Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair

Nathan Grant; Young Bae Sohn; N Matthew Ellinwood; Ericka Okenfuss; Bryce A Mendelsohn; Leslie E Lynch; Elizabeth A Braunlin; Paul R Harmatz; Julie B Eisengart

doi:10.1016/j.ymgmr.2022.100845

Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair

Mol Genet Metab Rep. 2022 Feb 2:30:100845. doi: 10.1016/j.ymgmr.2022.100845. eCollection 2022 Mar.

Authors

Nathan Grant¹, Young Bae Sohn², N Matthew Ellinwood³, Ericka Okenfuss⁴, Bryce A Mendelsohn⁴, Leslie E Lynch⁵, Elizabeth A Braunlin¹, Paul R Harmatz⁵, Julie B Eisengart¹

Affiliations

¹ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
² Department of Medical Genetics, Ajou University Hospital, Ajou University School of Medicine, Suwon, Republic of Korea.
³ National MPS Society, Durham, NC, USA.
⁴ Kaiser Permanente, Oakland, CA, USA.
⁵ UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA.

Abstract

Hunter syndrome, or mucopolysaccharidosis (MPS) II, is a rare lysosomal disorder characterized by progressive, multi-system disease. As most symptoms cannot be reversed once established, early detection and treatment prior to the onset of clinical symptoms are critical. However, it is difficult to identify affected individuals early in disease, and therefore the long-term outcomes of initiating treatment during this optimal time period are incompletely described. We report long-term clinical outcomes of treatment when initiated prior to obvious clinical signs by comparing the courses of two siblings with neuronopathic Hunter syndrome (c.1504 T > G[p.W502G]), one who was diagnosed due to clinical disease (Sibling-O, age 3.7 years) and the other who was diagnosed before disease was evident (Sibling-Y, age 12 months), due to his older sibling's findings. The brothers began enzyme replacement therapy within a month of diagnosis. Around the age of 5 years, Sibling-O had a cognitive measurement score in the impaired range of <55 (average range 85-115), whereas Sibling-Y at this age received a score of 91. Sibling-O has never achieved toilet training and needs direct assistance with toileting, dressing, and washing, while Sibling-Y is fully toilet-trained and requires less assistance with daily activities. Both siblings have demonstrated sensory-seeking behaviors, hyperactivity, impulsivity, and sleep difficulties; however, Sibling-O demonstrates physical behaviors that his brother does not, namely biting, pushing, and frequent elopement. Since the time of diagnosis, Sibling-O has had significant joint contractures and a steady deterioration in mobility leading to the need for an adaptive stroller at age 11, while Sibling-Y at age 10.5 could hike more than 6 miles without assistance. After nearly a decade of therapy, there were more severe and life-limiting disease manifestations for Sibling-O; data from caregiver interview indicated substantial differences in Quality of Life for the child and the family, dependent on timing of ERT. The findings from this sibling pair provide evidence of superior somatic and neurocognitive outcomes associated with presymptomatic treatment of Hunter syndrome, aligned with current considerations for newborn screening.

Keywords: ABR, Auditory brainstem response; CNS, central nervous system;; DAS-II, Differential Ability Scales, Second Edition;; ERT, enzyme replacement therapy;; Early intervention; Enzyme replacement therapy; GAG, glycosaminoglycan;; HCT, hematopoietic cell transplantation;; Hunter syndrome; IDS, iduronate-2-sulphatase;; IT, intrathecal;; MPS II, mucopolysaccharidosis type II, Hunter syndrome;; MPS, mucopolysaccharidosis;; MRI, magnetic resonance imaging;; Mucopolysaccharidosis type II; NBS, newborn screening;; Newborn screening; RUSP, Recommended Uniform Screening Panel; Sibling study.