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

TY - JOUR

T1 - An observational, prospective, multicenter, natural history study of patients with mucopolysaccharidosis type IIIA

AU - Wijburg, Frits A

AU - Aiach, Karen

AU - Chakrapani, Anupam

AU - Eisengart, Julie B

AU - Giugliani, Roberto

AU - Héron, Bénédicte

AU - Muschol, Nicole

AU - O'Neill, Cara

AU - Olivier, Sophie

AU - Parker, Samantha

N1 - Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2022/2

Y1 - 2022/2

N2 - 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.

AB - 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.

KW - Child

KW - Child, Preschool

KW - Cognition

KW - Cognitive Dysfunction

KW - Disease Progression

KW - Female

KW - Humans

KW - Infant

KW - Male

KW - Mucopolysaccharidosis III/diagnosis

KW - Prospective Studies

U2 - 10.1016/j.ymgme.2021.12.002

DO - 10.1016/j.ymgme.2021.12.002

M3 - SCORING: Journal article

C2 - 34991944

VL - 135

SP - 133

EP - 142

JO - MOL GENET METAB

JF - MOL GENET METAB

SN - 1096-7192

IS - 2

ER -