Can serial cerebral MRIs predict the neuronopathic phenotype of MPS II?

Audrey A.M. Vollebregt, Berendine J. Ebbink, Dimitris Rizopoulos, Maarten H. Lequin, Femke K. Aarsen, Elsa G. Shapiro, Ans T. van der Ploeg, Johanna M.P. van den Hout*

*Corresponding author for this work

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Objective: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients. Methods: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores. Results: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White-matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = −.90 for atrophy and −.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow-Robin spaces (VRS) on MRI were minimal. Conclusion: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy-scores were higher in young neuronopathic patients than in non-neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white-matter abnormalities.

Original languageEnglish
Pages (from-to)751-762
Number of pages12
JournalJournal of Inherited Metabolic Disease
Issue number3
Early online date16 Dec 2020
Publication statusPublished - May 2021

Bibliographical note

Funding Information:
We thank all Dutch MPS II patients and their families for their cooperation, Dr. E. Oussoren for her structural clinical follow‐up of the patients, Wilma Mouthaan for her planning of neuropsychological testing, David Alexander for critically reading the manuscript, and Priya Doerga for providing reference MRIs for training purposes. Research on MPS at Erasmus MC is financially supported by the European Community's Seventh Framework Programme (FP7/2007‐2013)—MeuSIX [304999] and by the Stichting Zeldzame Ziekten Fonds/WE Foundation, grant number 1415151.

Funding Information:
FP7 Health, Grant/Award Number: FP7/2007‐2013; MeuSIX, Grant/Award Number: 304999; Stichting Zeldzame Ziekten Fonds, Grant/Award Number: 1415151; European Community's Seventh Framework Programme Funding information

Publisher Copyright:
© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.


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