ORIGINAL RESEARCH published: 25 February 2021 doi: 10.3389/fmed.2021.652358 Challenges in Transition From Childhood to Adulthood Care in Rare Metabolic Diseases: Results From the First Multi-Center European Survey Karolina M. Stepien 1 , Beata Kieć-Wilk 2,3 , Christina Lampe 4 , Trine Tangeraas 5 , Graziella Cefalo 6 , Nadia Belmatoug 7 , Rita Francisco 8 , Mireia del Toro 9 , Leona Wagner 10 , Anne-Grethe Lauridsen 11,12 , Sylvia Sestini 13 , Nathalie Weinhold 14 , Andreas Hahn 15 , Chiara Montanari 6 , Valentina Rovelli 6 , Cinzia M. Bellettato 16 , Laura Paneghetti 16 , Corine van Lingen 16 and Maurizio Scarpa 16* Edited by: 1 Bruno Sepodes, Adult Inherited Metabolic Diseases, Salford Royal NHS Foundation Trust, Salford, United Kingdom, 2 Department of University of Lisbon, Portugal Metabolic Diseases and Diabetes, Krakow University Hospital, Krakow, Poland, 3 Department of Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland, 4 Department of Child Neurology, Center for Rare Diseases Giessen (ZSEGI), Reviewed by: Justus-Liebig University, Giessen, Germany, 5 Norwegian National Unit for Newborn Screening, Division of Paediatric and Maria Mavris, Adolescent Medicine, Oslo University Hospital, Oslo, Norway, 6 Department of Maternal and Child Health, San Paolo European Medicines Agency, Hospital, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy, 7 Referral Center for Lysosomal Diseases, AP-HP Nord, Amsterdam, Netherlands Beaujon Hospital, Paris University, Clichy, France, 8 Portuguese Association for Congenital Disorders of Glycosylation and Virginie Hivert, other Rare Metabolic Diseases, Lisbon, Portugal, 9 Pediatric Neurology Department, University Hospital Vall d’Hebron, European Organisation for Rare Universitat Autónoma de Barcelona, Barcelona, Spain, 10 German-Speaking Self-Help Group for Alkaptonuria (DSAKU) e.V., Diseases (EURORDIS), France Stuttgart, Germany, 11 International Gaucher Alliance, Dursley, United Kingdom, 12 Gaucher Association Denmark, Holbaek, Koenraad Norga, Denmark, 13 Italian Association of Patients With Alkaptonuria (aimAKU), Siena, Italy, 14 Metabolic Unit, Interdisciplinary Centre University of Antwerp, Belgium for Metabolism: Endocrinology, Diabetes and Metabolism (UP) and Children’s Hospital, Charité University Hospital Berlin, *Correspondence: Berlin, Germany, 15 Department of Child Neurology, Justus-Liebig University, Giessen, Germany, 16 MetabERN, Regional Maurizio Scarpa Coordinating Center for Rare Diseases, Udine University Hospital, Udine, Italy maurizio.scarpa@metab.ern-net.eu Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in Specialty section: This article was submitted to biochemical pathways. Earlier diagnosis and advances in treatment have improved the Regulatory Science, life expectancy of IMD patients over the last decades, with the majority of patients now a section of the journal Frontiers in Medicine surviving beyond the age of 20. This has created a new challenge: as they grow up, the Received: 12 January 2021 care of IMD patients’ needs to be transferred from metabolic pediatricians to metabolic Accepted: 08 February 2021 physicians specialized in treating adults, through a process called “transition.” The Published: 25 February 2021 purpose of this study was to assess how this transition is managed in Europe: a survey Citation: was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Stepien KM, Kieć-Wilk B, Lampe C, Tangeraas T, Cefalo G, Belmatoug N, Disorders (MetabERN) to collect information and to identify unmet needs regarding the Francisco R, del Toro M, Wagner L, transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) Lauridsen A-G, Sestini S, Weinhold N, Hahn A, Montanari C, Rovelli V, from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only Bellettato CM, Paneghetti L, ∼40% have received appropriate training in health issues of adolescent metabolic van Lingen C and Scarpa M (2021) patients. In most centers (∼67%) there is no designated transition coordinator. About Challenges in Transition From Childhood to Adulthood Care in Rare 50% of centers provide a written individualized transition protocol, which is standardized Metabolic Diseases: Results From the in just ∼20% of cases. In 77% of centers, pediatricians share a medical summary, First Multi-Center European Survey. Front. Med. 8:652358. transition letter and emergency plan with the adult team and the patient. According to our doi: 10.3389/fmed.2021.652358 responders, 11% of patients remain under pediatric care throughout their life. The main Frontiers in Medicine | www.frontiersin.org 1 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe. Keywords: rare disease, inherited metabolic disease(s), transition process, challenge, adulthood (18 years and older), continuity of care, adult metabolic patient INTRODUCTION of the disease. These new challenges require the care of adolescent IMD patients being transferred from metabolic pediatricians Inherited Metabolic Diseases (IMDs) encompass an expanding to metabolic physicians specialized in treating adults to an and comprehensive group of rare diseases caused by inherited increasing extent, including the development and coordination defects in various biochemical pathways. Currently, IMDs of a multidisciplinary team for each individual IMD (12). An include more than 1,400 different genetic diseases (1) that adult metabolic team is defined as a core multidisciplinary group can be classified into 130 biochemical groups according to consisting of the following health professions: adult physician, the underlying metabolic pathway (2). The first symptoms of specialized nurse and/or patient coordinator, metabolic dietician, IMDs are often non-specific and overlap with more common and with access to other sub-specialists. disorders, which delays diagnosis and frequently results in organ The transition process is critical to ensure that adolescent dysfunction or failure. Although the individual incidence is low patients with IMDs obtain the best quality of life possible as (from 1 in 10,000 to 1 in 1 million), the cumulative incidence adults. Also, patients and families need to become empowered of all IMDs is high, ranging from 1 in 800 to 1 in 2,500 new- and take full responsibility of their disease. To this end, an borns (3–8). appropriate and gradual transition program is pivotal: patients Clinical presentation and course of IMDs are variable, need to be informed and accompanied step-by-step as they spanning from acute life-threatening metabolic decompensation gradually switch from a pediatric care in which doctors and in the new-born period (e.g., hyperammonemic encephalopathy) caregivers are responsible for the patient—from organizing to a slowly progressive disease with initial symptoms manifesting medical visits to buying medications—to an adult care in which only in adulthood (9). Given the progressive nature of IMDs, the patient is aware of all the precautions and treatments early diagnosis and treatment initiation are extremely important, to manage her/his condition (under control) and avoid as this can slow down or even halt the progression of the deterioration. Only through a successful and gradual transition disease. In addition, because of the variability and complexity program will an IMD patient become fully independent and of IMDs, highly specialized, experienced, and coordinated capable of taking life-long care of her/his health (13). multidisciplinary teams are required in order to minimize Transitional care has been defined as “the purposeful, planned negative health effects and to sustain patients’ quality of life. movement of adolescents and young adults with chronic physical Earlier diagnosis and advances in treatment have much and medical conditions from child-centered to adult-oriented improved the prognosis and life expectancy of IMDs over the health care systems” (14). But up to now little has been last decades, meaning that more than 90% of rare metabolic done to ensure that transition in IMDs is performed in a patients will survive beyond the age of 20 years (10, 11). formalized, standardized, and authoritative manner. Although Moreover, the expanded use of next generation sequencing both current literature on transition for chronic diseases in general widens the phenotypic spectrum within known diseases and is quite extensive (15–17), for IMDs only a few centers have reveals new IMDs. However, the increased survival has created created specific transition guidelines (12, 18, 19). In addition, a number of new issues and challenges: the development of long- an overview of the different transition practices and challenges term age-related complications, the metabolic progression of the in Europe has never been attempted. The collection of these underlying condition, and the lack of data on the natural course important data can serve as a starting point for common European transition best practice recommendations. Abbreviations: AOA, amino and organic acids related disorders; C-FAO, The European Reference Network for Hereditary Metabolic carbohydrate, fatty acid oxidation and ketone bodies disorders; HCP, healthcare Disorders (MetabERN), established in 2017, connects centers provider; IMD, inherited metabolic disease; TPWG, transition project working group; SNW, subnetwork; WP, work package. specialized in rare metabolic diseases at EU level; it represents Frontiers in Medicine | www.frontiersin.org 2 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases 77 healthcare providers (HCPs) from 23 EU Member States RESULTS and 44 patient organizations. It is also endorsed by the Society for the Inborn Errors of Metabolism (SSIEM). Overall, the Data was collected from 63/77 (81%) HCPs from 20 EU countries network follows almost 33,000 IMD patients (16,586 adults and (Table 1). Responders were mostly metabolic pediatricians 16,277 pediatric patients as of November 2020). MetabERN is (65.1% pediatric vs. 11.1% adult metabolic physicians; 23.8% organized in nine work packages (WP) and in seven subnetworks clinical geneticists and other specialties), with representatives (SNW), each SNW being specific for the metabolic defects covering all disease SNW, but dominated by the largest disease and/or pathways involved in the disease (for details please entities: lysosomal storage disorders (LSD; 87.1%), amino and refer to https://metab.ern-net.eu). The WP9, representing patient organic acids related disorders (AOA; 83.9%), and carbohydrate, empowerment, has highlighted the need to take urgent care of the fatty acid oxidation and ketone bodies disorders (C-FAO; 80.7%) transition process. In 2019, MetabERN and SSIEM organized a (Table 1). webinar in which four MetabERN centers presented their own Of the responding centers, 6.4% are dedicated exclusively program on transition. Then, in the context of the WP4 on to adults, 84.1% of centers follow both adult and pediatric Guidelines, Care Pathways and Standardization for Medical Care patients, while 9.5% are pediatric only (Table 1). Overall, almost and Transition, MetabERN established the Transition Project all responding centers follow adult patients (93.7%), and the Working Group (TPWG), which is led by referral experts in the majority of these have a separate adult metabolic team. However, field in collaboration with the associations of patients. in only 30.7% of cases is the adult metabolic team available for As a first step in its activities, the TPWG has investigated all metabolic conditions (Table 1). The main reasons identified how the transition process is currently organized in European for the centers not to have an adult team include: (i) no interest metabolic centers, in particular what transition programs in the metabolic field from adult physicians (34.7%); (ii) no currently exist, whether there is any reimbursement for existing position (30.8%); (iii) lack of specialty adult training in metabolic patients available, and how the transition process the country (30.8%); and (iv) preference of patient/family to be could be supported further to facilitate smooth transition for followed by the pediatric team (30.8%) (Table 1). metabolic patients. In centers with existing transition programs, for over half the For this purpose, a survey was created and sent to all cases (52.4%) transition starts at 18 years of age. Consequently, the MetabERN centers to collect information and to identify the process is mostly finalized after the age of 18 (57.1 vs. 21.4% unmet needs. The survey covered not only medical, but also between 16 and 18 years of age), while 10.7% of patients never organizational, structural, social, administrative and educational transition because they remain under pediatric care throughout issues in order to explore and assess potential difficulties in the their life (Table 1). Of the doctors involved in the transition organization of an efficient transition process from the point of process, the majority of the respondents (87.7%) discuss the view of physicians dealing with patients with IMDs. This initial transition issue with the adolescent patients and parents, but overview of the current status of transition in Europe is essential <50% have a separate consultation with the child/adolescent. to raise awareness on the issue at a national and European level. Medical specialities involved in the medical care of adult metabolic patients are mainly internists (50%), followed by clinical geneticists and cardiologists (15.6% each) (Table 2). In the majority of centers (80.7%) the adult patients are MATERIALS AND METHODS followed also by other specialists, mainly neurologists (77.8%), cardiologists (64.8%), nephrologists (61.1%), and nutritionists The Survey Monkey platform was used to design the survey (59.3%) (Table 2). Importantly, it should be noted that among and collect the data. Invitations with the link to access the cardiologists and nephrologists participating in the survey, also platform were sent via email to all 77 MetabERN centers in pediatricians were represented, further increasing the percentage 23 EU countries. The survey included 34 questions aimed at of pediatricians caring for adult patients with an IMD. In most gathering information on the status of the transition process, its centers there is no designated transition coordinator (69.5%) organization and the associated difficulties and needs from the and no dedicated physician in charge of the transition on the perspective of HCPs (see Supplementary Material for full list adult side that collects and summarizes information from each of questions). The survey included multiple choice questions, sub-specialist (62.1%) (Table 2). with the possibility to write additional text under the option Almost half of the centers (48.2%) provide a written “Other” when available; only in the last question participants individualized transition protocol, which is standardized in were asked to add any relevant comment as free text (see nearly 20% of cases (Table 3). In the majority of centers (63.4%) Supplemental Material). Members of the TPWG prepared the no patient organization has been involved in the development survey in collaboration with adult IMD patients and patients of the transition plan (Table 3). In almost 77% of centers associations (see section Acknowledgments). The survey was pediatricians share a medical summary, transition letter and active for 20 months, from 1st October 2018 to 1st May an emergency plan (if applicable) with the adult team and the 2020. All participants (see section Acknowledgments) gave patient (Table 3). This document contains information such as their consent for data collection and publication. Data was medications and relative dosage, comorbidities, a short summary extracted and descriptive statistical analysis was performed using of the disease and precautions, an emergency regime, a nutrition Microsoft Excel. plan when healthy, and the last blood test results (Table 3). Frontiers in Medicine | www.frontiersin.org 3 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases TABLE 1 | Characteristics of the responders and the relative centers. TABLE 1 | Continued Category n (%) Category n (%) Profession: Age at which transition process is finalized: Metabolic pediatrician 41/63 (65.1) >18 years of age 32/56 (57.1) Adult metabolic physician 7/63 (11.1) 16–18 years of age 12/56 (21.4) Clinical geneticist 3/63 (4.8) Never, because the patient remains under pediatric care 6/56 (10.7) throughout his/her life Other (neurologist, cardiologist, psychologist, genetic counselor, 12/63 (19) 14–16 years of age 0/56 (0) clinical biochemist, internal medicine/endocrinology/diabetes specialist) 12–14 years of age 0/56 (0) Metabolic conditions followed by the responder: Never, because the patient is transferred to an adult clinic 0/56 (0) without any preparation LSD 54/63 (87.1) Other (for older patients the transition is finalizing now, 6/56 (10.7) AOA 52/63 (83.9) regardless of age, while for Fabry and other patients it is finalized C-FAO 50/63 (80.7) at 16 years of age; depends on the disease: some patients PM-MD 44/63 (71) remain at least in part managed by pediatricians) CDG 38/63 (61.3) AOA, Amino and organic acids-related disorders; PM-MD, Disorder of pyruvate PD 37/63 (59.7) metabolism, Krebs cycle defects, mitochondrial oxidative phosphorylation disorders, disorders of thiamine transport and metabolism; C-FAO, carbohydrate, fatty acid oxidation NOMS 37/63 (59.7) and ketone bodies disorders; LSD, lysosomal storage disorders; PD, peroxisomal Center status: disorders; CDG, congenital disorders of glycosylation and disorders of intracellular Adult and pediatric center 53/63 (84.1) trafficking; NOMS, disorders of neuromodulators and other small molecules. Pediatric center only 6/63 (9.5) Adult center only 4/63 (6.4) Center following adult patients with IMDs: Among the responding physicians, only 39.7% have received Yes 59/63 (93.7) appropriate training in managing health issues in adolescent No 4/63 (6.4) metabolic patients, while the others acquired the necessary Center with separate adult metabolic team: knowledge mainly through courses and internships in metabolic Yes, for all kinds of metabolic conditions 19/62 (30.7) centers (Table 4). The main challenges of HCPs in managing the transition Yes, for the majority of metabolic conditions 12/62 (19.4) process are lack of time (49.2%) and shortage of adult metabolic Yes, for selected groups of metabolic conditions 12/62 (19.4) physician positions (44.1%) (Table 4). This is reflected in the No, pediatric team follows patients life-long 5/62 (8.1) implementations that, according to the responders, are most Reasons for not having an adult metabolic team: required for a successful transition: medical staff dedicated to Lack of interest in IMDs among adult physicians 9/26 (34.6) transition (51.7%), a transition coordinator (45%), and specific Patient/caregiver’s preference to be followed by pediatric 8/26 (30.8) metabolic training for adult physicians (43.3%) (Table 4). Lastly, metabolic department 90% of responders report the absence of any financial support for Lack of special training for adult physicians in metabolic 8/26 (30.8) transition programs (Table 4). diseases in the country No existing position/vacancy for adult metabolic diseases at the 8/26 (30.8) center Lack of financial support 5/26 (19.2) DISCUSSION Lack of extra reimbursement for adult complex metabolic 5/26 (19.2) patients This survey provides the first European report on the status Lack of adult physicians willing to be involved 4/26 (15.4) of the transition process in rare metabolic diseases from the Other (historically, adult IMD patients have been taken care in 14/26 (53.9) HCPs perspective. With 63 centers responding from 20 EU the pediatric hospital; difficulties in getting more salaries for adult countries, our results may provide a representative overview of physicians; smooth transition by joint follow-up with both adult the current situation in European centers of excellence, selected and pediatric physician until the patient agrees to be followed by the internist) for their expertise in metabolic diseases. The pediatric specialty Age at which transition process starts: was the most prevalent responder group in our survey, reflecting 18 years of age 33/63 (52.4) predominantly the pediatricians’ point of view in the transition process. At the same time, our surveys show a large disproportion 16 years of age 12/63 (19) between the medical specialties looking after IMD patients. This 20 years of age 2/63 (3.2) underlines the multisystemic nature of IMDs and the peculiar Other (at 10 or 14 years of age; after 18 years of age or later; 16/63 (25.4) from 16 to 28 years of age, start discussion on transition from need of affected patients to be followed by multiple professionals, age 12; no transition process) who should interact and collaborate with one another within a well-defined multisystemic approach framework. Unfortunately, (Continued) in a real world situation patients are seen by different specialists Frontiers in Medicine | www.frontiersin.org 4 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases TABLE 2 | Specialties involved in the care of adult IMD patients and their TABLE 2 | Continued transition. Category n (%) Category n (%) Rheumatologist 9/54 (16.7) Specialty of the physician taking care of adult IMD patients: Psychiatrist 8/54 (14.8) Internist 16/32 (50) Designated transition coordinator at the center: Clinical geneticist 5/32 (15.6) Yes 18/59 (30.5) Cardiologist 5/32 (15.6) No 41/59 (69.5) Neurologist 4/32 (12.5) Dedicated physician collecting information from each specialist Diagnosis, geneticist 2/32 (6.3) at the center: Dietician/nutritionist 2/32 (6.3) Yes 22/58 (37.9) Orthopedist 2/32 (6.3) No 36/58 (62.1) Ophthalmologist 2/32 (6.3) Radiologist 2/32 (6.3) Social worker 2/32 (6.3) Surgeon 1/32 (3.1) that rarely know or communicate with each other, resulting in a Clinical trial technician 1/32 (3.1) fragmented, uncoordinated and suboptimal care. Coordinator/secretary 1/32 (3.1) Here we show that most HCPs discuss transition with the ICU and anesthetist 1/32 (3.1) family and share a medical summary with the adult physician and Gastroenterologist 1/32 (3.1) the patient. In most cases, this summary is not standardized and Genetic counselor 1/32 (3.1) includes a short description of the disease, its precautions Medical biochemist 1/32 (3.1) and comorbidities, type and dosage of medications, a detailed Neuro-pediatrician 1/32 (3.1) emergency regime, a nutrition plan, and the latest blood test results. Despite decades of increasing knowledge regarding the Otorhynolaryngologist 1/32 (3.1) importance of a properly structured transition for later health Palliative care 1/32 (3.1) outcomes (20, 21), our survey still demonstrates unmet needs and Pharmacist 1/32 (3.1) overall slow acquisition of the mandatory aspects for a successful Physical and rehabilitation medicine 1/32 (3.1) transition for rare metabolic patients, their families and adult Psychologist 1/32 (3.1) physicians in Europe. Pneumologist 1/32 (3.1) In most centers a transition coordinator is missing and the Special nurses 1/32 (3.1) process is fragmented or even non-existent, to a point where Epidemiologist 0/32 (0) about 10% of patients never transition and stay under pediatric Internist-rheumatologist 0/32 (0) care all their life. In this context, the presence of a transition Hepatologist 0/32 (0) coordinator is a major factor for a successful transition program, Neuropathologist 0/32 (0) as it ensures that adult care teams are aware of, and prepared Neuropsychologist 0/32 (0) for, the management of rare conditions and their peculiarities. Psychiatrist 0/32 (0) The coordinator schedules the transition meetings, collects and School educator 0/32 (0) updates all the necessary documentations, and ensures that all Stomatologist 0/32 (0) appropriate specialists and social professionals are present during Other (endocrinologist, nephrologist, pediatrician, metabolic 8/32 (25) the transition visits. Despite these differences, the transition physician) coordinator should have defined duties to ensure the highest Other specialists involved in the care of adult IMD patients: standards and success of the transition process. Our survey Neurologist 42/54 (77.8) identified that the appointment of a transition coordinator is Cardiologist 35/54 (64.8) necessary, which calls for immediate action from healthcare Nephrologist 33/54 (61.1) organizations and policy makers to improve the transition Nutritionist 32/54 (59.3) process across Europe. The need for this new administrative role Clinical geneticist 22/54 (40.7) has also been identified by De Castro et al. (22). Ophthalmologist 21/54 (38.9) Another main finding in our study is the shortage of Hepatologist 20/54 (37) physicians specialized in the adult care of IMDs. In fact, Hematologist 19/54 (35.2) only 11% of the respondents to the survey were adult Endocrinologist 19/54 (35.2) IMD professionals and most centers stated that an adult Laboratory geneticist 17/54 (31.5) team was only available for a subset of metabolic diseases. Rehabilitation specialist 14/54 (25.9) In this context, the lack of specific metabolic training for Gastroenterologist 12/54 (22.2) adult physicians regarding adolescent health issues must be General internal medicine 12/54 (22.2) emphasized, as this is a key factor for implementing a successful transition program. Education of adult specialists (Continued) in IMDs is important for a number of reasons: not only do Frontiers in Medicine | www.frontiersin.org 5 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases TABLE 3 | Information exchanged among physicians for/during transition. TABLE 4 | Shortcomings, challenges and needs related to transition. Category n (%) Category n (%) Written individualized plan/protocol/letter for transition provided: Members of team looking after adolescent patients with formal No, no particular documents are provided other than 22/56 (39.3) training in health issues in adolescent IMD patients: the medical record itself Yes 23/58 (39.7) Yes, a written individualized document for transition is 15/56 (26.8) No 31/58 (53.5) provided, but it is not standardized Other (SSIEM courses and conferences, only for some IMD, only 4/58 (6.9) Yes, the hospital has a standard operating procedure 6/56 (10.7) for general health issues in adolescents) for transition Informal methods used to acquire knowledge on treating Yes, a written standardized individualized protocol for 5/56 (8.9) adolescent IMD patients: each patient is provided Course 13/36 (36.1) Yes, a document for transition is provided, but without 1/56 (1.8) Placement in metabolic center 13/36 (36.1) knowing which physician to address it to if the patient will be followed at another hospital Non-recognized education program 11/36 (30.6) No, but an unwritten transition agreement/procedure is 1/56 (1.8) Fellowship 9/36 (25) arranged with the patient Other (personal study, clinical practice, part of another 12 (33.3) Other (ongoing protocol setup, summary letter, full 6/56 (10.7) specialization, prolonged work with IEM, cooperative interaction) documentation) Most difficult challenges in managing the transition process: Relevant patient organization(s) involved in the Lack of time 29/59 (49.2) development of a standard procedure for transition, Lack of adult metabolic physician positions/vacancies 26/59 (44.1) where this is available: Knowledge gaps on the topic amongst medical staff 17/59 (28.9) Yes 8/41 (19.5) Lack of reimbursement 14/59 (23.8) No 26/41 (63.4) Lack of interest 9/59 (15.3) Other 7/41 (17.1) Poor communication between pediatric and adult centers 7/59 (11.9) Pediatric team sharing medical summary, transition passport or letter and/or emergency care plan with adult Other (lack of pediatric metabolic physicians, growing number of 17/59 (28.8) team and patient: patients, lack of cases manager, metabolic medicine is not available as specialization, no financial support, no official Yes 43/56 (76.8) metabolic position, few doctors dedicated, low number of No 8/56 (14.3) pts/condition and diverse patient population) Other (emergency plan only, hospital discharge 5/56 (8.9) Most needed implementations for a successful transition: summary, in the making) More staff specifically dedicated to transition 31/60 (51.7) Information included in the medical summary: A dedicated transition coordinator 27/60 (45) Medications 45/49 (91.8) Special metabolic training for adult physicians 26/60 (43.3) Short summary of disease and precautions 44/49 (89.8) Dedicated (or interested) adult physicians 21/60 (35) Updated list of medications and dosages 44/49 (89.8) Adult metabolic positions 19/60 (31.7) Comorbidities 42/49 (85.7) A transition protocol/standard operating procedure 19/60 (31.7) Detailed emergency regime 39/49 (79.6) A physical space for transition clinics 17/60 28.3) Last blood test results 38/49 (77.6) Other (setup of a transition clinic; adult metabolic clinic; support 8/60 (13.3) Nutritional plan when healthy 36/49 (73.5) by paramedics such as dietitians, psychologists, social workers; Medications to avoid 29/49 (59.2) more protocols for adult patients; more pediatricians and Suggested blood tests when admitted to hospital 28/49 (57.1) metabolic adult physicians; more time to dedicate to transition) Anesthesia precautions 26/49 (53.1) Availability of additional financial support for transition clinics: Surgery preparation instructions 24/49 (49) Yes 3/60 (5) Other (pregnancy precautions, recurrence risk, 13/49 (26.5) No 54/60 (90) emergency regime, full history radiological images, Other (information unknown; no transition in place, process for 3/60 (5) psychological tests report, special needs) improvement is ongoing) an increasing proportion of pediatric patients survive with The SSIEM recently launched a survey to 89 adult specialist more complex disorders and with neurocognitive disabilities, members. Despite the fact that practical clinical experience with but a greater number of IMDs presenting in adulthood adult IMDs was considered key for their own education in are being diagnosed in the genomic era. As a part of rare metabolic diseases, most responders (73%) judged their education and optimization of the transition process, it education as poor or fair. The main message was the need for is important to develop cooperation and trust between formal training opportunities in adults and courses on IMDs pediatricians and adult physicians (22). This will facilitate a (23). These results were confirmed by our survey, in which only more harmonious and less stressful transition process for the about 40% of responders reported formal training in health issues IMD patients. regarding adolescent IMD patients, while informal training such Frontiers in Medicine | www.frontiersin.org 6 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases as fellowships, short courses, work placement, clinical practice strategy, the optimization of electronic medical records could be and personal studies were common. As a result, neither pediatric of help. nor adult clinicians are prepared to adequately address the The lack of financial resources is another aspect that complex developmental challenges that characterize adolescent makes it difficult to implement appropriate transition teams metabolic patients. Indeed, our survey indicates that the factors and programs. In the midst of the current COVID-19 that are mostly needed by HCPs are: adult physician positions, pandemic, which imposed great changes in healthcare funds a transition coordinator, and specific metabolic training for and organization, rare diseases must not be forgotten and adult physicians. The shortage of adult metabolic specialists has specific activities should be put into place to increase awareness increasingly been revealed by the advancements made over the in public institutions and authorities about IMDs and the last few decades in metabolic diseases. Adult physicians have transition process. historically not been involved in the management of IMDs From the patient perspective, there are significant challenges because until about 20 years ago 75% of metabolic patients died to be considered when transitioning from a family-centered, before reaching the adult age, resulting in a “skewed population developmentally-focused, and multidisciplinary pediatric care to of providers” (22). Today, thanks to better healthcare, improved a less supportive adult healthcare system that is often unfamiliar follow-up programs, and more treatments available there is an with rare diseases (13). Among them, there is the resistance and increasing number of metabolic patients that reach adulthood. In lack of trust of the patient and his/her family in regard to the adult this regard, both SSIEM and MetabERN are already organizing team, and the fear of a lack of expertise in the adult specialists. dedicated courses to create and train a new class of professionals, Indeed, in a recent study on expectations of adolescents with and in particular adult physicians, with expert knowledge and chronic disorders and their parents, the most important barriers practical experience in the long-term care and management of identified for successful transition were anxiety and lack of IMDs. However, additional support is needed from hospital information of the adult healthcare specialist (24). Therefore, managements, authorities, and the European Commission to it is important to predispose combined consultations with encourage adult physicians to focus on IMD patients. This will the pediatric and adult specialists, to anticipate the exchange be important also to overcome another aspect highlighted by our of medical records, and to establish clear communication survey, that is the lack of interest in IMDs by medical students strategies, which can be extremely beneficial in mitigating these and/or adult physicians. As rare and complex diseases, IMDs difficulties and in making the patient and the caregivers feel are not well known and are often overlooked in the medical more comfortable and continually cared for at the highest community; therefore, more effort is needed to disseminate standards. Better information and education on their disease, information about the challenges and opportunities offered by as well as greater active involvement in the decision-making the metabolic disease field and thus create novel interest in of their care, may be pivotal to improve patient and family this specialty. adherence to and satisfaction with transitioning (22, 25). In this Our results show that adult IMD patients are regularly context, the role of patient associations is important to promote followed mainly by internists, with the widespread involvement such measures. In addition, from a patient point of view, the of other sub-specialists, illustrating the complexity of the transition process is multidimensional, involving transitions with diseases. This is not surprising, as most adults with a chronic respect to development (adolescent becoming a young adult), condition demand surveillance by different specialists; however, situation (switch from pediatric services to adult health services) this also highlights the fact that healthcare is more fragmented and health–illness (role changes, self-management of a chronic in adulthood. This might create obstacles in guaranteeing condition) (25). Due to the heterogeneity of IMDs regarding a continuous and holistic care of adult metabolic patients. organ involvement and disease severity, an interdisciplinary Therefore, it is necessary to create a multidisciplinary team framework of care should be introduced stepwise to meet of HCP specialized in the treatment of adult patients with the biopsychosocial needs of early adolescents (11–15 years of IMDs; for example, a team coordinated by an internist age), late adolescents (16–18 years old), and emerging adults specialist in metabolic diseases. Regarding the type of specialties (18–25 years of age), thereby also differentiating between life- following IMD patients, these include mostly neurologists, threating IMDs, IMDs with chronic illness, and IMDs with cardiologists, nephrologists, orthopedist and nutritionists. This is severe disabilities and/or severe intellectual impairments (11, 25, not surprising, as it is a reflection of the multi-organ involvement 26). Since the current survey did not target patients and their of IMDs and the importance of a balanced diet to avoid families, a dedicated survey is necessary to focus on their point metabolic decompensation. of view. The whole process of transition is further complicated by This study has several limitations. Firstly, it provides only the the lack of standardized programs or specific guidelines shared MetabERN HCPs’ point of view. More specifically, the majority across Europe. This is a crucial aspect that needs to be addressed of respondents were pediatricians, as they have been the historical by institutions and policy makers in order to ensure that the managers of patients with IMD, leaving the adult perspective of best possible care—and therefore quality of life—is given not the transition process less represented. Moreover, transition is only to IMD and other rare disease patients, but to all patients a process involving several key players in the center of interest; with a chronic condition that arises during childhood. Indeed, therefore, the next survey to complement that of the HCPs should the transition issues that were highlighted with our survey may be targeted at patients and their associations to understand be shared by other chronic conditions. As a possible solution their point of view and especially to gather information on Frontiers in Medicine | www.frontiersin.org 7 February 2021 | Volume 8 | Article 652358 Stepien et al. Transition in Rare Metabolic Diseases the social and psychological aspects of transition, which seems AUTHOR CONTRIBUTIONS even more difficult in patients with multiple disabilities. Our survey focused on HCPs, which can provide information and GC, A-GL, and KMS developed the survey and revised the suggestions regarding the more practical and administrative manuscript. NB, MT, RF, AH, BK-W, CL, CM, TT, VR, SS, KMS, aspects of the transition process. In fact, no publications exist LW, NW, and CvL revised the manuscript. CMB and LP analyzed on the patient or caretaker point of view and indeed this is the data and wrote the manuscript. MS supervised the study and one of the next steps to be taken by MetabERN. Secondly, revised the manuscript. All authors contributed to the article and due to the design of the survey, we were not able to collect approved the submitted version. specific data regarding the percentage of pediatricians that are involved in the care of adult IMD patients. The majority of FUNDING our responders (65%) were pediatricians and at present we are not able to assess whether other specialists taking care of This work was generated within the European Reference adult patients are also pediatricians. Thirdly, specific questions Network for Rare Hereditary Metabolic Disorders (MetabERN), about the set-up and maintenance of a successful transition co-funded by the European Union within the framework of the process were missing, so at this stage we cannot provide Third Health Programme ERN-2016 - Framework Partnership exhaustive examples or recommendations on how to improve Agreement 2017–2021, Project ID No. 739543. the transition where this is difficult. Further work is needed to propose specific transition recommendations in the field ACKNOWLEDGMENTS of IMDs, for example by using templates from hospitals that have a long experience with transition and have made some We are grateful to all HCP representatives of the MetabERN written recommendations, also taking into account the patients’ collaboration group that replied to our survey: Giovanni perspective. Indeed, this is part of the further activities planned Ceccarini, Stefan Koelker, Sabine Fuchs, Luisa Diogo, Stephen by MetabERN’s TPWG. Attard, Niklas Darin, Salvatore Grosso, Maria Alice Donati, The final aim of MetabERN and the TPWG is to collaborate Carlo Dionisi-Vici, Julia Hennermann, Madara Masinska, Anibh and share expertise and good practices to develop possible Das, Terry Derks, Dorothea Moeslinger, Pavel Jesina, Viktor action guidelines and minimal standard of care. In this way, all Kozich, Ivo Barić, Athanasia Ziagaki, Ans van der Pleog, Per specialists involved in the care of IMD patients, and potentially Mathisen, Birute Tumiene, Maria-Estela Rubio-Gozalbo, Mojca in other fields, will have access to guidance and support in Zerjav Tansek, Angeles García Cazorla, Luis Aldámiz-Echevarría, the management of the critical process of transition, which in Annet M. Bosch, Olga Azevedo, Svetlana Lajic, Sabine Grønborg, turn will aid a successful and efficient transfer from pediatric Sarah Grünert, Katalin Szakszon, Montserrat Morales Conejo, to adult care for all patients. This study is the first step in Pascale de Lonlay, Annalisa Sechi, Corinne De Laet, Ana Gaspar, that direction. Giancarlo Parenti, Kurt Ullrich, Janice Andersen, Alessandro Simonati, Marie-Cecile Nassogne, Dominique Paul Germain, DATA AVAILABILITY STATEMENT François-Guillaume Debray, María Luz Couce, Klaus Mohnike, Serena Gasperini, Philippe Labrune, Esmeralda Martins, Eyskens The datasets presented in this article are not readily available Francois, Erle Kristensen, Allan M. Lund, Olga Azevedo. We because they are stored in a private depository. Requests also thank the patients organizations that were involved in to access the datasets should be directed to Maurizio the development of the survey: International Gaucher Alliance, Scarpa, maurizio.scarpa@metab.ern-net.eu. Gaucher Association Denmark and German-speaking Self-help Group for Alkaptonuria (DSAKU) e.V. ETHICS STATEMENT SUPPLEMENTARY MATERIAL Ethical review and approval was not required for the study on human participants in accordance with the local legislation and The Supplementary Material for this article can be found institutional requirements. The patients/participants provided online at: https://www.frontiersin.org/articles/10.3389/fmed. their written informed consent to participate in this study. 2021.652358/full#supplementary-material REFERENCES 4. Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child. (2006) 91:896– 1. Inborn Errors of Metabolism Knowledgebase (IEMbase). Available online 9. doi: 10.1136/adc.2005.091637 at: http://www.iembase.org (accessed November, 2020). 5. Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, 2. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed Cockburn F, et al. 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Transition from pediatric to adult care in adolescents with original author(s) and the copyright owner(s) are credited and that the original hereditary metabolic diseases: specific guidelines from the French network publication in this journal is cited, in accordance with accepted academic practice. for rare inherited metabolic diseases (G2M). Arch Pediatr. (2018) 25:344– No use, distribution or reproduction is permitted which does not comply with these 9. doi: 10.1016/j.arcped.2018.05.009 terms. Frontiers in Medicine | www.frontiersin.org 9 February 2021 | Volume 8 | Article 652358