IIIA
  • Natural history
  • Patient-reported outcomes
  • Sanfilippo syndrome

PubMed: MeSH publication types

  • Journal Article
  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't


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