Impact of Mucopolysaccharidosis Type II in Young Children from the Caregiver’s Perspective: A Qualitative Study

Abstract

Introduction

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is a rare, progressive X-linked lysosomal storage disorder that clinically manifests in children around 2–4 years of age. It affects nearly all organ systems, and in about two-thirds of patients, follows a severe neuronopathic course marked by developmental delay and cognitive decline. This study examined caregivers’ perspectives on the most important symptoms and impacts of MPS II in young children.

Methods

Caregivers of children aged 2–5 years with MPS II in the UK or USA were interviewed about the symptoms and impacts of MPS II in their child using a concept elicitation approach. A content analysis approach was used to analyze qualitative data collected.

Results

Sixteen caregivers (n = 13 USA, n = 3 UK; mean age 34.0 years) of 16 children with MPS II participated. All 15 children for whom sociodemographic data were available were male and neuronopathic (mean age 4.2 years). All 16 caregivers reported cognitive decline in their child and disruption of family life. Other areas where MPS II burdens their children included problems with verbal communication/speech (n = 15), walking/climbing stairs (n = 15), hand movement (n = 15), hearing loss (n = 15), infection (n = 15), frustration (n = 14), interaction with non-family members (n = 14), nonverbal communication (n = 13), endurance (n = 13), stiff joints or muscles (n = 13), incontinence (n = 12), and skin issues (n = 10). Caregivers considered communication, mobility, and joint and muscle issues the “most bothersome” impacts.

Conclusion

Despite the availability of enzyme replacement therapy since 2006, MPS II substantially affects the lives of young children and their families.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-026-03643-y.

Key Summary Points

Why carry out this study?

All phenotypes of MPS II, especially those with significant neuronopathic manifestations, have a major impact on both patients and caregivers. Caregivers provide extensive daily support (e.g., approximately 11 h/day) while also navigating significant financial, social, and emotional challenges.

Previous research has utilized surveys and questionnaires but did not focus specifically on young children (when symptoms first appear) and had design limitations that restricted deeper understanding of symptoms and impacts.

What was learned from the study?

Children with mucopolysaccharidosis type II frequently experienced difficulties with walking/climbing stairs and hand movement, as well as hearing loss, incontinence, skin problems, and frustration.

Family disruption was also commonplace.

Despite enzyme replacement therapy being available since 2006, mucopolysaccharidosis type II continues to substantially affect the lives of young children and their families.

Introduction

Mucopolysaccharidosis type II (MPS II; ORPHA:580), also known as Hunter syndrome, is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase, which leads to the pathological accumulation of glycosaminoglycans and progressive disease affecting nearly all organ systems [1, 2]. MPS II is exceedingly rare, affecting 1 in 100,000 to 1 in 170,000 live births [3]. Clinical manifestations typically emerge in early childhood, around 2 to 4 years of age, and include skeletal deformities, respiratory impairment, cardiac abnormalities, hernias, organomegaly, coarse facial features, and progressive hearing loss [1]. MPS II exists along a clinical spectrum; in approximately two-thirds of patients, MPS II follows a severe, neuronopathic course with central nervous system involvement and marked by developmental delay, progressive cognitive decline, speech and language impairment, behavioral problems, and neurologic involvement, including seizures, ataxia, and gait disturbances. However, even patients with an attenuated form of the disease may have neurologic manifestations such as attention deficits or retinopathy [2–4]. Moreover, life expectancy is greatly reduced in patients with MPS II, with many dying in adolescence [5, 6]. Among the reported causes of death, respiratory failure is the most frequent, followed by cardiac arrest, and cardiorespiratory failure [7, 8]

All phenotypes of MPS II, especially those with significant neuronopathic manifestations, substantially affect the lives of patients and their caregivers. One US survey found that, on average, primary caregivers spent 11 h per day on direct care [9]. Caregivers and their families must also manage the downstream financial, social, and emotional costs of MPS II [9–11]. Because of their experience in managing and dealing with their children’s illness, caregivers are uniquely positioned to help in the development of new treatments, especially for rare diseases like MPS II, where little information may be available [12].

The current standard of care for MPS II is enzyme replacement therapy with weekly intravenous idursulfase, approved in 2006; yet there remain substantial unmet needs [13, 14]. Because idursulfase does not cross the blood–brain barrier, it cannot address the neuronopathic manifestations of the disease, and its impact on somatic symptoms is incomplete [15]. Idursulfase has been shown to moderately reduce the risk of death and extend survival [15, 16]. Τhe recent survival analysis of 1300 patients with up to 18 years of follow-up in Hunter Outcome Survey reported approximately 10 years of survival gain among treated patients compared with untreated [7]. However, life expectancy in MPS II remains markedly reduced, particularly in patients with the neuronopathic form, who often die in the second decade of life [15]. Therapy with hematopoietic stem cell transplantation could provide a permanent source of idursulfase enzyme, but it is not routinely used in MPS II as a result of concerns around safety [1]. To directly target the nervous system, intrathecal and intracerebroventricular delivery (ICV) of idursulfase and several gene therapy approaches have also been studied [13]. Two therapies have since been approved in Japan including ICV ERT and a blood–brain barrier-penetrating enzyme replacement therapy. However, these therapies are approved only in limited geographies [17–19]. Globally, there remains an unmet need for a therapy that addresses the underlying cause of the disease in both the brain and the periphery, so patients need substantial supportive care in addition to standard-of-care treatment with idursulfase [2].

Several survey- and questionnaire-based studies [9, 20–22] have examined the impacts of MPS II, but these studies have not specifically assessed impacts in young children, when neuropathic and somatic symptoms begin to manifest, and the study designs limit detection and exploration of symptoms and impacts. Here, we used a cognitive elicitation approach to interview caregivers and collect more detailed information about their perspectives on the symptoms and humanistic impact of MPS II on young children and their families.

Methods

Study Design

This was a cross-sectional, qualitative study conducted between January 7 and March 17, 2020. A qualitative concept elicitation approach was used to collect information from caregivers about the symptoms and impacts of MPS II in their young children with MPS II. The research was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study protocol and informed consent procedures were approved by Advarra Institutional Review Board (Columbia, MD, USA; Pro00040794). The study is reported according to the COREQ reporting guidelines [23]. Prior to interviews, participating caregivers provided informed consent and consent to be audio recorded.

Study Population

Caregivers of children with MPS II were recruited using a purposive sampling approach to participate in this study via patient advocacy groups in the USA and UK that work specifically with MPS II families. Participants were approached by the patient advocacy groups directly using a variety of recruitment methods (e.g., direct email/mail, flyers, website/social media posts, etc.) to invite them to participate. If caregivers were interested in participating in the study, they were directed to a study-specific telephone number and e-mail address to request a screening and eligibility assessment. Participants had to be adults (≥ 18 years of age) and be the primary guardian for a 2- to 5-year-old child (at the time of screening) with physician-confirmed MPS II. Participants had to be currently living with the child and to have lived with the child for at least 6 months. Only one caregiver could participate in the study for each child with MPS II. Participants could not be a caregiver of a child with an additional serious chronic medical condition that could confound the reporting of signs or symptoms of MPS II. The caregivers and the number of MPS II patients they care for included in the study was estimated to be sufficient to assess and achieve concept saturation of MPS II related impacts. Concept saturation was reached and no new concepts were identified after 12 caregiver interviews.

Study Data Collection

Prior to interviews, participating caregivers provided informed consent. One-on-one interviews were conducted with participants in English by telephone by a team of experienced researchers (Supplemental File 1) using a semi-structured interview guide. Only the caregiver and the interviewer were present during the interviews. To build rapport prior to the start of the interview, interviewers screened and asked participants to provide consent, during which time participants were given the opportunity to ask questions. The semi-structured interview guide was based on a targeted literature review of information on MPS II published between 2009 and 2019 and an interview of two expert clinicians. Interviews began with an introduction to the study and the study objectives, with time given for participants to ask questions. Participants were first asked open-ended questions about their child’s MPS II diagnosis and disease history experiences. They were then asked to describe the signs, symptoms, and impacts of MPS II that their child experiences, with the goal of obtaining spontaneous descriptions without prompting by interviewers. Interviews lasted approximately 60 to 90 min and, with the participants’ permission, were audio recorded. In addition, written notes were taken by the interviewers. Participants also completed and sent by mail a sociodemographic questionnaire about themselves and their child with MPS II. Participants received a prepaid card worth $150 or £115 following the interview.

Data Analysis

A content analysis approach was used to analyze qualitative data collected from the interviews. Audio data collected during the interviews were transcribed verbatim by a professional transcription service (TransPerfect, New York, NY). Transcripts were cleaned, cross-checked against the audio files for accuracy, and de-identified by removing all protected health information. A coding dictionary was developed based on the interview guide and used to code the transcripts. Themes were identified through deductive coding based on the interview guide, with new concepts added to the codebook as they emerged. Qualitative data from the interviews were analyzed using ATLAS.ti version 8.0 (ATLAS.ti Scientific Software Development GmbH, Berlin, Germany). Transcripts were coded by two experienced researchers who also interviewed participants (Supplemental File 1). Quantitative data were collected using DataFax (DF/Net Research Inc., Seattle, WA, USA).

Results

Sociodemographic Characteristics of Children with MPS II and Their Caregivers

Of 17 potential participants screened, 16 were eligible and were interviewed, of whom 13 resided in the USA and three in the UK. One potential participant was lost to follow-up and did not participate. Sociodemographic data, which were to be mailed in, were not received from one participant.

Children with MPS II

Of the 15 children for whom sociodemographic data were available, all were male and had neuronopathic MPS II (Table 1). On average, the children were 4.2 years of age (standard deviation [SD] 1.2; range 2–6), and most were white (n = 11) and in school outside of the home (n = 10). The diagnosis of MPS II occurred at an average age of 2.0 years (SD 0.7; range 0.3–3.0). Most caregivers rated the severity of their child’s MPS II as moderate or worse (n = 12). All caregivers reported that their child exhibited signs of MPS II all or most of the time (n = 13). In addition, all caregivers reported that their child had trouble with speech and communication (n = 15), and most reported difficulties with mobility (n = 14), hearing (n = 14), toileting (n = 13), behavior (n = 13), and sleep (n = 10) (Supplemental File 2).

Table 1.

Sociodemographic characteristics of children cared for by the study participants

Characteristics	Overall (N = 15a)
Age (years), mean (SD) [range]	4.2 (1.2) [2–6b]
Male, n (%)	15 (100)
Ethnicity, n (%)
Hispanic or Latino	3 (20)
Not Hispanic or Latino	10 (67)
Missing	2 (13)
Race, n (%)c
Asian	3 (20)
Black or African American	1 (7)
Native Hawaiian or other Pacific Islander	1 (7)
White	11 (73)
Schooling, n (%)
No schooling outside of home	3 (20)
Daycare or preschool program outside of home	6 (40)
Primary/elementary school	4 (27)
Otherd	2 (13)
Age when diagnosed (years), mean (SD) [range]	2.0 (0.7) [0.3–3.0]
MPS II considered neuronopathic, n (%)	15 (100)
Severity of MPS II, n (%)
Mild	3 (20)
Moderate	7 (47)
Severe	3 (20)
Very severe	2 (13)
Frequency of signs, observable behaviors, and verbalizations related to MPS II, n (%)
Some of the time	2 (13)
Most of the time	6 (40)
All of the time	7 (47)

MPS II mucopolysaccharidosis type II, SD standard deviation

^aSociodemographic data were not available for one child

^bOne child was 5 years old at screening but was 6 years old at the time of the caregiver’s interview

^cResponses are not mutually exclusive

^dHome schooling special education program pre-kindergarten (n = 1), prescribed pediatric extended care (n = 1)

Caregivers

For the 15 caregivers for whom sociodemographic data were available, the average age was 33.7 years (SD 4.3; range 23–40), and most were female (n = 13), white (n = 11), not Hispanic or Latino (n = 12), married (n = 9), and the mother or stepmother of the child (n = 13) (Table 2). Most had a university degree or had technical training (n = 12). Of the 14 caregivers who provided employment status, few (n = 3) worked full-time away from home. The others worked part-time away from home (n = 4) or only at home (n = 7).

Table 2.

Caregiver sociodemographic characteristics

Characteristic	Overall (N = 15)a
Age (years), mean (SD) [range]	33.7 (4.3) [23–40]
Female, n (%)	13 (87)
Ethnicity, n (%)
Hispanic or Latino	2 (13)
Not Hispanic or Latino	12 (80)
Missing	1 (7)
Race, n (%)b
American Indian or Alaska Native	1 (7)
Asian	3 (20)
Native Hawaiian or other Pacific Islander	1 (7)
White	11 (73)
Missing	1 (7)
Marital status, n (%)
Single	2 (13)
Single, in a relationship	1 (7)
Married	9 (60)
Divorced/separated	3 (20)
Employment status, n (%)
Work full time away from home	3 (20)
Work part time away from home	4 (27)
Work only at home (in addition to caregiving)	7 (47)
Missing	1 (7)
Education, n (%)
Secondary/high school	2 (13)
Associate degree, vocational, technical, or trade school	4 (27)
Some college (< 1 year)	1 (7)
University/college degree	6 (40)
Postgraduate degree	2 (13)
Relationship to child with MPS II, n (%)
Mother/Stepmother	13 (87)
Father/Stepfather	2 (13)
Other family members with MPS II, n (%)	2 (13)

MPS II mucopolysaccharidosis type II, SD standard deviation

^aSociodemographic data were not available for one caregiver

^bResponses are not mutually exclusive

Impacts of MPS II in Young Children as Described by Caregivers

Overall, the burdens most frequently reported by caregivers for their children with MPS II were problems with symptoms and impacts of the condition, namely, cognitive decline (n = 16); disruption of family life (n = 16); difficulties with verbal communication/speech (n = 15), walking/climbing stairs (n = 15), and hand movement (n = 15); hearing loss (n = 15); frequent infections (n = 15); feelings of frustration (n = 14); difficulties interacting with non-family members (n = 14); problems with nonverbal communication (n = 13); reduced endurance (n = 13); stiff joints or muscles (n = 13); incontinence (n = 12), and skin issues (n = 10) (Table 3). Sample quotes are provided in Table 4. No new concepts were introduced after the 12th of the 16 interviews, suggesting concept saturation (Supplemental File 3).

Table 3.

Caregiver-identified impacts of MPS II on children with MPS II

Category	Impact endorsed	n (%)
		Overall	Spontaneous	Probed
		(N = 16)	(N = 16)	(N = 16)
Neurologic
Developmental	Cognitive decline	16 (100)	13 (81)	3 (19)
Communication	Verbal communication/speech	15 (94)	15 (94)	0 (0)
	Nonverbal communication	13 (81)	12 (75)	1 (6)
	Follows directions	2 (13)	1 (6)	1 (6)
	Engaged in eye contact	1 (6)	1 (6)	0 (0)
Emotional, behavioral, and social
Emotional issues	Frustrated	14 (88)	13 (81)	1 (6)
	Medical trauma/fear	5 (31)	5 (31)	0 (0)
	Anxious	4 (25)	4 (25)	0 (0)
	Irritable	4 (25)	4 (25)	0 (0)
	Discouraged	3 (19)	3 (19)	0 (0)
	Fear	2 (13)	2 (13)	0 (0)
	Depressed	2 (13)	2 (13)	0 (0)
Behavior issues	Aggression	13 (81)	13 (81)	0 (0)
	Hyperactivity	6 (38)	5 (31)	1 (6)
	Resisting toileting	5 (31)	5 (31)	0 (0)
	Lack of fear	3 (19)	3 (19)	0 (0)
	Fixated behavior	4 (25)	4 (25)	0 (0)
	Impulsivity	3 (19)	2 (13)	1 (6)
	Resisting behavior	3 (19)	3 (19)	0 (0)
	Sensory processing issues	1 (6)	1 (6)	0 (0)
	Running away	1 (6)	1 (6)	0 (0)
	Indifference	1 (6)	1 (6)	0 (0)
	Repetitive chewing	2 (13)	2 (13)	0 (0)
	Overeating	8 (50)	0 (0)	8 (50)
	Picky eater	7 (44)	1 (6)	6 (38)
	Difficulty with certain foods	1 (6)	1 (6)	0 (0)
	No appetite	1 (6)	1 (6)	0 (0)
Social impacts	Family life (time or emotional impact)	16 (100)	0 (0)	16 (100)
	Interaction with others (not family)	14 (88)	5 (31)	9 (56)
Somatic
Mobility	Walking/stairs	15 (94)	12 (75)	3 (19)
	Hand movement	15 (94)	8 (50)	7 (44)
	Endurance	13 (81)	8 (50)	5 (31)
	Clumsy movement	2 (13)	2 (13)	0 (0)
	Inactive	1 (6)	1 (6)	0 (0)
Joint and muscle issues	Stiff joints or muscles	13 (81)	12 (75)	1 (6)
	Joint pain	7 (44)	7 (44)	0 (0)
Sleep issues	Waking at night	6 (38)	6 (38)	0 (0)
	Trouble sleeping/waking	4 (25)	3 (19)	1 (6)
	General tiredness	2 (13)	2 (13)	0 (0)
	Irregular day sleep	1 (6)	1 (6)	0 (0)
	Obstructive sleep apnea	1 (6)	1 (6)	0 (0)
General incontinence and stool quality	General incontinence	12 (75)	5 (31)	7 (44)
	Runny stool	5 (31)	4 (25)	1 (6)
	Diaper-rash pain	3 (19)	2 (13)	1 (6)
	Frequent defecation	3 (19)	3 (19)	0 (0)
	Intestinal pain	1 (6)	1 (6)	0 (0)
Respiratory problems	Airway obstruction	9 (56)	8 (50)	1 (6)
	Airway infections	6 (38)	6 (38)	0 (0)
	Loud breathing	2 (13)	1 (6)	1 (6)
Activities of daily living	Changing clothes	15 (94)	0 (0)	15 (94)
	Bathing	13 (81)	0 (0)	13 (81)
	Eating	12 (75)	0 (0)	12 (75)
	Study/school	12 (75)	1 (6)	11 (69)
Other	Hearing loss	15 (94)	8 (50)	7 (44)
	Infection	15 (94)	11 (69)	4 (25)
	Skin issues	10 (63)	0 (0)	10 (63)
	Vision problems	9 (56)	0 (0)	9 (56)

MPS II mucopolysaccharidosis type II

Table 4.

Caregiver quotations about key impacts of MPS II

Impact	Quotation
Neurologic
Cognitive decline	“Lack of understanding of things sometimes…his brain is not for a five-year-old. I would say like a two and a half” (caregiver 4)
	“He is nowhere near where he should be at his age mentally…speech-wise he’s probably mentally capable of less than a year old or right at a year old” (caregiver 8)
Communication	“…his speech is affected, and the difficulty comes from a cognitive impact, where it really seems like his brain is just not able to get his little mouth to formulate the correct sounds” (caregiver 11)
	“…the main thing for him is communication…. I guess the number one [is] not be[ing] able to say what he wants or he try, you know, like pointing, bring you, come here. But it’s sometimes hard for him” (caregiver 4)
	“He can’t talk. And for me as a parent that’s frustrating that he can’t communicate” (caregiver 2)
	“…his speech and language are delayed compared to other kids his age…he…speaks mostly in single words and a few short…two-word utterances…and his articulation…or pronunciation is pretty poor” (caregiver 3)
	“It’s difficult with him being nonverbal…. Last night is a classic example…he’d obviously either bit his lip or knocked his lip on something. So, his lip was bleeding, but he wasn’t crying out in pain. He was sort of just looking at me. It was a little bit like he was upset…he wasn’t crying out in pain and couldn’t tell what he’d done” (caregiver 12)
	“Like, for example, somebody asks ‘How are you?’ He doesn’t know what...that mean[s]. What’s your name? What color is that car? Things like that, he won’t be able to answer that” (caregiver 4)
Emotional, behavioral, and social
Emotional issues	“…he gets frustrated if we don’t give him something and then he cannot argue because then he cries and stuff” (caregiver 9)
	“I think there’s a level of frustration. And we’ve had conversations with his doctor and with his school that a lot of it is frustration from not being able to communicate” (caregiver 2)
Behavioral issues	“Yes, he has a lot of aggression. Like if we can’t do something his way, he flips out on us” (caregiver 8)
	“If he gets yelled at or we say, don’t do that, he has a tendency to hit. He gets frustrated and hits. And we tell him not to hit, he’ll bite…his thumb and instead of hitting he’ll bite himself and we know that he’s trying not to hit” (caregiver 2)
	“We’ve noticed, since he’s been diagnosed, an increase in hyperactivity. And a lack of focus at times…. And it definitely seems to have increased since last year” (caregiver 11)
	“He doesn’t listen. He doesn’t stay still. He doesn’t sit down. He can’t sit down. He will sit down for, like, 10 s and then that’s it” (caregiver 7)
	“He has no sense of danger whatsoever. We can’t just sort of leave him in his bedroom if he’s awake because chances are, he’s probably trying to climb over a staircase or out of a window or... something” (caregiver 17)
	“He is a runner. So we can’t go outside or anything like that or he runs away from me. Can’t go on trips because he runs away from me, and he doesn’t understand, and he throws a fit” (caregiver 8)
Social	“It takes just a lot of time and a lot of energy from us getting him to these different medical procedures. It’s not always surgery. It’s talking with doctors, routine checkups, meeting with people to get diagnostics. It takes time from other things that we need to be doing” (caregiver 2)
	“It’s really hard. And it’s hard on my daughter as well because she’s going through it as well as us. And obviously she can see people staring at her brother and she gets quite protective of him. So, that’s quite a big daily impact” (caregiver 15)
Somatic
Mobility	“… sometimes he’ll be achy. Like the days when like the weather is kind of bad. Like if it’s raining, if it’s colder outside, we notice he’s more like on the tired side. So, like climbing stairs and even just walking a great distance, he’ll be slower” (caregiver 5)
	“Well, because he is clumsy… sometimes it’s better than others…almost after every 10 steps he’ll fall” (caregiver 4)
	“Yes. He can’t stand. He can’t stand or walk for long periods of time, so he constantly needs to have either a medical stroller or a double stroller” (caregiver 2)
	“I mean the most he can walk is like 15 min and then he gets tired. He says to me, oh, mommy, I can’t walk, like he gets tired” (caregiver 7)
Joint and muscle issues	“I would say his shoulders and hips are pretty stiff, so climbing and playing is a little different for him. He’s very cautious because I think he is nervous. I think he even realizes that he can’t really do the typical kid stuff. He can’t climb as well, so he’s very cautious in that way I guess” (caregiver 1)
	“He definitely has a hard time in the car seat. So I had to get him a footrest because he would complain of his legs kind of hurting. And he can’t cross them Indian style or put them up very well” (caregiver 14)
Hand movement	“We do work on like, snaps, like a, for like a baby onesie type of snap. Like he could do that. And we work on buttons, but they’re really difficult for him” (caregiver 11)
	“Um, and then his fingers that have that little bit of curvature at the end. So, the fingers are the main appearance change” (caregiver 3)
Sleep issues	“He had also started to have bad sleep patterns. He was waking up in the middle of the night and staying awake for long periods of time or just waking up at 3.00 am, 4.00 am, or 5.00 am and not going back to sleep” (caregiver 6)
	“He wakes very early, and then sometimes he’ll wake up just screaming and so then that’s a challenge” (caregiver 11)
General incontinence and stool quality	“He just doesn’t tell us that he needs to go or has an accident in his diaper. He has no interest. It’s difficult for him. We’d have to sit him on the toilet for a very long time and keep forcing him back on the toilet and then in a matter of time, okay, yeah, he’ll go. But for the most part, he does not want to sit on the toilet” (caregiver 10)
	“He has a lot of diarrhea. He’s never really had a hard stool in his whole life” (caregiver 8)
	“It’s definitely soft to bordering on loose at times and very frequent. And I would say the impact is, um, mostly that we just have to change his diaper very regularly” (caregiver 3)
Respiratory problems	“We started seeing his tongue, which is hard to explain but we had saw that coming out of his mouth more often, and there was very loud breathing” (caregiver 13)
	“He definitely can’t keep up running. He gets very winded very quickly. He just stops playing” (caregiver 14)
Other	“We have to take him in his pushchair because he can’t walk for long distances” (caregiver 12)
	“Hearing loss is another one. He wears hearing aids. His hearing loss keeps getting worse” (caregiver 1)
	“The hearing loss is still a big factor in his development and his communication” (caregiver 13)
	“But he would always have a chest infection or he’d always be very snotty…. He was always quite unwell. Like, bad chest, always full of mucus, like conjunctivitis type thing, ear infection, chest infection, just generally not well” (caregiver 15)
	“…when he does get sick it’s not like just any other kid that would just kind of get over it within like 24 h. It does take him longer to recover sometimes” (caregiver 5)
	“…so he had ear infections pretty bad with MPS. And... he had an ear infection that burst his eardrum that was bleeding” (caregiver 14)

MPS II mucopolysaccharidosis type II

Caregivers most frequently considered communication, mobility, and joint and muscle issues to be amongst the top three most bothersome impacts of MPS II (Supplemental File 4). Verbal communication was the most frequently cited as one of the most bothersome communication impacts and walking and climbing stairs as the most bothersome mobility impact.

Cognitive/Developmental Impacts

Cognitive decline was mentioned by all 16 caregivers as an impact of MPS II. Cognitive decline was discussed as an inability to learn new things or retain them, as well as in terms of forgetting, regressing, or losing skills they once had. Caregivers also often described cognitive decline in terms of how their children were not keeping up with other children their age or had not reached the same learning milestones as others in the same age group. For example, one caregiver explained, “his brain is not for a five-year-old. I would say like a two and a half” (caregiver 4). Another explained that their child was, “Regressing…forgetting things that he’s already learned or mastered” (caregiver 10).

Caregivers reported a variety of communication issues related to MPS II and strategies children with MPS II used to compensate for these issues. Reported communication issues included difficulties with verbal/speech communication (n = 15), nonverbal communication (n = 13), following directions (n = 2), and engaging in eye contact (n = 1). Caregivers noted that their children with MPS II had delayed speech for their age and, because of their difficulties with this, often felt frustrated and become demonstrative in ways that might seem aggressive to others. One caregiver stated simply, “He can’t talk” and expressed frustration with their child’s inability to communicate (caregiver 6). Another said, “he…speaks mostly in single words and a few short…two-word utterances” (caregiver 3). Caregivers noted that the inability to communicate often resulted in avoiding public places with their child because they would often scream or talk much louder to try and get their point across. Not being able to communicate verbally also affected children’s abilities to form social bonds with children their own age and with other non-parent or caregiver adults, such as teachers. Caregivers also articulated that speech and verbal communication in children with MPS II was related to both cognitive decline and hearing problems. For example, one caregiver said, “his speech is affected and the difficulty comes from a cognitive impact, where it really seems like his brain is just not able to get his little mouth to formulate the correct sounds” (caregiver 11).

Given the problems with verbal communication, caregivers (n = 13) reported how children with MPS II had learned to compensate by using nonverbal communication such as signs, demonstrations, and other vocalizations that were not actually words. In addition to yelling and screaming, caregivers noted that their children often developed other ways of communicating through sounds that mimicked speech but were not actually words. Caregivers had learned to understand the different tones in their child’s vocalizations to be able to understand and communicate with them. One caregiver related, “So he will usually say, ‘Come on’ like with his hands, not say it, but…motion me to come on after he just babbled something that nobody understood. And then he can tell me where he wants to go or what he wants to do in a nonverbal way. So I guess that’s more what his communication looks like…. Just motioning to go somewhere. He does know a little bit of sign language” (caregiver 14).

Caregivers related that not being able to communicate in words could sometimes result in their child’s injuries going unnoticed because they were unable to express pain or injury. Although their children may not have been able to communicate verbally, two caregivers described how they were able to follow directions. Engaged eye contact, particularly for nonverbal children, was seen as an important marker of understanding, and something that parents and caregivers would look toward as a sign of improvement in a clinical trial.

Emotional, Behavioral, and Social Impacts

Caregivers noted that children often felt frustrated (n = 14), particularly around communication and being misunderstood or not being able to be understood at all, and that they expressed frustration, sometimes as aggression, because they may not have known how to communicate this feeling to others. One caregiver said about his child that “he gets frustrated if we don’t give him something and then he cannot argue…” (caregiver 9). Others said that “a lot of it is frustration from not being able to communicate we think” (caregiver 2) and that their child “has a lot of aggression. Like if we can’t do something his way, he flips out on us” (caregiver 8). Caregivers also reported that their children frequently experienced anxiety, sadness, and depressed moods, often around communication, not being able to participate in activities like other children, and from feeling unsafe or scared in surroundings where people familiar to them are not around. They also frequently described their children as having medical trauma and fear of medical professionals, settings, and situations. In addition, they reported that their children often had to make frequent visits to hospitals and doctors and that they had a strong fear of these places and people due to past experiences, which often made it difficult to conduct medical procedures and tests.

The primary behavioral impacts described by caregivers in their children with MPS II were aggression (n = 13), hyperactivity (n = 6), and resisting toileting (n = 5). Other behaviors discussed by caregivers included fixated behaviors (n = 4), impulsivity (n = 3), resisting behavior (n = 3), and lack of fear (n = 3). Sensory processing issues, running away, and indifference were all described spontaneously by one caregiver each. Caregivers also reported behavioral issues related to eating and appetite, including overeating (n = 8), being a picky eater (n = 7), repetitive chewing (n = 2), having difficulty with certain foods (n = 1), and having no appetite (n = 1).

Caregivers described two main categories of social impacts, including disruptions of family life (n = 16) and interactions with others outside of the family (n = 14). Caregivers often described the impact of having a child with MPS II on their abilities to manage their own time and activities as well as their emotions. This often related to having to always be with the child, the need for frequent medical visits, and difficulty leaving them with others. One caregiver explained that their child “needs constant attention, activity…. When I’m at home with him, I can barely get my own tasks done because he’s always seeking something” (caregiver 10). Another explained, “it takes just a lot of time and a lot of energy from us getting him to these different medical procedures” (caregiver 2).

Somatic Impacts

Caregivers described three main types of respiratory problems in their children with MPS II: airway obstruction (n = 9), airway infections (n = 6), and loud breathing (n = 2). Caregivers described how these main respiratory problems affect their children’s sleep, mood, and energy levels. Children were described as being tired more often because of breathing problems and not being able to play as long or hard as other children. Caregivers also described how respiratory problems led to chronic upper respiratory tract infections and the need for the child to have medical interventions to remove mucus and phlegm.

Caregivers commonly reported an impact of MPS II on their child’s physical function. Nearly all caregivers (n = 15) described difficulties with mobility, especially walking, using stairs, and climbing things, particularly when at parks or play areas. Caregivers also described how, because of their difficulties with walking for long periods of time, their child could be clumsy (n = 2). Much of the difficulty with walking, using stairs, and climbing was described as related to pain, as caregivers noted how children would then avoid these activities to avoid pain. One caregiver also noted that because of difficulties with mobility, her child had become inactive and had gained weight, which in turn caused more stress on his joints and abilities to be active. One of the caregivers said, “sometimes he’ll be achy…and more like on the tired side. So, like climbing stairs and even just walking a great distance, he’ll be slower” (caregiver 5). Others described their children only being able to walk for “15 min and then…get[ting] tired” (caregiver 7) or needing a “pushchair because he can’t walk for long distances” (caregiver 12).

Along with descriptions of mobility in general, caregivers also described how MPS II affected hand movement (n = 15). Caregivers described how the hands of children with MPS are “like claws” and “curled at the end”. For some children hand movement had not yet become restricted, while for others difficulty with hand movements manifested in difficulties with the ability to button shirts, write, and do other daily activities that require use of the hands, like playing on playground equipment. One caregiver noted that her child’s hand movements becoming more restricted in the future will be a sign alerting her to the fact that the disease is progressing.

Caregivers frequently (n = 13) described how MPS II had an effect on their child’s endurance levels, particularly with relation to walking, using stairs, climbing, and playing. Caregivers noted that children were not able to walk for long periods of time and required the use of a stroller or wheelchair when outside of the home. They also described how their endurance levels inhibited their abilities to be as physically active as long as other children their age.

Caregivers described stiff joints and muscles (n = 13) and perceived joint pain (n = 7) in their children. Some caregivers described being able to visually see this in their children’s hands, noting that they were like “claws”, while others described their children’s joint pain as something they assumed they were experiencing as a result of wincing, and avoiding play and other mobility-related activities. Joint pain was specifically described by seven caregivers and noted as being found throughout all areas of the body, including the feet, ankles, hips, shoulders, hands, and wrists. Caregivers described how joint pain caused an increase in stiffness as well as a decreased flexibility and range of motion, particularly in the arms, legs, hips, shoulders, and knees, impacting activities of daily living like dressing (putting on shirts and pants). Joint pain also was described as preventing their children from being “normal kids” and doing “typical kid stuff” and causing increased clumsiness and falls. One caregiver also described how, because of the joint pain and reduced range of motion, her son had to wear clothes that were much bigger than those for children his age so that his limbs could be contorted to fit in the clothing.

Caregivers often described that their child had difficulty with sleep, especially waking up at night (n = 6), trouble sleeping or waking up (n = 4), general tiredness (n = 2), irregular day sleep patterns (n = 1), and obstructive sleep apnea (n = 1). Caregivers noted how children would wake up in the middle of the night and be restless and unable to fall back asleep or wake up very early in the morning. They also described how chronic and frequent infections would impact their sleep as well as how joint and muscle pain would cause them to wake up or be unable to sleep well. One caregiver explained that their child “started to have bad sleep patterns. He was waking up in the middle of the night and staying awake for long periods of time” (caregiver 6). They also reported that their son “probably doesn’t get as good a sleep like he should on a regular basis, so he’s probably a little bit sleepier, a little crankier throughout the day” (caregiver 6).

Caregivers often (n = 12) described problems with incontinence and stool quality. When describing stool quality, caregivers described runny stools (n = 5), diaper-rash pain (n = 3), frequent defecation (n = 3), and intestinal pain (n = 1). In describing general incontinence, caregivers noted how children were difficult to potty train and were often in diapers and that, because of not being able to eat harder types of foods or because of the medications they had to take, they had loose stools like diarrhea. They also noted that children would often have several stools in a day, sometimes up to three or four, and that because they were loose stools it could be burdensome to constantly change the children’s diapers.

Nearly all the caregivers (n = 15) in this study described how children with MPS II had hearing loss or difficulty hearing. Often this was a sign or symptom that prompted parents to take their child to a specialist, which resulted in further testing and often an MPS II diagnosis. One reported that their child “wears hearing aids” and that “His hearing loss keeps getting worse” (caregiver 1). Another reported “…hearing loss is…a big factor in his development and his communication” (caregiver 13).

Caregivers described how their children with MPS II experienced frequent infections (n = 15), most commonly ear and upper respiratory tract infections. In addition to frequent illnesses, caregivers described how children with MPS II often took much longer than other children to clear infections. One caregiver reported their child being “always quite unwell. Like, bad chest, always full of mucus, like conjunctivitis type thing, ear infection, chest infection, just generally not well” (caregiver 15). Another said, “when he does get sick it’s not like just any other kid that would just kind of get over it within like 24 h. It does take him longer to recover sometimes” (caregiver 5).

Discussion

MPS II is an exceedingly rare progressive disorder that manifests in early childhood, around 2 to 4 years of age [1]. Caregiver insights are essential to learning about its symptoms and impacts in young children. This study builds on the existing literature on the impact of MPS II in children by providing qualitative data on the symptoms and impacts of MPS II on families with very young neuronopathic children.

This study recruited 16 caregivers of young children with MPS II who described a combination of early developmental, behavioral, and somatic symptoms of concern in their children. Although the caregivers universally described cognitive decline and an impact on family life, they considered verbal communication, mobility, and joint issues the most bothersome impacts. The findings also highlight that, although the participants’ children were as young as 2 years of age, MPS II was already having a substantial impact on them and their caregivers and families, and not only because of effects on the central nervous system.

In children with neuronopathic MPS II, a delay in global developmental milestones is one of the first signs of brain involvement [2] and can be detected in children as young as 2 years of age [24]. Developmental delay was also a prominent theme in the current study, with many parents noting that their toddlers were slow to reach speech and cognitive milestones or that their skills plateaued. The caregivers also reported emerging behavioral differences, such as unusual levels of hyperactivity, attention deficits, and sleep disturbances. Such neurobehavioral issues are known to occur across the spectrum of MPS II, although they are more pronounced in the severe (neuronopathic) disease [2]. The current study underscores that, by 2 to 4 years of age, when severe MPS II begins to manifest, changes in development and behavior may emerge—even before overt physical features appear.

In addition to neurological concerns, caregivers consistently observed respiratory complications, including recurrent ear, nose, and throat symptoms and other physical changes. Children with MPS II are known to frequently experience chronic otitis media, upper airway infections, and nasal obstruction due to enlarged tonsils/adenoids [25]. In addition, the current study confirmed that hearing difficulties are frequent and that they begin at a young age in children with MPS II, adding to difficulties communicating due to neurological deficits.

Alongside ear, nose, and throat symptoms, caregivers sometimes noted somatic abnormalities that were revealing when viewed together. One example was the gradual appearance of the characteristic coarse facial features of MPS II, which corresponds to a known early somatic sign [25]. Other examples include difficulties with bowel and bladder training and sleep disturbance. In fact, these symptoms, along with increased activity, behavior difficulties, seizure-like behavior, and perseverative chewing behavior have been identified as clinical markers of neurologic decline [26].

Although the focus of the study was on the impact of MPS II in young children as observed by their caregivers, the study also provided some insight into the burden of the disease on caregivers and their families. Caregivers have a heavy burden in handling not only their child’s cognitive decline and communication difficulties but also behavioral issues such as frustration, aggression, fear of medical professionals and settings; and various other symptoms like reduced incontinence, stool quality, and eating issues. The constant need to give their children with MPS II attention and accompany them to care visits, combined with the difficulty leaving them with others, disrupted their family life, interfered with their social interactions, and added to their emotional burden.

This study focused on patients with MPS II for whom the available standard-of-care treatment, intravenous idursulfase, does not cross the blood–brain barrier and therefore is not effective at slowing neurodegeneration and its associated manifestations [15]. A recent Delphi study of patients with MPS II and their parents supported measuring survival, airway obstruction, and quality of life and, for younger children, swallowing, cognitive development, ability to participate in education, and communication as endpoints for clinical trials and clinical practice [27]. Hearing has also been an endpoint used in MPS II clinical trials and is monitored in clinical practice [2, 28]. Our study builds on this body of work by underscoring the importance of verbal communication, mobility, joint function, and hearing for young children with MPS II. For nonverbal children, engaged eye contact was also considered by participants as a potential marker of improvement. Collectively, these findings suggest, that for young children with MPS II, quality of life, development, and communication impairments are the most important to patients and families, highlighting urgent need for innovative therapies that address these impairments.

This study used a concept elicitation approach, which provides a deeper, more nuanced understanding of the symptoms and impacts of MPS II that are important to caregivers and the young children they care for. A potential limitation of the study is that, as a result of the rarity of MPS II, the sample size was small, which may have prevented identification of some impacts. However, concept saturation was reached, suggesting that most were identified. Another potential limitation is that the caregivers were members of rare disease support networks so may have been better informed or have had children with more severe disease than the broader MPS II caregiver population, which could have resulted in certain symptoms being emphasized over others because of memory biases or knowledge gained after diagnosis. Presence or absence of treatment may have affected caregivers’ perspectives on symptoms and impacts of MPS II; however, collecting data on treatment experience was outside the scope of this study. This study included caregivers of children with MPS II within the USA and UK; therefore, the results may not fully represent the impact of MPS II in other geographies or in people with different racial or ethnic backgrounds. Finally, sociodemographic data were missing for one caregiver and child, although this is not expected to change the conclusions of this study.

Conclusions

Despite the advent of enzyme replacement therapy in 2006 with intravenous idursulfase, which remains the standard of care, this qualitative study showed that MPS II remains a substantial burden to patients, including very young patients, and their families. MPS II poses many different challenges, affecting multiple aspects of children’s cognitive function, behavior, and physical function and thus the quality of life of patients and their families. Progressive deterioration of verbal communication, mobility, and joint function were especially burdensome impacts of MPS II in young children. These findings reinforce the critical need for new therapies that can address these burdensome impacts of MPS II beginning in early childhood.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Jessica Baldwin contributed to interpretation of results and writing the manuscript; Natalie Engmann contributed to study conception, study design, and interpretation of results; Sonya Stanczyk contributed to study design, data collection, data analysis, interpretation of results, and writing the manuscript; Kristin McKay contributed to the study conception; and Robin Pokrzywinski contributed to study conception, study design, data collection, data analysis, interpretation of results, and writing the manuscript. In addition, all authors provided comments on the manuscript and approved the final version to be submitted for publication.

Funding

This study and the rapid service and open access journal fees were funded by Denali Therapeutics.

Data Availability

The data that support the findings of this study are available from the authors upon reasonable request.

Declarations

Conflict of Interest

Jessica Baldwin and Natalie Engmann are employees of Denali Therapeutics, which funded this study. Sonya Stanczyk and Robin Pokrzywinski are employees of Thermo Fisher Scientific and members of the PPD™ Evidera™ Patient Centered Research team, hired by Denali Therapeutics to consult on this project. Kristin McKay is an employee of Project Alive, which receives financial support from Denali Therapeutics through event sponsorships and grants.

Ethical Approval

The research was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study protocol and informed consent procedures were approved by Advarra Institutional Review Board (Columbia, MD, USA; Pro00040794). Prior to interviews, participating caregivers provided informed consent and consent to be audio recorded.