Modern medical advances have transformed many childhood-onset disorders in manageable chronic conditions with extended life expectancy and improved clinical and patient-reported outcomes.^1–4 Thus, more adolescents and young adults (AYA, individuals aged 14–26 years) with special healthcare needs are reaching the critical transition period to adulthood with corresponding risks of lapses of healthcare and psychosocial supports. Transition-related challenges are magnified for AYA with rare disease due to the complexity of these disorders, frequent comorbid intellectual disability, lack of trained adult providers, and limited coordination between pediatric and adult care systems.^5,6 The current healthcare transition (HCT), the planned, purposeful movement from pediatric to adult-centered healthcare, for this population is non-standardized and occurs infrequently in the United States.^6,7 Transition should be developmentally-appropriate and address medical self-management, independent living skills, educational or vocational rehabilitation, financial assistance, and decision-making support). The transition process usually begins at age 14 years with a graduated, individualized approach to independence.⁸ Historically, pediatricians have been responsible for transition. With increased life expectancies for many complex childhood-onset conditions, subspeciality providers are now initiating more transition planning.⁴ However, our ability to design and implement effective HCT is limited by knowledge gaps on social and medical outcomes for adults with childhood-onset rare disease.

Inherited metabolic disorders (IMD) are a subset of rare disease with a rapidly growing young adult population due to the expansion of newborn screening programs in the early 2000s.⁹ Though individually rare, the collective incidence of all IMD range from 1:800 to 1:2500.¹⁰ Population-based screening programs have lead to early diagnosis and treatment, transforming historically fatal childhood diseases to manageable chronic conditions.^11,12 Recent estimates suggest that over 90% of individuals with IMD are now reaching adulthood.^1,13 However, many face barriers in achieving social and medical autonomy due to the complexity of care for their multisystemic conditions and high prevalence of intellectual or learning disabilities. IMD require multidisciplinary management that may include strict dietary restrictions, invasive medications, and affected individuals must balance their medical needs with the general demands of daily living.^12,14,15 Additionally, IMD are among the first rare diseases for which therapeutics have been leveraged to change the natural course of these disorders, suggesting a road map for other disorders in the era of emerging gene therapy.^16–18 As pediatric-onset IMD were historically confined to childhood, the lived experience of adults with IMD, including their transition from adolescence to adulthood, is largely unknown. Exploring the current status of adults with IMD, including their experiences with education, vocation, romantic partnerships, and navigating the transition to adult-oriented healthcare, offers insights to guide HCT for AYA with chronic childhood-onset conditions.

Among the IMD, Maple Syrup Urine Disease (MSUD) provides a representative population for how adults with pediatric-onset rare disease navigate the transition to adulthood. This autosomal recessive disorder is caused by decreased activity of the branched chain α-ketoacid dehydrogenase, the enzyme responsible for catabolism of isoleucine, leucine, and valine.¹⁹ Leucine and its conjugate α-ketoacid are specifically neurotoxic, and its accumulation can lead to acute symptoms of cerebral edema, encephalopathy and death as well as cause chronic neurodevelopmental symptoms such as poor feeding, intellectual impairment, and neuropsychiatric differences.²⁰ Treatment is lifelong and involves strictly limiting dietary intake of branched chain amino acids, emergently managing catabolic stressors, including illness, pregnancy, and prolonged fasting, and, for some individuals, liver transplantation to partially restore branched chain amino acid metabolism. As the worst sequalae are preventable through early detection and treatment, population screening of newborns for MSUD has been recommended since 2005.²¹ For many affected individuals, neurocognitive differences persist despite early intervention, potentially impacting their ability to obtain milestones of independent adulthood.^20,22 HCT may alleviate these challenges, yet it is offered to few adolescents with MSUD.²³

This study used qualitative methods to describe the experiences of being an adult with MSUD. It expanded on challenges previously identified for adolescents with MSUD – dietary adherence, maintaining relationships, and frustration with continued medical care in pediatric spaces,²³ by incorporating more milestones of adulthood including romantic partnership, reproductive planning, educational and vocational attainment, and financial independence. Experience with HCT and obtaining medical self-management skills was investigated in detail, as our participants should have completed this process. Emerging themes demonstrated (1) an increasingly mature perspective on managing chronic disease with less emphasis on the burdens of diet, (2) greater concern about gaps in HCT readiness, including limited supports needed to achieve independent living, and (3) wide ranging functional outcomes for education, employment, romantic partnership, parenthood, and financial independence. This research recognizes new priorities for HCT that centers social needs alongside medical self-management skills.

Setting and Participants: Participants for this study were initially recruited for a larger, international study on neurocognitive outcomes in adults with MSUD.¹⁴ Recruitment occurred through the newsletter of the MSUD Family Support Group (FSG), social media, and informational meetings with the young adult members of the MSUD FSG. During the initial consent process, subjects indicated their interest in participating in 1–2 hour-long semi-structured interviews. Subjects also volunteered contact information for a childhood caregiver who would be willing to partake in the qualitative aim. A purposive sampling method was used to achieve a diverse sample of adults and caregivers regarding race/ethnicity, age, geographic location, and neurocognitive ability (Table 1).²⁴ Affected adults were required to be older than 21 years for greater exposure to the transition process. Interviews were conducted in English, so non-English speakers were excluded from enrollment. Ten affected adults aged 23–39 years-old and 8 caregivers to adults aged 21–40 years-old participated in the study. Our purposive sample strategy prioritized enrolling caregivers to adults with intellectual disability. Thus, only two caregiver-adult dyads were included. Two caregivers had multiple adult children with MSUD. Table 1 summarizes the demographics for the affected adults who were represented by self-report or caregiver report. The sample size was dependent on data saturation and was anticipated to be 15–25 based on literature review.^23,25,26 Participants were contacted by telephone or email. Verbal informed consent was obtained from all participants. This study was approved by the Children’s Hospital of Philadelphia IRB (IRB#21-18443).

Data Collection: Two semi-structured interview guides were developed for either affected adults or caregivers. These guides were informed by previously performed qualitative studies with adolescents with MSUD and a broad review of IMD and HCT literature.²³ Interview guide revisions occurred through discussion among experts in qualitative research methods, clinical care of MSUD, and HCT. The MSUD Adult Interview consisted of 32 open-ended questions and was developed to explore the experience of transitioning from adolescence to adulthood with MSUD, while the Caregiver Interview consisted of 36 open-ended questions addressing the caregiver perspective on HCT and attaining adult milestones. Questions were divided into 6 categories based on domains emphasized in HCT⁸: (1) life experiences with MSUD; (2) Relationships and Reproductive health; (3) Education; (4) Employment; (5) Independent living and finances; and (6) Medical experiences and HCT. Telephone interviews were conducted by a single researcher from June to October 2022. All interviews occurred in private spaces and were audio-record with participants’ consent. Audio recordings were then sent to the University of Pennsylvania’s Mixed Methods Research Lab where they were transcribed by a HIPPA-compliant service and de-identified.

Data Analysis: The codebook was developed by two members of the research team using a modified grounded-theory approach.^27,28 Transcript analysis using this codebook was supported by NVivo software (http://www.qsrinternational.com). The same two members of the research team completed three rounds of inter-rater reliability with κ = 0.8, using double coding on 17% of the transcripts (n = 3). Coding discrepancies was discussed and resolved in each session. The remaining transcripts were divided evenly between the two research team members and coded separately.

Qualitative Overview with central themes

The design of our interview guide fulfilled two main purposes. First, we wanted to explore how MSUD impacts adulthood. Participants reflected on their current living situation, employment, romantic relationships, and medical management. The second goal was to recount the process of making it to adulthood by describing necessary supports, graduated approaches to independence, and HCT-related planning. Together, our themes depict adult lifestyles, but also illustrate a path forward for the next generation of adolescents with MSUD. Table 2 includes themes with illustrative quotes. Overall, our interviews demonstrated a wide spectrum of functioning for adults with MSUD from complete independence to continued reliance on caregivers for medical, financial, and living assistance.

Preparation for Adulthood - Healthcare Transition

Despite an international call for metabolic clinicians to lead transition due to their greater disease knowledge, long-standing therapeutic relationships, and multidisciplinary approach,⁷ only one participant discussed transition planning with their metabolic provider. Households that successfully helped their children become responsible for MSUD care accomplished this by gradually introducing more responsibility, without formal HCT planning. As one caregiver explained: “It's just been a process over the years that we've just -- it's just like happened naturally. But I don't remember ever sitting down with a healthcare professional and talking about it.” It was not uncommon for caregivers to continue to manage insurance and finances well into adulthood.

Without a formal transition process, there was a wide range of independent medical management among adults with MSUD. Eight out of 10 adults relied on their caregivers to schedule appointments, pick up formula, and measure dosages, while seven split the responsibilities, often either attending appointments by themselves or taking care of their own formula. Three adults reported complete independence in medical management. The typical first medical responsibility was preparing their own formula, which started in grade school at the earliest. Dietary self-management tended to be the most common topic of transition planning with few resources provided for the other aspects of independent adulthood. For liver transplant recipients, compliance with immunosuppression was the primary transition topic.

One challenge in transition planning was the lack of clinicians trained to care for adults with MSUD. All participants reported close relationships with their metabolic teams, who have provided lifelong care. However, all ten adults with MSUD had reservations about their continued care in pediatric spaces. One shared: “I feel like maybe it almost delegitimizes MSUD because it makes it seem like it's something that affects you mostly when you're younger because you're seeing a doctor that primarily deals with children. […] Sometimes I feel like as an adult with MSUD because these doctors are so used to dealing with children that they tend to speak to us like we are children and we're full grown adults with... We deserve to be treated with respect and dignity, not talked down to.” Adults expressed concerns about the lack of knowledge on aging with MSUD and about their metabolism providers’ ability to balance MSUD management with chronic adult-onset conditions. One participant expressed that “In my opinion, it matters very little whether I'm at [Hospital 1] or [Children’s Hospital], in that department. All my concerns are as novel probably at [Hospital 1] as they are at [Children's Hospital].” Both caregivers and adults felt that MSUD was used to explain any health issue, without adequate exploration into other causes.

Seven out of 10 adults with MSUD noted changes in their MSUD symptoms as they aged. Starting in their late teens, metabolic decompensations presented as headaches, fatigue, panic attacks, and brain fog, rather than their earlier presentations with predominant somatic symptoms, dysarthria, and ataxia. “I don't really get like lose balance or anything like that. Now it's more like, I just feel out of it. You just feel like a fog, you don't feel yourself.” Three adults described decompensations that were triggered by emotional stress, such as high-pressure situations at work rather than a physical stressor like illness or fasting. One participant was concerned that her metabolic clinicians were not adequately assessing presenting symptoms for adults. She suggested that clinicians could talk to patients, “more frequently when they have an episode to figure out what their symptoms are as they're getting older because their symptoms just change…. The more they hone down on what their adult symptoms are, the easier it will be for the adult to figure out when they're sick.” These knowledge gaps of the adult MSUD spectrum could lead to inadequate transition planning.

Dietary Management

The strain of lifelong compliance to strict dietary restriction has been previously reported for adolescents with MSUD.²³ In contrast, our adults reported both personal and societal acceptance for their diet: “There’s not as much of a social stigma around restrictive diets these days because a lot of people are gluten-free or lactose intolerant or vegan.” Several adults described a moment of personal acceptance of their low-protein diet. These revelations tended to occur in their late teens to early twenties. Seven adults began to notice the trade-offs between dietary noncompliance and challenges in education, vocation, or intrapersonal relationships. One said: “I was mad at myself because [my GPA] ended up at 3.1 and I wasn't where I thought I would be by the end of freshman year. But when I got home and I found out what my levels had been, it dawned on me that I was just making not great choices at the dining hall. I got my levels down to 3 [mg/dL] and then the rest of college was great.” Despite personal acceptance, three adults voiced concern about how the restrictive diet for MSUD impacts their overall health: “When I see the dietician, they're not thinking about necessarily diabetes or heart health or whatever with MSUD. They're thinking about, you have MSUD. And so you need this diet, and then I'm overweight and I need to not have all the sugar and fat. And then you look at all the sodium in all the low protein products and I'm like, this is great. I already stressed enough about what's in food and there's all these mixed messages and there's nobody here who's like, how do we look at all these things and put together a plan that you could actually live with.”

Mental Health

The impact of mood on medical compliance was a new theme from our interviews. Four caregivers and two adults reported that depression led to significant differences in their diet or ability to self-manage their MSUD. Both adults shared that they stopped following their protein-restricted diet as a method of self-harm. One shared: “I started having really bad depression, where I just didn't want to drink my formula, I didn't want to eat, I didn't want to do anything. And I started becoming suicidal and everything. I slowly was making myself sick by not drinking my formula.” Five out of 10 adults had received intensive or inpatient care for psychiatric illness. Most other participants noted a history of depression, anxiety, panic attacks or post-traumatic stress disorder. Difficulty finding a mental health professional was a common barrier to obtaining care.

Impact on relationships

Social: Five out of ten adults described their friends as sources of support and potential advocate, with one advising: “Make sure that your friends know what to do in case you ever exhibit any kind of issues.” For those whose MSUD was a hidden disability, discretion about their diagnosis was possible and often preferred. Adults with more visible disabilities reported more adversity, including the impact of prolonged school absences and mental health concerns on developing social skills. Four caregivers expressed worry over their child’s judgement in choosing friends and shared examples of exploitative friendships: “More likely than not these people she meets tend to take advantage of her emotionally and financially. She pretty much drained her bank account quite a few times.” Childhood caregiver accommodations, such as chaperoning class trips to ensure dietary adherence, did not readily translate to adulthood, leaving caregivers only able to offer advice.

Romantic: Romantic relationships in our sample population ran the gambit from single to married to divorced. Both participants and their caregivers expressed their desire for romantic partnership as a symbol of normalcy. Those in relationships tended to disclose their MSUD diagnosis prior to or during a first date, either to demonstrate trust or to screen for incompatibility: “I don’t want to say that [disclosure] was a test, but if I’m telling you this and you can’t accept it then you’re not right for me anyway.” One participant noted her future spouse’s willingness to mix her formula as a significant moment early in their relationship. Five caregivers to adults with more significant disabilities, particularly those affecting decision-making and independence, expressed more apprehension around dating. Multiple caregivers recounted instances where their children have engaged in romantic relationships that were concerning for inappropriate or predatory behavior. Caregivers often intervened to help set boundaries, especially when technology is involved: “We’ve had to talk about pictures. I know she was talking to this boyfriend through the screen when she would be in a state of undress. I think she intellectually knows that this is dangerous, that people can capture these images and they can be out there forever, but that doesn’t translate into her behavior.” However, they also recognized the limits of their influence on their adult children.

Reproductive Health: Conversations about reproduction frequently referenced genetic testing. Some adults did not plan to pursue genetic testing prior to pregnancy as they were comfortable managing MSUD in potential offspring. One adult’s spouse opted for genetic screening due to concerns over work-life balance: “I don’t think I can be a mom with kids with your disease. I think it would be just too hard because you and I both have careers.” Siblings of affected adults also underwent genetic screening – which was reported to be influenced by the burden of MSUD on the entire family. MSUD also affected some participants’ interest in having children. Four adults noted their continued reliance on their parents and expressed concerns about their ability to parent: “I feel like taking care of a child would drain me to no end.” One adult felt that managing a pregnancy with MSUD would be too dangerous. Other participants spoke about their desire to be pregnant. Two adults relayed challenges with infertility and spontaneous abortions, which caused a negative impact on their mood.

Three participants had successful pregnancies and spoke about their experience. Pregnancy required meticulous management, primarily by dietitians, but was overall safe. One adult experienced post-partum hyperleucinosis that required hospital admission. Another patient’s pregnancy was complicated by gestational diabetes that required multidisciplinary collaboration between metabolism, endocrinology, and maternal fetal medicine. Metabolism led the coordination due the unique characteristics of MSUD, include the risk of post-partum complications. One participant’s pregnancy was complicated by a congenital defect in her fetus. She shared feelings of guilt and frustration over knowledge gaps on MSUD’s potential impact on embryogenesis.

Academic Competencies

Participant experience with academics varied widely. Educational attainment by participants with MSUD ranged from partial high school education to completion of a PhD. Affected adults shared academic experiences from elementary school through college. Challenges at school arose from both learning differences and MSUD-related medical complications. Participants noted the difficulty of maintaining academic performance while dealing with prolonged admissions for acute metabolic crises. Four adults and two caregivers recognized the impact of co-occurring ADHD, further impeding academic success. One participant noted “feeling like I’m at a detriment, because I also have these other coexisting [MSUD, ADHD, and mental health issue]. So it’s kind of like a perfect storm, but I wish it wasn’t.”

There was no consensus about disclosing MSUD to teachers. One caregiver reported increased support from teachers after explaining MSUD. However, one participant noted the risk of increased social stigma: “In high school, we were learning about genetics in biology. And the teacher brought up MSUD and how they said you could smell of maple syrup… he used the word retarded. So, after the class, I walked up to him and said, “I have this disorder. You pretty much told me I was retarded and if anyone else found out now they’re going to think I’m retarded.” And he was so embarrassed.... And he’s like, “Do you want to do a case study and explain what it is?” I’m like “No, you just told everyone all these bad things that kids are already pick on me. If I give a moment, it would be like giving more material to pick on me for.” So I made sure no one ever found out.”

Academic accommodations were common through primary schooling. Of the eight caregivers interviewed, seven mentioned that their child had an Individualized Education Plan (IEP) that covered MSUD and other medical needs, such as ADHD, autism, dyslexia, and cerebral palsy. Accommodations ranged from reinforcement of dietary requirements to extended time and modified testing to enrollment in specialized school for children with disabilities. Participants did not report barriers in obtaining IEPs or adapting them when needed.

Our interview guide specifically asked about enrollment in post-high school transitional education or vocational programs. Six of eight caregivers mentioned that their child participated these programs, which ranged from a vocational track within the school system to a multi-year residential program, which allowed a young adult with MUSD to gain independent living skills in a monitored environment. Two caregivers reported that they received no guidance about transitional education: “I don’t think the school does a very good job in helping kids who have any kind of disability. You graduate and then you are kinda on your own.”

College Experience: Overall, thirteen affected adults attended college – eight from our adult interviews and five from our caregiver interviews. Of these, three lived independently on their college campus. One participant struggled with the transition to college and returned home after her first semester. For seven adults, increased independence in college complicated their dietary management, with challenges in adhering to their low-protein restrictions and ensuring that they ate regular meals. One reflected: “In high school, my mom was still doing things for me, still calling me to eat. When I got to college it was upon myself to do all of that…and it was never easy to remember to eat.” For one affected adult, parents eased the transition to college by making and delivering individual servings of formula. Affected adults tended to be more discrete about their MSUD in college, though one adult registered with Disability Services as a proactive measure against MSUD complications, explaining: “My mom basically said “You want to have something in place in case something happens and you’re delirious or whatever and you need to reschedule an exam. You have some paperwork that says you’re not going to get a zero.” One caregiver recognized the overlap between substance use and the symptoms of a metabolic decompensation: “We met with the health services and explained everything. There was a banner that ran across the top of his record that said don’t assume he’s drunk or high if you see unsteady gait, dizziness… call his doctor or his parent.”

Employment

As with education, vocation varied widely among the adults with MSUD. Some were unemployed, some had part-time jobs in food service, others were pursuing careers as librarians, financial assistants, or scientists. Skills needed for employment ranged from manual labor to operating heavy machinery, such as forklifts, to extensive case management, including patient care. Accordingly, workplace disclosure and accommodations were highly dependent on the individual needs for each job. One participant adamantly denied any reason to disclose, saying: “I feel it doesn’t really impact me at the end of the job.” Some participants were able to successful disclose their diagnosis without consequence: “They understand I have some medical issues and they know I have my limits too. So they’re very, very nice about it.” Proactive communication about emergent medical management was critical. One caregiver described an incident where her child required a prolonged hospital admission that was not adequately communicated to her boss leading to termination. Concurrently, the caregiver recognizes that disclosure can be harmful: “So that’s a huge challenge to have this disease if you feel like you disclose, why would anyone hire you? And yet, if you don’t disclose, look what happens?”

Independent living skills in adulthood

Driving: Fourteen adults with MSUD had a driver’s license with one adult currently studying for the test. Among adults, confidence behind the wheel varied greatly. One patient reported growing recognition of delayed reaction time and creating a personal rule equating driving impairment with seeking emergent medical care. Five caregivers had reservations about their child driving due to concerns about reactivity and brain fog. Access to transportation facilitated independence and employment and adults without licenses frequently used rideshare services for work.

Living Situation: The caregiver interviews were split evenly between those who lived with their adult children and those whose children lived independently. Patient competencies with daily tasks such as chores, food preparation, and financial management varied greatly in these interviews. Four caregivers felt that their children would never be able to live fully independently, and had taken legal and financial measures to ensure that their children would continue to receive adequate care. This included filing for legal guardianship, power of attorney, and establishing a trust. Five of eight caregivers mentioned feeling apprehensive about their child’s options for care after the caregiver’s death.

Patients had varied living situations and levels of independence. Some lived independently or with spouses, while others lived with their parents or in apartments or suites connected to their parent’s house. Approaches to mealtime varied. For those living at home or semi-independently, it was not uncommon for caregivers to help with food preparation for the patient. Other times, households chose to cook separate dinners. However, some households attempted to provide low-protein options alongside more standard fare. One patient mentioned that there was occasional tension between her and her spouse, as he was not good at making meals that she could also eat: “If my husband's the one that decides to make dinner, he never makes something low protein for me unless I explicitly asked him, it's usually me making myself something separate and if I'm too tired to make them dinner, usually I'm too tired to make myself dinner too kind of thing and it's just something that I don't like to have to explicitly state.” Affected adults and caregivers both mentioned that fatigue made it challenging for adults with MSUD to complete daily tasks One caregiver mentioned that all three of her children with MSUD struggled with their energy levels and had grown accustomed to napping. One affected adult with unaffected children reported that fatigue occasionally impacted her ability to parent, including delaying meals or homework supervision.

This study is among the first to capture the lived experience of being an adult with an IMD. Our interview guides focused on the topics that are typically addressed through transition planning as representations of milestones for adulthoods. Similar to our previous quantitative study²², our interviews illustrated the wide range of functional outcomes experienced by adults with MSUD. Some adults with MSUD are successfully completing college, living independently, enjoying romantic partnerships, and finding full-time employment. There are also adults with MSUD who are unable to obtain these markers of independent adulthood, who continue living with caregivers and need assistance with activities of daily living. Participants reported a shift in their priorities as they age. They have a better understanding of their MSUD and its management, but need more support related to adult-onset conditions, mental health, and long-term care planning. Health care transition was fragmented or unaddressed for all participants and many caregivers navigated this life stage without assistance from their metabolic team. Overall, our interviews demonstrated the variability of outcomes for adults with MSUD and the need to develop systems that provide adequate support for these individuals in adulthood.

One of the primary goals of this study was to describe current functional outcomes for adults with MSUD. Knowledge of the possibilities of adulthood with MSUD is helpful for affected individuals of all ages. Across all IMD, we lack information about long-term outcomes and are frequently only able to provide anecdotes about life expectancy, quality of life, and prognosis. This knowledge gap impedes our ability to properly counsel families. While we did not use MSUD history for purposive enrollment, all affected participants have classical MSUD and nearly all (16/19) were symptomatic at diagnosis. Thus, the long-term outcomes described do not appear to have a direct correlation to disease severity. This variability demonstrates our continued challenges in prognostication - some high-achieving adults had severe neonatal presentations or frequent crises in childhood. However, we are able to raise the ceiling on the possibilities of being an adult with MSUD. We should appreciate these possibilities and use them as motivation to develop systems that support their successes.

Our interviews demonstrate that adults are not just big children. Participants voiced changing priorities. There was less emphasis with diet adherence and greater concern about how a high fat, high carbohydrate diet will impact an aging body. Participants reported that it was nearly impossible to find clinicians who could integrate common medical complaints with rare disease knowledge, creating wariness around healthcare. For our participants, mental health had an increased influence on daily life with emotional stress becoming a significant trigger for metabolic decompensation. Participants described new symptoms of elevated leucine that may not be elucidated by traditional metabolic questions. Yet mental health emerged as a domain where transition planning was notably absent, despite caregivers and adults reporting that depression directly influenced dietary management and metabolic stability. Our participants were primarily older than 21 years - the age in the United States known as “the cliff,” where available services drastically disappear.⁵ These repercussions were apparent in many interviews where affected adults lack support to balance their health with employment and relationships. While many are facing the demands of independence, neither adults nor their caregivers felt prepared for this life change. Unpreparedness stems partly from HCT protocols designed around dietary self-management, a domain where participants reported confidence, rather than the psychosocial and adult-onset medical complexities that increasingly dominate lived experiences of adults with IMD.

Healthcare transition was limited and primarily remains diet-related.^6,22 This emphasis may explain why dietary compliance decreased in importance for adults. It is possible that many years of routinely discussing dietary self-management instills greater confidence and skill. If true, this experience reinforces the role of the metabolism team in promoting healthcare transition. Subspecialty providers are increasingly recognized as the preferred arbiters of transition planning due to their specialized knowledge, and their strong therapeutic relationship. ^4,29 The multidisciplinary metabolism team is well formulated to provide holistic care to the young adult IMD population. Standardization of healthcare transition interventions will strengthen the metabolic provider’s role and ensure that topics other than diet receive similar dedication. Metabolic practices may benefit from formalizing their transition process using the steps outlined by Got Transition.⁸ However, IMD-specific adjustments will be needed. Metabolism practices may need both ambulatory- and hospital-based transition policies. The ambulatory policy could cover when patients are expected to speak with providers independently, outline transition milestones like scheduling appointments or calling for refills, and standardize discussions on educational, vocational, financial, and decision-making supports. A hospital-based policy would create standards around admissions including age limits for pediatric hospital admissions and a checklist for adult hospital admissions that recognizes the need for patients to bring their own formula and IMD-specific medications. These policies should be developmentally-appropriate and tailored to each individual’s abilities Metabolic clinicians have an advantage, because barring a revolution in the genetics workforce, they will likely be providing lifelong care to adults with IMDs. This longstanding care offers the opportunity to assess transition successes and revise policies to match adult needs.

At the risk of invoking all transition-related cliches, we must also address the notion of “little kids, little problems - big kids, big problems.” Our interviews show that many adults with MSUD are facing hard challenges that require conversations that can be awkward or uncomfortable. One of the most striking reports from this study is self-harm through dietary or medication noncompliance. Here, adults have successfully learned medical self-management, but leveraged this knowledge to deliberately provoke metabolic decompensation. Adults with MSUD are at high risk for depression and anxiety. Having a chronic illness also increases the risk of self-harm.^30,31 These risk factors require screening at each ambulatory appointment. Metabolic providers should incorporate screening measures, such as the PHQ-9 for depression or the GAD-7 for anxiety. These scales should be enhanced by directly asking if mood has ever affected IMD management, due to the high risk of injury from noncompliance. Clinicians should be prepared to ask about other challenging topics including substance abuse, sexual activity, contraception, and safety. Predatory relationships, either sexual or financial, were a repeated concern among caregivers. Metabolic teams can be important advocates for our adult patients – by proactively encouraging adoption of decision-making support and financial protections and by regularly reviewing these supports. These topics may be less familiar to pediatrics-trained providers, the predominant pathway for metabolic physicians in the United States. Thus, dedicated adult-centered metabolic training and a multidisciplinary approach with social work and case managers may be beneficial.

HCT does not occur in a vacuum and is a process for both patients and caregivers. Among pediatric-onset conditions, there is greater recognition that successful transition requires a partnership between patients, caregivers, and medical teams.^32,33 While caregivers may take a step back during transition, they should be encouraged to be active supporters throughout the process and adulthood in general. The high levels of independence achieved by our participants were only possible through consistent caregiver support. Caregiver activities could be logistical - all adults who lived on campus during college routinely returned home to portion out a week’s worth of formula with parental assistance -- or it could be financial with parents subsidizing rent so an affected adult could live independently. While transition planning should encourage building skills for autonomy, it should also create an environment where a young adult feels comfortable asking for help. Teamwork is already an ethos of many metabolic practices and this should continue through adulthood.

This study has limitations. We were able to sample a small subset of adults with MSUD. Our purposive sampling aimed include the range of intellectual and functional outcomes of MSUD. We did not include any affected individuals who were diagnosed through newborn screening, so our results may not be representative of the current adolescent MSUD population. Further, we did not obtain detailed medical histories from participants. Our previous adults with MSUD study suggests that long-term outcomes cannot be directly inferred from clinical history alone.^14,20 The goal of this study was to broadly describe aspects of being an adult with MSUD. While more people with MSUD are reaching adulthood, MSUD remains a rare disease and many clinicians are only familiar with their clinic population. Collecting the larger experience of adults with MSUD, even from a small number, helps universalize the condition. It also generates a starting point for defining transition- and adult-related priorities.

While this study focused on adults with MSUD alone, we believe the results are generalizable for individuals with many other pediatric-onset IMDs and rare disease. People with IMDs are entering adulthood with many unanswerable questions about their long-term health and functional outcomes. They desire independence but lack clarity on the supports needed to obtain autonomy. Metabolic clinicians are well poised to lead transition planning, but need resources that standardize education and counseling. Ideally, these resources would be applicable across many IMDs and incorporate different developmental abilities. Having a better understanding of the long-term outcomes of these rare diseases is also crucial for identifying measurable outcomes for transition interventions. Newborn screening for treatable IMDs has been remarkably successful over the last 25 years. Standardized transition protocols informed by lived experiences and evolving priorities of adults with IMD, not predetermined clinical checklists, are needed to match the level of care that newborn screening has provided.