Natural History Study of Participants With Sanfilippo Syndrome Type IIIC

This is a multi-center, natural history study of subjects with Sanfilippo syndrome type C or MPS IIIC. This study will combine a retrospective review of medical records and an ongoing collection of clinical data on an observational basis. Real-world data will be collected at home using a recording device.

Participants will be asked to attend clinic visits in person on a yearly basis. In clinic visits will include neurocognitive, developmental, behavioral, biochemical, imaging measures as well as retrospective medical record analysis.

At 6-month intervals between clinic visits, participants will be contacted remotely for some safety assessments (e.g., collecting information about concomitant medications, concurrent illnesses, and procedure-related adverse events \[AEs\] and serious AEs \[SAEs\] since last clinic visit).

At 6-month intervals, caregivers will complete questionnaires and record home video assessments using a dedicated, compliant study application (app) called C-RARE (Recording Application for Real-World Evidence). The C-RARE app consists of 9 tasks of Activities of Daily Living and socialization as well as three parent reported Sanfilippo specific questionnaires.

The objectives of this study are:

* To enhance the understanding of the natural history and progression of MPS IIIC syndrome on behavior, cognitive abilities, mobility, vision, hearing, speech, and expressive and receptive language
* To define and categorize clinical endpoints that may be used in future clinical trials

Primary outcomes

• Change From Baseline in Development Quotient (DQ) Using Bayley Scales of Infant Development Assessment Fourth Edition [Baseline, 12 months and 24 months]: The Bayley Scales of Infant and Toddler Development, 4th edition (Bayley-4) is a standardized developmental assessment that provides raw scores for 5 subtests (cognitive, expressive communication, receptive communication, fine motor, gross motor) and standard score norms converted to percentiles for 3 scales (cognition, communication, motor). The Bayley-4 raw scores range from 0-162 for the cognitive subtest, 0-84 for the receptive communication subtest, 0-74 for the expressive communication subtest, 0-92 for the fine motor subtest, and 0-116 for the gross motor subtest; a higher score denotes a better outcome. The Bayley-4 standard score norms are converted to percentiles from <0.1 to >99.9 for the cognitive, language, and motor scales; a higher percentile denotes a better outcome.
• Change From Baseline in Vineland Adaptive Behavior Scales Second Edition (VABS-II) Development Quotient (DQ) Score [Baseline, 12 months and 24 months]: The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The DQ is a means to express a neurodevelopmental/cognitive delay. The DQ was computed as a ratio and expressed as a percentage using the age-equivalent score divided by the age at testing (\[age-equivalent score/chronological age\] × 100; range, 0, 100). The overall DQ score is calculated from the mean age-equivalent score obtained by averaging out the age-equivalent scores for the all the sub-domains except for Gross and Fine motor skills. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). A positive value indicates improvement in health and cognition.

Secondary outcomes

• Change From Baseline on the Color Trail Test Time Score [Baseline, 12 months and 24 months]: Children's Color Trail Test (CCTT) assesses sustained attention, sequencing, and other executive functions while reducing reliance on language. A shorter time to completion denotes a better outcome.
• Change From Baseline of Regional Brain Volumes [Baseline, 12 months and 24 months]: Assessed by MRI, and especially cortical grey matter volume (CGMV). The brain MRI will assess volumes of the whole brain, basal ganglia, cerebellum, cerebellar gray matter, cerebellar white matter, cerebral white matter, cortical gray matter, cortical white matter, subcortical gray matter and ventricles; corpus callosum, cortical thickness; and whole brain apparent diffusion coefficient.
• Change From Baseline on the Assessment of Behavioral Changes in Sanfilippo (ABCS) [Baseline, 6 months, 12 months, 18 months, 24 months]: There are 12 questions in the ABCS relating to behavior(s) that caregivers of children with Sanfilippo might find challenging to manage. Change from baseline will be determined by raw scores, a higher score denoting improvement in behavior.
• Change From Baseline on the Functional Abilities Descriptive Analysis of Type C- Recording Application for Real-world Evidence (C-RARE) [Baseline, 6 months, 12 months, 18 months, 24 months]: Participants functional abilities will be captured via the C- RARE app at baseline, 6 months, 12 months, 18 months, 24 months while performing tasks of Activities of Daily Living (ADLs). ADLs include: Clothing Management, Eating and Drinking, Chewing and Swallowing, Hygiene, Maintaining and Changing positions, Writing Skills, and Walking.
• Change From Baseline on the Peabody Picture Vocabulary Test, Fifth Edition [Baseline, 12 months, 24 months]: The PPVT-5 is a norm-referenced and individually administered measure of receptive vocabulary. Upon hearing a word, the child will be asked to indicate (by pointing) which picture among four options is specified.
• Change From Baseline on the Expressive Vocabulary Test Third Edition [Baseline, 12 months, 24 months]: The EVT-3 is a norm-referenced and individually administered test of expressive language.
• Change From Baseline in Speech Through Picture Description [Baseline, 12 months, 24 months]: Picture Description will be used to measure speech rate, utterance length, grammatical competence, lexical retrieval ability, and motor speech features in subjects.

Sex: All, ages: 12 Months to any

Inclusion Criteria:

Confirmed diagnosis of Sanfilippo syndrome type C disease by all of the following:

* Deficiency in heparan-alpha-glucosaminide N-acetyltransferase enzyme activity
* Has presented with signs/symptoms consistent with Sanfilippo syndrome type C, or, for individuals who have not presented with signs/symptoms of disease (eg, siblings of known patients), the determination of eligibility will be at the discretion of the Sponsor in conjunction with the site Investigator
* Genomic DNA analysis demonstrating homozygous or compound heterozygous, pathogenic and/or potentially pathogenic variants in the HGSNAT gene
* Accumulated GAG HS in urine
* Written informed consent from parent or legal guardian and assent from patient, if required
* Parent/legal guardian willing to accompany the patient to all study visits
* Ability to comply with protocol requirements, in the opinion of the Investigator
* Negative urine pregnancy test at screening (nonsterile females of childbearing potential only).

Functional abilities:

* Able to take food or liquid by mouth, able to walk with or without assistance.
* Has an age equivalent on the Vineland Adaptive Behavior Scales (VABS) of ≥1 year.

Exclusion Criteria:

Patients who meet any of the following criteria will not be eligible to participate in the study:

* Have received an investigational drug within 30 days prior to the Baseline Visit
* Concomitant illness or medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the patient's ability to comply with protocol requirements, the patient's well-being or safety, or the interpretability of the patient's clinical data
* The presence of significant non-MPS IIIC-related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study

• Nathalie Guffon, MD, Principal investigator, Hospices Civils de Lyon