Trigger points of palliative care assessment in inherited metabolic diseases

Trigger points of palliative care assessment in inherited metabolic diseases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Trigger points of palliative care assessment in inherited metabolic diseases Gustavo Marquezani Spolador, Rita Tiziana Verardo Polastrini, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6692221/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract The interaction between palliative care (PC) and inherited metabolic diseases (IMD) has increased. However, in clinical practice, few correspondences are found, mainly due to the misunderstanding about the specialty, refuse to refer, lack of resources and specific eligibility criteria for IMD. This article aims to establish trigger points to PC referral in IMD field. Three pairs of illness trajectories were established based on literature and considering the pathophysiological groups of IMD. The first pair comprises the intoxication disorders with 2 models of outcomes: Model 1 – organic acidurias, urea cycle disorders and some aminoacidopathies; Model 2 - metabolite repair defects, amino acids synthesis defects and the fatty acids synthesis defects. The second pair represents the energy disorders: Model 1 – FAOD and MCT/GLUT; Model 2 – Some mitochondrial disorders. The last pair contemplates the complex molecules disorders and also shows 2 patterns of evolution: Model 1 – storage disorders and CDGs; Model 2 – Cellular processing and trafficking defects. The trigger points consist in diagnosis moment; the uncertainly of disease’s course; the dietary and treatment management and their burdens; the metabolic crisis; the multimorbidity and the new normal; new therapies and the end-of-life. This framework is an opportunity to establish a partnership to improve the care beyond the illness, looking at the protagonist of the trajectory: the patient. inborn errors of metabolism. metabolic diseases. palliative care. pediatrics. metabolism. pediatric palliative care Figures Figure 1 Figure 2 Figure 3 Synopsis It is never too late to start: points of action for palliative care professionals in the trajectory of inherited metabolic diseases. 1. Introduction The palliative care (PC) has been an ally to many specialties in terms of symptoms management, psychological assessment and decision-making process. Reinforcing the premise of to offer early care for patients and their relatives, the PC has been a tool to inherited metabolic diseases (IMD) setting and has become a public health issue regarding costs reduction and life prolonging with quality of life. 1 , 2 , 3 The intersection between PC and IMD has increased since last 5 years. Few but robust publications has showed the expressive number of IMD patients in follow up with the PC team. From a general symptoms panorama, highlighting the neurologic, respiratory and gastrointestinal as being the most frequent in this group, to an epidemiological outlook of each IMD groups into PC setting, regarding the age of diagnosis, the age of PC referral and the time between diagnosis and PC referral. 4 , 5 Nevertheless, in IMD clinical practice, it is a challenge to integrate the PC in a natural and non-stigmatized way, considering some barriers as such as: lack of resources to refer to; not knowing that resources exist; ignorance regarding what palliative care is; reluctance to refer; reluctance of patient and/or family to be referred and restrictive specialist palliative care service program eligibility criteria. 6 Concerning the knowing of those resources, the ignorance and reluctance of professionals and patients, an institutional continuing education program about PC and multicenter collaboration for scientific publications can improve the misconception of the specialty and establish a new healthcare framework assembling the PC as a rule. About the eligibility criteria, this article aims at transforming the stigma of palliative care assessment into a useful tool for metabolic physicians throughout the patient's trajectory, highlighting the trigger points for PC referral. 2. Methods 2.1. Review of articles approaching IMD in PC We made a review of scientific publications in PubMed, using the terms Palliative Care or Palliative Medicine or Hospice Care and Metabolic Diseases or Inborn Errors of Metabolism or Inherited Metabolic Diseases. Regarding the descriptors, they have not based on the Medical Subject Headings (MeSH), since there is little literature associating the two themes, non-uniformity to the use of IMD term and articles, in which PC was only cited not extensively discussed. In this way, we found four articles addressing the intersection between PC and IMD the last ten years. The two oldest date from 2018 and present a general perspective of IMD in PC setting, highlighting for the first time the prevalence of these disorders. In 2021, a study scrutinized the IMD profile in hospitalized patients during two months, introducing the most prevalent symptoms in this population and advocating for PC to promote the best care by controlling symptoms. 4 , 7 , 8 Finally, the newest publication presented a global evaluation of IMD, according to pathophysiological groups and establishing a relationship between the time of diagnosis and the referral to PPC group. 5 2.2. Establishing a parallel between IMD and PC trajectories A recent and innovative publication proposed an adaptation of pediatric palliative care groups to metabolic diseases, considering the pathophysiological groups of IMD, their most frequent outcomes and the four types of illness trajectories established by Hain (2008) from conditions eligible to Pediatric Palliative Care (PPC) defined by Association of Children’s Palliative Care. 9 , 10 , 11 This proposal does not cover all the IMD, but it has begun a discussion about the potential patients who could benefit from the early introduction of palliative care based on the recognition of their trajectories. 10 2.3. Identifying the common trigger points Regarding to the concept of chronic complex conditions, the conditions eligible to PPC, their trajectories and the adaptation of these to IMD, we identified common trigger points of PC entrance. 12 These trigger points were established considering the pathophysiological IMD groups and their main characteristics. 9 Furthermore, we defined a thermometer of time to PC referral, reflecting the WHO recommendation and the clinical practice. 1 , 13 3. Results The proposal of IMD trajectories in context of palliative care were used as a basis for the trigger point’s allocation. 10 Regarding to the pathophysiological groups of IMD (intoxication, energy and complex molecules), two models of trajectories were established considering the heterogeneous manifestation of each disorder. In relation to the group 1 (intoxication disorders), the model 1 contemplates the most common courses of organic acidurias, urea cycle disorders and some aminoacidopathies. Additionally, the model 2 considers the metabolite repair defects, amino acids synthesis defects and the fatty acids synthesis defects, which present a different pattern of evolution than the first ones. The Fig. 1 summarizes the trajectories of intoxication IMD (IIMD) and highlights the trigger points and a scale of the best moment to referral to PC. The group 2, represented by the energy disorders, also presents two patterns of trajectories. The model 1 comprises the fatty acid oxidation disorders (FAOD) and the disorders of energetic molecules carriers, as such as monocarboxylate transporters (MCTs) and solute carriers (e.g. GLUT1). The model 2 discloses the most severe presentations of mitochondrial disorders. In these cases, it is important to reinforce that not all mitochondrial disorders will present the outcome shown below in Fig. 2 -B. Finally, the group 3 of pathophysiological classification characterized by the complex molecules disorders presenting a model 1 of trajectory, mainly in storage disorders and congenital disorders of glycosylation (CDGs) and a model 2 comprising the cellular processing and trafficking defects, the newest IMD group. The Fig. 3 shows these 2 models of trajectories and also highlight the trigger points of PC entrance and a thermometer of the best time to referral to this specialty. 4. Discussion As stated above, the integration of PC and IMD has faced some barriers. However, an integrated perspective of PC to metabolic clinic can be adapted from a typical chronic illness trajectory. Trigger points as such as the diagnosis moment, the uncertainly of disease’s course, multimorbidity and end-of-life are common to all chronic complex diseases and will be discussed in detail below. 8 Adding to IMD context, the dietary management and its burden, metabolic crisis and the advent of new therapies – especially gene therapy – are also addressed, which increases the familiarity of the referral time and personalize the PC to IMD field. Finally, some gaps in literature even in PC have been described. The decision-making process and the possibility of withdrawing treatments, still very incipient and involving bioethical issues, and the anticipatory grief assessment, an underestimated topic in any specialty in the healthcare field. The diagnosis The moment of an illness diagnosis is a vivid event throughout family’s life and it is the beginning of a new trajectory. 14 The diagnosis is considered highly relevant for parents of children with intellectual disability. It helps them to deal with emotions, available treatments and family planning. 15 The emotional reaction of parents is influenced by the diagnostic process, which can last from one year up to 8 years, depending on the clinical presentation, access to exams and the healthcare system in a course called diagnostic odyssey. 16 , 17 However, some families are faced to an unknown diagnosis. This “not knowing” can be a source of distress, due a future incertitude, impossibility to do something or to connect with other similar families. In this context, the communication is the best tool of health professionals to guide the caregivers during the diagnosis process. 17 The uncertainly According to the diagnosis of an IMD and its outcome, parents and caregivers are faced to uncertainties throughout life. Since the diagnosis odyssey, depending on country and condition in terms of diagnosis methods and access to these technologies, to the child’s life outcome, regarding to metabolic crisis, a new clinical plateau establishment and drugs response. There are an extensive literature proofing the impact of IMD diagnosis in parents. The most prevalent stressors included emotional, social, financial, medical and lack of freedom. Guilty and the unpredictable nature of symptoms and eventual factors that can trigger those symptoms were also sources of stress. 4 , 18 , 19 Coping with the diagnostic odyssey, understanding the child needs, recognizing changes involving the family dynamics, and navigating challenges in professional health systems are aspects that permeate the trajectories of this caregivers. 20 Dietary management and its burden Throughout the diagnostic process and outcome uncertainty, some metabolic diseases require specific dietary management, which can be a stressful care for the parents. Recent studies reinforce the caregiver’s burden associated with dietary restrictions, mainly in organic acidurias (OA), urea cycle disorders (UCD) and maple syrup urine disease. 21 Nevertheless, the impact of food restriction in patients and their caregivers is theme of literature a long time ago, mostly considering that dietary requirements as a social and emotional barriers since they difficult to grasp and communicate in a social environment. 22 Metabolic crisis Much of the burden in dietary management consists of the possibility of metabolic crises. There is an influence in health-related quality of life (HrQoL) of caregivers, because the strain atmosphere about the new episode and a sense of guilty when it occurs. 21 The fear of metabolic decompensation is a reality of IIMD and FAOD families and consists of the possibility of the death of the loved one, the outcomes of this episode, in terms of multimorbidity and the emergence of new symptoms, requiring greater care and greater dependence. 23 Multimorbidity and the new normal Navigating on stranger tides is another challenge for these families. After an acute episode of decompensation, there is a possibility of a new clinical plateau , a new normal. It was very clear after the COVID-19 pandemic. Even in healthy children, the effect of an acute event in functional status in caregivers is huge, reflecting how the child's symptoms affect their daily life and their family situation, the guilty, feeling lost, the fear as stated above and the hope for an uncertain future. 24 Withdraw treatment Still little talked about in the area of ​​metabolic diseases, especially regarding enzyme replacement therapies (ERT), withdrawing treatments requires experience, technical knowledge and a bioethical approach depending on the course of the patient's disease. A parallel can be made with neuromuscular disorders, in which the ventilatory support is in discussion about withdrawal based on careful planning and communication, promotion of patient and parent choice, and ongoing psychosocial and bereavement support for family. 25 Decision making process Defining the best treatment to that patient demands a bioethical perspective, in addition to a clinical one. Moreover, it is possible through the decision making process. The decision making process is a process of open discussion on topics including the treatment options, living wills, personal values and preferences for end-of-life (EOL) care. 26 A four-step model to guide the clinician for the decision making process was proposed and compromises: Step 1 (Ethics of accuracy) is about the disease, its course, prognosis and treatments; Step 2 (Ethics of Comprehension) emphasizes the biographies of patients, their values, perceptions of suffering and treatment preferences; Step 3 (Ethics of situational awareness) presents the clinical judgment and the health team communication, conciliating evidence based treatments with the patient’s values and biography; Step 4 (Ethics of Deliberation) reinforces the patient-provider goals of care, ensuring the patient’s values and the acceptable clinical practices. 27 Only through a shared decision process can we achieve better care for patients and their families. New therapies Since the development of PKU formula in the mid-50s, new drugs have been developed, especially in the last two decades with the advent of technology. Dietary management, hematopoietic stem cell transplantation, ERT and solid organ transplantation are some of the options for the IMD. 28 In addition to medical progress, gene therapy has been gaining ground in the metabolic field, as a hope of brighter outcomes and better quality of life for the patients. 29 However, on the contrary of some health professional’s concept about palliative care, this specialty is not against the targeted treatment for the disease, but understand that the burden comes not only from the disease but also from its treatment, which justifies the follow-up with PC regardless of the result. 30 End-of life Unfortunately, there is no article approaching the process of end of life in IMD patients, especially in relation to advanced care planning, most frequent symptoms and bereavement assistance. Nevertheless, it is already known that the advance care planning together with the patient and family through the share decision-making process impacts in higher death preparedness, less aggressive treatments, better quality of life of patients, better post-loss bereavement outcomes, reduced decision burden and lower distress. 31 Moreover, this is important, considering the PC assessment as a continuum . It persists beyond the patient's death and focuses on following the bereavement of families. 1 Anticipatory Grief assessment Still on the topic of bereavement, a concept that is rarely discussed is anticipatory grief (AG), which is the caregivers’ reaction to the perception of multiple losses of their loved ones with a life-threatening illness or when their loved ones are approaching death. 32 This concept was proposed in 1955 from a perspective of mothers of children with leukemia until the course of a fluctuating illness, anchoring the findings to the anxieties of parents and child. 33 In parents of fatally ill child, the grief starts immediately after the diagnosis, continues some months before the child dies during the disease’s trajectory and prolongs afterwards. 34 After 70 years of its description, the AG could be quantify, being present in almost 25% of caregivers of persons with a life-threatening illness. The burden of care and the personal losses support the mental, physical and social problems, such as anxiety, guilt, shame and tiredness. 32 The AG is also a source of distress and an ambivalent experience, due the anticipation of death and secondary losses face to patient’s physical presence and care needs. 35 5. Conclusion Establishing a visual framework of trigger points to PC assessment helps the metabolic clinicians to identify windows of opportunity to establish a partnership to improve the care beyond the illness. As stated above, the diagnosis of complex chronic diseases carries a variety of aspects to the patients and their caregivers. Allowing and demystifying the earliest referral to PC is the way to ensure that we look at the protagonist of this trajectory: the patient. Declarations Ethics approval and consent to participate The study protocol underwent rigorous scrutiny and was subsequently approved by the Ethics Committee of the Universidade de São Paulo (USP), bearing the approval number CAAE 69446222.1.0000.00681 in accordance with the 466/12 Resolution of National Health Council. Consent for publication This article does not contain any studies with human or animal subjects performed by any of the authors. Availability of data and material No clinical data were used in this article. Competing interests The authors Gustavo Marquezani Spolador, Rita Tiziana Verardo Polastrini, Ivete Zoboli, Ana Cristina Henrique, Elaine Freitas, Andréa Gislene do Nascimento, Camila Pugliese, Fernando Kok, Silvia Maria de Macedo Barbosa, Clarissa Bueno declare no conflict of interest. Funding This work was supported by author’s resources. Authors' contributions . 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Cite Share Download PDF Status: Published Journal Publication published 29 Dec, 2025 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 08 Aug, 2025 Reviewers agreed at journal 28 May, 2025 Reviewers invited by journal 28 May, 2025 Editor assigned by journal 21 May, 2025 First submitted to journal 20 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6692221","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":463076522,"identity":"d2a6cdd8-a282-4dd4-b8ba-a1396041c587","order_by":0,"name":"Gustavo Marquezani 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Freitas","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Elaine","middleName":"","lastName":"Freitas","suffix":""},{"id":463076527,"identity":"3d074add-f3c8-46f8-afd5-921ff6eead1b","order_by":5,"name":"Andréa Gislene do Nascimento","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Andréa","middleName":"Gislene do","lastName":"Nascimento","suffix":""},{"id":463076528,"identity":"d9cd0c13-c73a-4cfb-97cf-77c2c9366583","order_by":6,"name":"Camila Pugliese","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Camila","middleName":"","lastName":"Pugliese","suffix":""},{"id":463076529,"identity":"613aa9e9-690e-4808-9eed-a5ca783f0d16","order_by":7,"name":"Fernando Kok","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"","lastName":"Kok","suffix":""},{"id":463076530,"identity":"52682ab8-9e33-4359-88e5-70a13e721b45","order_by":8,"name":"Clarissa Bueno","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Clarissa","middleName":"","lastName":"Bueno","suffix":""},{"id":463076531,"identity":"d5a89ccf-a401-40a9-8b32-7f1111175e72","order_by":9,"name":"Silvia Maria de Macedo Barbosa","email":"","orcid":"","institution":"Universidade de São Paulo Instituto da Criança: Universidade de Sao Paulo Instituto da Crianca","correspondingAuthor":false,"prefix":"","firstName":"Silvia","middleName":"Maria de Macedo","lastName":"Barbosa","suffix":""}],"badges":[],"createdAt":"2025-05-18 14:19:00","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6692221/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6692221/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-025-04128-x","type":"published","date":"2025-12-29T15:58:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83893671,"identity":"3c29f37a-3894-4c24-8536-1665647969f3","added_by":"auto","created_at":"2025-06-04 08:29:06","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":301399,"visible":true,"origin":"","legend":"\u003cp\u003eTrajectories of Intermediate IMD (IIMD). A – The most common IIMD represented by organic acidurias, urea cycle disorders and some of aminoacidopathies. B – Some synthesis defects of amino acids and fatty acids and metabolite repair defects present this trajectory.\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6692221/v1/d0f45d03bb8ebeacb6a8418c.jpg"},{"id":83893669,"identity":"230ed3a1-701b-4a2a-9330-2ec24df9e773","added_by":"auto","created_at":"2025-06-04 08:29:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":263932,"visible":true,"origin":"","legend":"\u003cp\u003eTrajectories of Energy IMD (EIMD). A –. Fatty Acid Oxidation Disorders and carriers defects can present stability moments with metabolic crisis. B – Some presentations of mitochondrial disorders present this trajectory.\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6692221/v1/430f9dd9c30e54dd67fef290.jpg"},{"id":83893672,"identity":"c345c8d7-0ccf-4128-9f5a-9ad1189539c2","added_by":"auto","created_at":"2025-06-04 08:29:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":292061,"visible":true,"origin":"","legend":"\u003cp\u003eTrajectories of Complex Molecules Disorders. A - Trajectories of storage disorders and congenital disorders of glycosylation, showing the earliest indication of PC referral. B – The outcomes of cellular processing and trafficking defects, the newest group of IMD presenting unique diagnostic difficulties.\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6692221/v1/22452ddb496c0d512425876f.jpg"},{"id":99545436,"identity":"78416f25-3cca-424d-b8fe-7fbf279bc5cb","added_by":"auto","created_at":"2026-01-05 16:07:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1477354,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6692221/v1/6c1b1037-b0ce-4798-a36f-98a3588bea9e.pdf"}],"financialInterests":"","formattedTitle":"Trigger points of palliative care assessment in inherited metabolic diseases","fulltext":[{"header":"Synopsis","content":"\u003cp\u003eIt is never too late to start: points of action for palliative care professionals in the trajectory of inherited metabolic diseases.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eThe palliative care (PC) has been an ally to many specialties in terms of symptoms management, psychological assessment and decision-making process. Reinforcing the premise of to offer early care for patients and their relatives, the PC has been a tool to inherited metabolic diseases (IMD) setting and has become a public health issue regarding costs reduction and life prolonging with quality of life.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe intersection between PC and IMD has increased since last 5 years. Few but robust publications has showed the expressive number of IMD patients in follow up with the PC team. From a general symptoms panorama, highlighting the neurologic, respiratory and gastrointestinal as being the most frequent in this group, to an epidemiological outlook of each IMD groups into PC setting, regarding the age of diagnosis, the age of PC referral and the time between diagnosis and PC referral.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNevertheless, in IMD clinical practice, it is a challenge to integrate the PC in a natural and non-stigmatized way, considering some barriers as such as: lack of resources to refer to; not knowing that resources exist; ignorance regarding what palliative care is; reluctance to refer; reluctance of patient and/or family to be referred and restrictive specialist palliative care service program eligibility criteria.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eConcerning the knowing of those resources, the ignorance and reluctance of professionals and patients, an institutional continuing education program about PC and multicenter collaboration for scientific publications can improve the misconception of the specialty and establish a new healthcare framework assembling the PC as a rule.\u003c/p\u003e \u003cp\u003eAbout the eligibility criteria, this article aims at transforming the stigma of palliative care assessment into a useful tool for metabolic physicians throughout the patient's trajectory, highlighting the trigger points for PC referral.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Review of articles approaching IMD in PC\u003c/h2\u003e \u003cp\u003eWe made a review of scientific publications in PubMed, using the terms Palliative Care or Palliative Medicine or Hospice Care and Metabolic Diseases or Inborn Errors of Metabolism or Inherited Metabolic Diseases.\u003c/p\u003e \u003cp\u003eRegarding the descriptors, they have not based on the Medical Subject Headings (MeSH), since there is little literature associating the two themes, non-uniformity to the use of IMD term and articles, in which PC was only cited not extensively discussed.\u003c/p\u003e \u003cp\u003eIn this way, we found four articles addressing the intersection between PC and IMD the last ten years. The two oldest date from 2018 and present a general perspective of IMD in PC setting, highlighting for the first time the prevalence of these disorders. In 2021, a study scrutinized the IMD profile in hospitalized patients during two months, introducing the most prevalent symptoms in this population and advocating for PC to promote the best care by controlling symptoms.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFinally, the newest publication presented a global evaluation of IMD, according to pathophysiological groups and establishing a relationship between the time of diagnosis and the referral to PPC group.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Establishing a parallel between IMD and PC trajectories\u003c/h2\u003e \u003cp\u003eA recent and innovative publication proposed an adaptation of pediatric palliative care groups to metabolic diseases, considering the pathophysiological groups of IMD, their most frequent outcomes and the four types of illness trajectories established by Hain (2008) from conditions eligible to Pediatric Palliative Care (PPC) defined by Association of Children\u0026rsquo;s Palliative Care.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis proposal does not cover all the IMD, but it has begun a discussion about the potential patients who could benefit from the early introduction of palliative care based on the recognition of their trajectories.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Identifying the common trigger points\u003c/h2\u003e \u003cp\u003eRegarding to the concept of chronic complex conditions, the conditions eligible to PPC, their trajectories and the adaptation of these to IMD, we identified common trigger points of PC entrance.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThese trigger points were established considering the pathophysiological IMD groups and their main characteristics.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Furthermore, we defined a thermometer of time to PC referral, reflecting the WHO recommendation and the clinical practice.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe proposal of IMD trajectories in context of palliative care were used as a basis for the trigger point\u0026rsquo;s allocation.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Regarding to the pathophysiological groups of IMD (intoxication, energy and complex molecules), two models of trajectories were established considering the heterogeneous manifestation of each disorder.\u003c/p\u003e \u003cp\u003eIn relation to the group 1 (intoxication disorders), the model 1 contemplates the most common courses of organic acidurias, urea cycle disorders and some aminoacidopathies. Additionally, the model 2 considers the metabolite repair defects, amino acids synthesis defects and the fatty acids synthesis defects, which present a different pattern of evolution than the first ones. The Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the trajectories of intoxication IMD (IIMD) and highlights the trigger points and a scale of the best moment to referral to PC.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe group 2, represented by the energy disorders, also presents two patterns of trajectories. The model 1 comprises the fatty acid oxidation disorders (FAOD) and the disorders of energetic molecules carriers, as such as monocarboxylate transporters (MCTs) and solute carriers (e.g. GLUT1).\u003c/p\u003e \u003cp\u003eThe model 2 discloses the most severe presentations of mitochondrial disorders. In these cases, it is important to reinforce that not all mitochondrial disorders will present the outcome shown below in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFinally, the group 3 of pathophysiological classification characterized by the complex molecules disorders presenting a model 1 of trajectory, mainly in storage disorders and congenital disorders of glycosylation (CDGs) and a model 2 comprising the cellular processing and trafficking defects, the newest IMD group.\u003c/p\u003e \u003cp\u003eThe Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows these 2 models of trajectories and also highlight the trigger points of PC entrance and a thermometer of the best time to referral to this specialty.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAs stated above, the integration of PC and IMD has faced some barriers. However, an integrated perspective of PC to metabolic clinic can be adapted from a typical chronic illness trajectory. Trigger points as such as the diagnosis moment, the uncertainly of disease\u0026rsquo;s course, multimorbidity and end-of-life are common to all chronic complex diseases and will be discussed in detail below.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAdding to IMD context, the dietary management and its burden, metabolic crisis and the advent of new therapies \u0026ndash; especially gene therapy \u0026ndash; are also addressed, which increases the familiarity of the referral time and personalize the PC to IMD field.\u003c/p\u003e \u003cp\u003eFinally, some gaps in literature even in PC have been described. The decision-making process and the possibility of withdrawing treatments, still very incipient and involving bioethical issues, and the anticipatory grief assessment, an underestimated topic in any specialty in the healthcare field.\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe diagnosis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe moment of an illness diagnosis is a vivid event throughout family\u0026rsquo;s life and it is the beginning of a new trajectory.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe diagnosis is considered highly relevant for parents of children with intellectual disability. It helps them to deal with emotions, available treatments and family planning.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The emotional reaction of parents is influenced by the diagnostic process, which can last from one year up to 8 years, depending on the clinical presentation, access to exams and the healthcare system in a course called diagnostic odyssey.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, some families are faced to an unknown diagnosis. This \u0026ldquo;not knowing\u0026rdquo; can be a source of distress, due a future incertitude, impossibility to do something or to connect with other similar families. In this context, the communication is the best tool of health professionals to guide the caregivers during the diagnosis process.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eThe uncertainly\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAccording to the diagnosis of an IMD and its outcome, parents and caregivers are faced to uncertainties throughout life. Since the diagnosis odyssey, depending on country and condition in terms of diagnosis methods and access to these technologies, to the child\u0026rsquo;s life outcome, regarding to metabolic crisis, a new clinical plateau establishment and drugs response.\u003c/p\u003e \u003cp\u003eThere are an extensive literature proofing the impact of IMD diagnosis in parents. The most prevalent stressors included emotional, social, financial, medical and lack of freedom. Guilty and the unpredictable nature of symptoms and eventual factors that can trigger those symptoms were also sources of stress.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCoping with the diagnostic odyssey, understanding the child needs, recognizing changes involving the family dynamics, and navigating challenges in professional health systems are aspects that permeate the trajectories of this caregivers.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eDietary management and its burden\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThroughout the diagnostic process and outcome uncertainty, some metabolic diseases require specific dietary management, which can be a stressful care for the parents.\u003c/p\u003e \u003cp\u003eRecent studies reinforce the caregiver\u0026rsquo;s burden associated with dietary restrictions, mainly in organic acidurias (OA), urea cycle disorders (UCD) and maple syrup urine disease.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNevertheless, the impact of food restriction in patients and their caregivers is theme of literature a long time ago, mostly considering that dietary requirements as a social and emotional barriers since they difficult to grasp and communicate in a social environment.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eMetabolic crisis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eMuch of the burden in dietary management consists of the possibility of metabolic crises. There is an influence in health-related quality of life (HrQoL) of caregivers, because the strain atmosphere about the new episode and a sense of guilty when it occurs.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe fear of metabolic decompensation is a reality of IIMD and FAOD families and consists of the possibility of the death of the loved one, the outcomes of this episode, in terms of multimorbidity and the emergence of new symptoms, requiring greater care and greater dependence.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eMultimorbidity and the new normal\u003c/b\u003e \u003c/p\u003e \u003cp\u003eNavigating on stranger tides is another challenge for these families. After an acute episode of decompensation, there is a possibility of a new clinical \u003cem\u003eplateau\u003c/em\u003e, a new normal. It was very clear after the COVID-19 pandemic.\u003c/p\u003e \u003cp\u003eEven in healthy children, the effect of an acute event in functional status in caregivers is huge, reflecting how the child's symptoms affect their daily life and their family situation, the guilty, feeling lost, the fear as stated above and the hope for an uncertain future.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eWithdraw treatment\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStill little talked about in the area of ​​metabolic diseases, especially regarding enzyme replacement therapies (ERT), withdrawing treatments requires experience, technical knowledge and a bioethical approach depending on the course of the patient's disease.\u003c/p\u003e \u003cp\u003eA parallel can be made with neuromuscular disorders, in which the ventilatory support is in discussion about withdrawal based on careful planning and communication, promotion of patient and parent choice, and ongoing psychosocial and bereavement support for family.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eDecision making process\u003c/b\u003e \u003c/p\u003e \u003cp\u003eDefining the best treatment to that patient demands a bioethical perspective, in addition to a clinical one. Moreover, it is possible through the decision making process.\u003c/p\u003e \u003cp\u003eThe decision making process is a process of open discussion on topics including the treatment options, living wills, personal values and preferences for end-of-life (EOL) care.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eA four-step model to guide the clinician for the decision making process was proposed and compromises:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eStep 1 (Ethics of accuracy) is about the disease, its course, prognosis and treatments;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStep 2 (Ethics of Comprehension) emphasizes the biographies of patients, their values, perceptions of suffering and treatment preferences;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStep 3 (Ethics of situational awareness) presents the clinical judgment and the health team communication, conciliating evidence based treatments with the patient\u0026rsquo;s values and biography;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStep 4 (Ethics of Deliberation) reinforces the patient-provider goals of care, ensuring the patient\u0026rsquo;s values and the acceptable clinical practices.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eOnly through a shared decision process can we achieve better care for patients and their families.\u003c/p\u003e \u003cp\u003e \u003cb\u003eNew therapies\u003c/b\u003e \u003c/p\u003e \u003cp\u003eSince the development of PKU formula in the mid-50s, new drugs have been developed, especially in the last two decades with the advent of technology. Dietary management, hematopoietic stem cell transplantation, ERT and solid organ transplantation are some of the options for the IMD.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn addition to medical progress, gene therapy has been gaining ground in the metabolic field, as a hope of brighter outcomes and better quality of life for the patients.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHowever, on the contrary of some health professional\u0026rsquo;s concept about palliative care, this specialty is not against the targeted treatment for the disease, but understand that the burden comes not only from the disease but also from its treatment, which justifies the follow-up with PC regardless of the result.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eEnd-of life\u003c/b\u003e \u003c/p\u003e \u003cp\u003eUnfortunately, there is no article approaching the process of end of life in IMD patients, especially in relation to advanced care planning, most frequent symptoms and bereavement assistance.\u003c/p\u003e \u003cp\u003eNevertheless, it is already known that the advance care planning together with the patient and family through the share decision-making process impacts in higher death preparedness, less aggressive treatments, better quality of life of patients, better post-loss bereavement outcomes, reduced decision burden and lower distress.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMoreover, this is important, considering the PC assessment as a \u003cem\u003econtinuum\u003c/em\u003e. It persists beyond the patient's death and focuses on following the bereavement of families.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eAnticipatory Grief assessment\u003c/b\u003e \u003c/p\u003e \u003cp\u003eStill on the topic of bereavement, a concept that is rarely discussed is anticipatory grief (AG), which is the caregivers\u0026rsquo; reaction to the perception of multiple losses of their loved ones with a life-threatening illness or when their loved ones are approaching death.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis concept was proposed in 1955 from a perspective of mothers of children with leukemia until the course of a fluctuating illness, anchoring the findings to the anxieties of parents and child.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn parents of fatally ill child, the grief starts immediately after the diagnosis, continues some months before the child dies during the disease\u0026rsquo;s trajectory and prolongs afterwards.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAfter 70 years of its description, the AG could be quantify, being present in almost 25% of caregivers of persons with a life-threatening illness. The burden of care and the personal losses support the mental, physical and social problems, such as anxiety, guilt, shame and tiredness.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe AG is also a source of distress and an ambivalent experience, due the anticipation of death and secondary losses face to patient\u0026rsquo;s physical presence and care needs.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eEstablishing a visual framework of trigger points to PC assessment helps the metabolic clinicians to identify windows of opportunity to establish a partnership to improve the care beyond the illness. As stated above, the diagnosis of complex chronic diseases carries a variety of aspects to the patients and their caregivers. Allowing and demystifying the earliest referral to PC is the way to ensure that we look at the protagonist of this trajectory: the patient.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol underwent rigorous scrutiny and was subsequently approved by the Ethics Committee of the Universidade de São Paulo (USP), bearing the approval number CAAE 69446222.1.0000.00681 in accordance with the 466/12 Resolution of National Health Council.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis article does not contain any studies with human or animal subjects performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo clinical data were used in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors Gustavo Marquezani Spolador, Rita Tiziana Verardo Polastrini, Ivete Zoboli, Ana Cristina Henrique, Elaine Freitas, Andréa Gislene do Nascimento, Camila Pugliese, Fernando Kok, Silvia Maria de Macedo Barbosa, Clarissa Bueno declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by author’s resources.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGMS\u003c/strong\u003e: Conceptualization, Formal analysis, Investigation, Resources, Writing - Original Draft; \u003cstrong\u003eRTVP\u003c/strong\u003e: Formal analysis, Investigation, Resources; \u003cstrong\u003eIZ\u003c/strong\u003e: Visualization, Supervision; \u003cstrong\u003eACH\u003c/strong\u003e: Visualization. \u003cstrong\u003eEF\u003c/strong\u003e: Visualization; \u003cstrong\u003eAGN\u003c/strong\u003e: Visualization; \u003cstrong\u003eCP\u003c/strong\u003e: Visualization; \u003cstrong\u003eFK\u003c/strong\u003e: Supervision, Project administration;\u0026nbsp;\u003cstrong\u003eCB\u003c/strong\u003e: Supervision;\u0026nbsp;\u003cstrong\u003eSMMB\u003c/strong\u003e: Supervision, Project administration.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld Hospice Palliative Care Alliance [homepage on the Internet]. Global atlas of palliative care at the end of life. Geneva: WHO; 2020. Available from: http://www.thewhpca.org/resources/item/global-atlas-of-palliative-care-2nd-ed-2020http://www.thewhpca.org/resources/item/global-atlas-of-palliative-care-2nd-ed-2020\u003c/li\u003e\n\u003cli\u003eLo DS, Hein N, Bulgareli JV. Pediatric palliative care and end-of-life: a systematic review of economic health analyses. Rev Paul Pediatr. 2022 Jan 5;40:e2021002.\u003c/li\u003e\n\u003cli\u003eTemel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, Dahlin CM, Blinderman CD, Jacobsen J, Pirl WF, Billings JA, Lynch TJ. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42.\u003c/li\u003e\n\u003cli\u003eHoell JI, Warfsmann J, Distelmaier F, Borkhardt A, Jan\u0026szlig;en G, Kuhlen M. Challenges of palliative care in children with inborn metabolic diseases. 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JIMD Rep. 2023 Dec 5;65(1):25-38. \u003c/li\u003e\n\u003cli\u003eRajasekar P, Gannavarapu S, Napier M, Prasad AN, Vasudev A, Mantulak A, Potter BK, Prasad C. Parental psychosocial aspects and stressors involved in the management of inborn errors of metabolism. Mol Genet Metab Rep. 2020 Oct 5;25:100654. \u003c/li\u003e\n\u003cli\u003eB\u0026ouml;sch F, Landolt MA, Baumgartner MR, Fernandez S, Forny P, Gautschi M, Gr\u0026uuml;nert SC, H\u0026auml;berle J, Horvath C, Karall D, Lampis D, Rohrbach M, Scholl-B\u0026uuml;rgi S, Szinnai G, Huemer M. Caregiver burden, and parents\u0026apos; perception of disease severity determine health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism. Mol Genet Metab Rep. 2022 May 6;31:100876. \u003c/li\u003e\n\u003cli\u003eRajasekar P, Gannavarapu S, Napier M, Prasad AN, Vasudev A, Mantulak A, Potter BK, Prasad C. 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Patients\u0026apos; perception of hope in palliative care: A systematic review and narrative synthesis. Patient Educ Couns. 2023 Oct;115:107879.\u003c/li\u003e\n\u003cli\u003eFalzarano F, Prigerson HG, Maciejewski PK. The Role of Advance Care Planning in Cancer Patient and Caregiver Grief Resolution: Helpful or Harmful? Cancers (Basel). 2021 Apr 20;13(8):1977.\u003c/li\u003e\n\u003cli\u003eKustanti CY, Chu H, Kang XL, Pien LC, Chen R, Tsai HT, Chou KR. Anticipatory grief prevalence among caregivers of persons with a life-threatening illness: A meta-analysis. BMJ Support Palliat Care. 2024 Jan 8;13(e3):e1074-e1083.\u003c/li\u003e\n\u003cli\u003eBozeman MF, Orbach CE, Sutherland AM. Psychological impact of cancer and its treatment. III. The adaptation of mothers to the threatened loss of their children through leukemia. I. Cancer. 1955 Jan-Feb;8(1):1-19.\u003c/li\u003e\n\u003cli\u003eBowlby, J. (1980). Attachment and Loss. Vol. 3: Loss, Sadness and Depression. New York: Basic Books.\u003c/li\u003e\n\u003cli\u003eCoelho A, Barbosa A. Family Anticipatory Grief: An Integrative Literature Review. Am J Hosp Palliat Care. 2017 Sep;34(8):774-785.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"inborn errors of metabolism. metabolic diseases. palliative care. pediatrics. metabolism. pediatric palliative care","lastPublishedDoi":"10.21203/rs.3.rs-6692221/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6692221/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe interaction between palliative care (PC) and inherited metabolic diseases (IMD) has increased. However, in clinical practice, few correspondences are found, mainly due to the misunderstanding about the specialty, refuse to refer, lack of resources and specific eligibility criteria for IMD. This article aims to establish trigger points to PC referral in IMD field. Three pairs of illness trajectories were established based on literature and considering the pathophysiological groups of IMD. The first pair comprises the intoxication disorders with 2 models of outcomes: Model 1 \u0026ndash; organic acidurias, urea cycle disorders and some aminoacidopathies; Model 2 - metabolite repair defects, amino acids synthesis defects and the fatty acids synthesis defects. The second pair represents the energy disorders: Model 1 \u0026ndash; FAOD and MCT/GLUT; Model 2 \u0026ndash; Some mitochondrial disorders. The last pair contemplates the complex molecules disorders and also shows 2 patterns of evolution: Model 1 \u0026ndash; storage disorders and CDGs; Model 2 \u0026ndash; Cellular processing and trafficking defects. The trigger points consist in diagnosis moment; the uncertainly of disease\u0026rsquo;s course; the dietary and treatment management and their burdens; the metabolic crisis; the multimorbidity and the new normal; new therapies and the end-of-life. This framework is an opportunity to establish a partnership to improve the care beyond the illness, looking at the protagonist of the trajectory: the patient.\u003c/p\u003e","manuscriptTitle":"Trigger points of palliative care assessment in inherited metabolic diseases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-04 08:29:01","doi":"10.21203/rs.3.rs-6692221/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-08-08T11:18:47+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-28T13:47:32+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-28T12:18:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-21T04:44:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-05-20T04:56:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b4c44591-a1c4-4ffa-b027-27d5079f6f1d","owner":[],"postedDate":"June 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:03:41+00:00","versionOfRecord":{"articleIdentity":"rs-6692221","link":"https://doi.org/10.1186/s13023-025-04128-x","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2025-12-29 15:58:06","publishedOnDateReadable":"December 29th, 2025"},"versionCreatedAt":"2025-06-04 08:29:01","video":"","vorDoi":"10.1186/s13023-025-04128-x","vorDoiUrl":"https://doi.org/10.1186/s13023-025-04128-x","workflowStages":[]},"version":"v1","identity":"rs-6692221","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6692221","identity":"rs-6692221","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}