A Prospective Natural History Study of Mucopolysaccharidosis Type IIIA

doi:10.1016/j.jpeds.2015.11.079

The Journal of Pediatrics

Volume 170, March 2016, Pages 278-287.e4

https://doi.org/10.1016/j.jpeds.2015.11.079 Get rights and content

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Objectives

To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials.

Study design

Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured.

Results

Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time.

Conclusion

Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy.

Trial registration

ClinicalTrials.gov: NCT01047306.

AEq

Age-equivalent score

BSID-III

Bayley Scales of Infant and Toddler Development, Third Edition

CSF

Cerebrospinal fluid

Developmental quotient

FPSS

Four-Point Scoring System

GAG

Glycosaminoglycan

Heparan sulfate

KABC-II

Kaufman Assessment Battery for Children, Second Edition

MPS IH

Mucopolysaccharidosis type IH

MPS IIIA

Mucopolysaccharidosis type IIIA

MRI

Magnetic resonance imaging

p-tau

phospho-tau

Rapidly progressing

SGSH

N-sulphoglucosamine sulphohydrolase

Slowly progressing

T-tau

Total tau

VABS-II

Vineland Adaptive Behavior Scales, Second Edition

Cited by (0)

: Supported by Shire, Lexington, MA, and the National Center for Advancing Translational Sciences, the National Institutes of Health (NIH), through University of Minnesota (UL1TR000114 [to K.R.]). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. E.S. received investigator-initiated grants from Shire; Longitudinal Studies of Brain Structure and Function in MPS Disorders (CON000000026631), Characterizing The Neurobehavioral Phenotype in MPS III (CON000000037827), A Phase I/II Safety, Tolerability, Ascending Dose Frequency Study of Recombinant Human Heparan N-Sulfate Intrathecal Administration via an Intrathecal Drug Delivery Device in Patients with Sanfilippo Syndrome Type A (SAN-055) (CON000000027966), Observing the Disease Course in the Natural History of Sanfilippo Syndrome Type A: A follow-up of SAN-053 participants (CON000000046817), and consulting fees outside of the submitted work from Shire. I.N. received investigator-initiated grants from Shire; An Open-Label Extension Study of HGT-SAN-055Evaluating Long-Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo Syndrome Type A (CON000000031061), Analysis of MRI images from Patients Enrolled in the 12-month Longitudinal, Prospective, Natural History Study of Patients with Sanfilippo Syndrome Type B (CON000000049923,) and consulting fees outside of the submitted work from Shire. K.D. received consulting fees from Shire. N.N., C.R., and P.H. were employees of Shire during the study. C.W. received an institutional trial contract for this study from Shire (CON000000021641).

^∗: Current affiliation: Vertex Pharmaceuticals, Boston, MA.

^†: Current affiliation: uniQure, Cambridge, MA.

^‡: Current affiliation: Alnylam Pharmaceuticals, Lexington, MA.