We have chronicled the long-term outcomes, in system-by-system fashion, for a pair of siblings who began ERT for neuronopathic Hunter syndrome at different ages, because the diagnosis from clinical disease in the elder 3.7-year-old brother prompted diagnosis in the 12-month-old brother, who was minimally symptomatic. After nearly a decade of therapy, there were more severe and life-limiting disease manifestations for the elder-treated sibling (Sibling-O) in terms of skeletal/joint disease (with related limitations to mobility and basic dental care), and neurocognitive and neurobehavioral function. These differences in disease progression were felt by the parents to have a profound effect on the boys’ quality of life, creating disparate experiences for the two boys, tied to the lag to starting ERT. The younger-treated brother, Sibling-Y, has “a better chance of enjoying life” due to his ability to engage in many classic childhood diversions such as biking, swimming, playing with puzzles, and understanding movies and stories, and to complete many tasks of daily living without the need for full hands-on adult assistance. By contrast, the elder-treated brother, Sibling-O, experiences disease-related barriers to all of these diversions as well as basic tasks of daily living due to his severely limited mobility and comprehension.
Findings of fewer and less severe disease manifestations in Sibling-Y align with a recent report that used statistical models to assess and to predict outcomes of ERT in patients from the Hunter Outcome Survey patient registry (NCT03292887); specifically, Muenzer and colleagues [23] found that predicted outcomes after 5-8 years of ERT were more favorable across all clinical parameters for patients who began ERT before age 18 months. Even prior to this report, a Delphi consensus recommended presymptomatic ERT for neuronopathic MPS II [24]. Further, the present study’s outcomes are consistent with two other MPS II studies reporting superior treatment response for a presymptomatically diagnosed sibling compared to a clinically diagnosed older sibling. One such case study reported 32-month outcomes of standard ERT in a sibling pair who began treatment at 3 years old and 4 months old, respectively: The younger-treated sibling was generally spared most of the somatic complications of Hunter syndrome seen when his older brother had been his same age, including joint contractures [25]. Dysostosis multiplex was evident in both siblings but much milder in the younger; neurocognitive function was impaired in the older treated brother, and slowly sloped downward from average to just below average in the younger treated brother. A more recent sibling case study involved prenatal diagnosis of one child following the diagnosis in a 2-year-old sibling, with standard ERT beginning at 1 month old and 2 years old, respectively [26]. The younger child was transitioned to a blood-brain barrier penetrating ERT at age 1 year 11 months whereas the elder remained on standard ERT. The two-year follow-up data suggest the younger had not developed any disease symptoms and maintained an average neurocognitive developmental trajectory, whereas the elder’s course involved several systemic manifestations of disease and neurocognitive impairments. In both of these case reports, the authors called for longer-term examination of outcomes.
Skeletal and joint disease are pervasive and difficult to address manifestations of Hunter syndrome. It has been noted that improvements in these areas could be reasonably assumed to improve function and quality of life in MPS II [19], and the present findings provide data to support these assumptions. Prevention of skeletal and connective tissue involvement of a patient with MPS I treated with ERT from birth [27] raises the possibility that the superior outcomes for Sibling-Y may have been even better, were ERT started before age 13 months.
Cardiac valvulopathy was recently found to have a higher incidence over a 10-year follow-up period than in previous reports [11]. In line with those findings, Sibling-O showed mild cardiac valve thickening at 3 years 9 months, but by 10 years of age developed unmistakable valve thickening of both valves and mild aortic regurgitation. By contrast, Sibling-Y showed no valve thickening at 13 months of age but mild thickening of the aortic valve, with neither regurgitation nor stenosis of the valve, over the ensuing 10 years. The cardiac findings seen in these brothers are subtle but lend support to the importance of early treatment in delaying the onset of, and possibly attenuating, cardiac valvulopathy in MPS II. Indeed, the only therapeutic approach to fully prevent difficult-to-address pathologies, such as cardiac disease, in large animal MPS models involved therapy from birth, such as in the canine model in MPS I [28]. With first echo and treatment at 13 months of age, Sibling-Y was already ‘old’ by standards for another MPS type, MPS I, which was added to the RUSP in 2016. Thanks to NBS, most children with severe MPS I would already have begun ERT within weeks of birth, and bone marrow transplantation within the first 6-9 months of life, if not earlier. Emerging evidence supports the concept of improved outcomes with early transplant for Hurler syndrome [29].
The potential for therapy from birth would be afforded by newborn screening for MPS II, which is under consideration for addition to the RUSP. MPS I was added to the RUSP in 2016, in large part due to the body of evidence demonstrating neurocognitive benefit of early hematopoietic stem cell transplant for the neuronopathic phenotype of MPS I, Hurler syndrome [30]. The present report aligns with this concept in similar pattern for MPS II, because when each brother was around 5 years old, Sibling-Y measured too neurocognitively high, and Sibling-O measured too low, to meet eligibility criteria for enrollment in a clinical trial (NCT02055118). Neurobehavioral impairments also differed, with the elder-treated brother showing substantially more physical behaviors including forcefully pushing others and biting, which were not exhibited by the younger-treated brother. Parent explanation of these behaviors as non-aggressive but rather sensory-seeking aligns with findings from a recent report of the multiple meanings behind the neurobehavioral features of this condition [4]. Both brothers, but to a more significant degree Sibling-O, display elopement behaviors, which are a cause of premature death due to drowning, traffic accident, and injury in pediatric populations with neurodevelopmental differences such as autism [31, 32]. The present study offers unexpected data suggesting neurocognitive and neurobehavioral benefit associated with earlier initiation of ERT for the neuronopathic phenotype of MPS II. While standard intravenous ERT is not expected to cross the blood-brain barrier, this pattern of better CNS functional status with early ERTs has been seen in MPS I, with speculation that general feelings of wellness and increased physical flexibility enabled more opportunities for learning and absorbing information without the burdensome distraction of intense pain, joint disease, and/or other disease symptoms [33, 34]. Additionally, there may be other aspects of systemic ERT that address aspects of CNS disease by as yet unrecognized mechanisms.
Regardless of the potential explanations for differences in neurocognitive and neurobehavioral signs, a significant problem with MPS II is that the prediction of phenotype is challenging for a larger segment of the MPS II population than for MPS I. In MPS II, phenotype based on genotype can be particularly unreliable, except in cases of previously characterized disease-causing alleles [35]. However, a lack of neurocognitive phenotype prediction does not actually create a significant quandary with respect to initiating ERT, as the present study demonstrated benefits distinct and independent from the benefits for neurocognitive and neurobehavioral function. Specifically, the differences in skeletal/joint disease (Fig. 3) and mobility have determined the types of activities that the boys may engage in, with far greater limits for the elder-treated boy. While the neurocognitive and neurobehavioral symptoms undoubtedly have a role in reducing the boys’ independence, it is not neurodegeneration underlying Sibling-O’s need for an adaptive stroller, but rather severe multiple joint contractures and skeletal disease. Skeletal and other somatic disease manifestations are present regardless of phenotype and can be severe even in individuals with minimal neurocognitive effects [9–11], which is a meaningful point to consider when concerned about phenotype prediction.
While caregiver and family burden is incompletely characterized in MPS disorders [4, 6, 7, 36–38], the present report illustrates caregiver physical strain associated with the joint and mobility limitations experienced by Sibling-O, whose physical support needs require intensive and continual caregiver assistance throughout the day. This physical assistance for a growing child who loses mobility has been reported as a serious factor in caregiver burden in another neuronopathic MPS, Sanfilippo syndrome [37, 38]. Thus the physical complications, independent of neurocognitive or neurobehavioral outcome, may be implicated in “spillover effects” on caregiver health as the physical strain of caregiving is considerable, and there have been calls to conceptualize “health as a family affair” [39]. Information on the caregiver experience has been recognized by regulatory bodies as an important source of information on disease progression and response to treatment [40].
One limitation of the present report is the change in systemic therapies to include clinical trials of ERTs during the retrospective study period. Unchanged treatment with only FDA-approved therapy may have afforded a purer analysis of disease change over time, and could reduce doubt that some of Sibling-Y’s benefit was attributable to novel therapy rather than early intervention. However, benefit of pre-symptomatic treatment was already evident before enrollment in the first clinical trial, as seen by striking differences in joint disease (Fig. 3) and in neurocognitive function. With a number of novel therapies targeting CNS function currently approved outside the United States [41, 42], in trial (NCT04571970, NCT03566043, and NCT04251026), or in development, it is likely that the treatment picture for MPS II will soon be changing, but decisions about therapy-from-birth are still meaningfully and actionably informed by the current report and others [25, 26].