Response to: Investigating the neurobehavioral symptoms of neuronopathic Hunter syndrome.

We appreciate the opportunity to respond to the points Mr. Grant raised in his Letter to the Editor [1].

Neurobehavioral symptoms in neuronopathic Hunter syndrome are complex, difficult to manage, and incompletely understood. Our study found that some symptoms were vulnerable to misinterpretation as aggressive or defiant [2]; Mr. Grant asked how intentional aggression was distinguished from another explanation (e.g., social overture) [1]. His question highlights the critical importance of a collaborative, open-minded and trusting relationship between clinicians and/or researchers and affected families. Family perspective is crucial for understanding patient needs and functioning. To this point, our findings of misattribution were reported by caregivers, rather than solely determined by the study team (e.g., Fig. 1 legend [2]); caregivers may be the truest experts for decoding the children's behaviors.

We agree with Mr. Grant's assertion that the association between pain and neurobehavioral symptoms warrants further study [1]. Our hope is that the neurobehavioral measurement tool built from this study will quantify neurobehavioral change and clarify its relationship with somatic manifestations. At the individual level, pain is an important consideration for differentials and symptom management [3].

Mr. Grant notes that we describe the impact of neurobehavioral symptoms on parents, but not siblings [1]. We selected the term “caregiver” to be inclusive of all “care-giving” individuals, including not only parents but also other family members or non-family individuals, as has been previously summarized [4,5]. Caregivers who responded to our enrollment announcements were all parents; thus first-hand accounts of siblings were not obtainable. We agree that sibling-specific impact needs greater understanding, aligned with Mr. Grant's previous work [6], and increased attention to caregiver burden in mucopolysaccharidosis [3,[7], [8], [9]].

In summary, we believe our study and Mr. Grant's letter raise compatible issues that warrant continued investigation for this complex disorder, to optimize patient management and ultimately relieve multi-faceted, multi-individual suffering.

Disclosures

Eisengart: Research support from Lysogene, Sangamo and Shire/Takeda; consultant to Denali Therapeutics, Sangamo, Sanofi Genzyme, and Shire/Takeda; advisory boards for Amicus, bluebird bio, Orchard Therapeutics, and Sanofi Genzyme; contract work for Shapiro Neuropsychology Consulting, LLC.

King: Research support from Alexion Pharmaceuticals, Inc., Shire/Takeda, and Sanofi Genzyme, and contract work for Shapiro Neuropsychology Consulting, LLC.

Shapiro: Partner, Shapiro Neuropsychology Consulting, LLC.

Whitley: Research support from Shire/Takeda; consultant to Shire/Takeda.

Muenzer: Consultant to BioMarin, Shire/Takeda, PTC Therapeutics, Green Cross, Sanofi Genzyme, Eloxx, Regenxbio, Denali Therapeutics, Sangamo and JCR Pharmaceuticals. Serves on advisory boards for BioMarin, Sanofi Genzyme, Green Cross, JCR Pharmaceuticals and Shire/Takeda. He is principal investigator for phase 1/2 and phase 2/3 trials that investigate intrathecal ERT for patients with neuronopathic Hunter syndrome, a phase 1/2 gene editing clinical trial for adults with Hunter syndrome and a phase 1/2 intravenous ERT clinical trial for MPS IIIA.

Funding

This investigator-initiated research was supported by a grant from Shire Human Genetic Therapies Inc., Lexington, MA, a member of the Takeda group of companies through # IIR-USA-001644, and by NIH U54NS065768. Historic chart review and analysis was funded by NIH U54NS065768. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, and the National Center for Advancing Translational Sciences. This consortium is funded through a collaboration between the National Center for Advancing Translational Sciences, the National Institute of Neurological Disorders and Stroke, and the National Institute of Diabetes and Digestive and Kidney Diseases. Data curation was supported by the National Institutes of Health's National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health's National Center for Advancing Translational Sciences. Resources for convening the caregiver advisory board and sharing of data was provided by Denali Therapeutics (South San Francisco, CA). The advisory board was facilitated by the first author (JBE). Infrastructure support was provided by the National MPS Society, Project Alive, MPS Superhero Foundation, the University of Minnesota Department of Pediatrics, and the University of Minnesota's Center for Neurobehavioral Development. None of the funding sources had any role in study design; collection, analysis and interpretation of data; writing or revision of the original manuscript; the decision to submit the article for publication; nor writing or revision of the Response to Mr. Grant.