Introduction: Cobalamin C (cblC) deficiency represents arare but treatable and potentially underrecognized cause of thrombotic microangiopathy (TMA) in both pediatric and adult populations. It is a multisystem disorder with heterogeneous clinical manifestations. TMA occurs in 10-25% of affected individuals. Case presentation: A ten-year-old girl presented with vomiting and abdominal pain, followed by generalized status epilepticus and hypertensive crisis. Neuroimaging was unremarkable. Laboratory evaluation demonstrated severe renal impairment (creatinine 506 & micro;mol/L), microangiopathic hemolysis and thrombocytopenia. Atypical hemolytic uremic syndrome (aHUS) was suspected and treated with eculizumab and intermittent hemodialysis. Genetic analysis identified biallelic pathogenic variants in the MMACHC gene, confirming cblC deficiency. Metabolic treatment (parenteral hydroxocobalamin, betaine, L-carnitine, and folinic acid) was initiated promptly. During the clinical course, the patient experienced relapses of hypertensive crises despite stable metabolic parameters and well-controlled fluid balance. Blood pressure control required a regimen of six antihypertensive agents, and renal replacement therapy was administered for ten weeks. At follow-up, blood pressure and renal function have improved (eGFR 60 mL/min/1.73 m2, Schwartz formula), and no neurological sequelae were observed. Conclusion: CblC deficiency should be considered in all pediatric cases of atypical hemolytic uremic syndrome (aHUS). Measurement of plasma total homocysteine and/or methylmalonic acid in blood or urine, followed by molecular genetic confirmation, is essential to avoid diagnostic delay. Early initiation of targeted metabolic therapy can substantially improve renal outcomes and survival. Conclusion: Diagnosis and CI referral in Thailand occurred well beyond internationally recommended ages, and age-group differences in non-verbal performance were observed, underscoring the need to strengthen early hearing detection and referral systems.

Cystathionine β-synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non-responders (NR) or partial responders (PR) and require treatment with a low-methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E-HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine-responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine-free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time-to-event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).

The digital twin concept promises to revolutionize all dimensions of the health sector, including healthcare planning and delivery, health promotion and education, and medical research. The present article maps the key legal and ethical challenges which will need to be addressed for a successful roll-out of digital twin models for children living with rare diseases, using the example of phenylketonuria (PKU) as model disease. The main legal challenges, which will arise in virtually all jurisdictions worldwide, have been analyzed with a focus on European Union law: data protection, medical device regulation, AI regulation, intellectual property, and product liability. The main ethical challenges have been analyzed using research and digital ethics frameworks of the WHO, UNESCO, HLEG-AI, and CIOMS: autonomy, informed consent to research, trust, and the impact on interpersonal relations, identity and self-understanding. Based on our analysis, we will identify shortcomings of current laws, regulations, and ethics guidelines. Clear legal and ethical guidance is, however, urgently needed to protect vulnerable groups of patients from harm, notably children living with rare diseases, and to help innovators navigate the complex legal and ethical issues the digital twin concept raises. Therefore, we call for an expansion of ongoing efforts to regulate artificial intelligence (e.g., at the EU and Council of Europe level) and of ethics guidance and training in the field (e.g., by the WHO and the UNESCO) to include guidance on the key challenges raised by digital twin models.

Background:Rare diseases affect fewer than one in 2000 people and impact approximately 400 million individuals globally. High costs, uncoordinated care, and inadequate provider knowledge pose challenges to rare disease care. We aimed to examine the relationship between healthcare access and utilisation among rare disease patients in Switzerland. Study design:A cross-sectional survey was conducted with 314 individuals with a rare disease. Methods:Participants completed the Perception of Access to Healthcare Questionnaire (PAHQ) and provided data on healthcare utilisation (institutional and provider levels). Network analysis assessed nodes were based on expected influence (EI), predictability, and bridge centrality (BC). Results:Four PAHQ subscales (acceptability, availability, adequacy, and awareness) exhibited higher EI and predictability. Conversely, accessibility and affordability of healthcare services had lower EI and predictability scores. In terms of healthcare utilisation, hospitals, private practices, general practictioners (GPs), mental health professionals, and emergency services demonstrated elevated EI and predictability. Specialists and holistic healthcare providers exhibited lower EI and predictability. Affordability, disease course, as well as hospital, and GP utilisation had elevated BC values and emerged as key connectors between access and utilisation. Conclusion:This study illuminates the intricate dynamics of healthcare experiences for patients with rare diseases. This work validates network analysis as a valuable tool for examining healthcare systems. Findings can inform policies that address challenges faced by this vulnerable population, namely care integration for individuals with an unstable disease course.

Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.

PURPOSE:Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far. METHODS:We performed a comprehensive literature search to identify all published cases of HMGCS2D (n = 59). Additionally, the data of 16 patients with this disorder who are yet undescribed were collected. Clinical course, biochemical findings, and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided. RESULTS:Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only 1 variant was identified to be common, (HMGCS2) NM_005518.4:c.634G>A p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established. CONCLUSION:This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of HMGCS2 variants identified in affected individuals.

Classical homocystinuria is a rare disease caused by mutations in cystathionine β-synthase( CBS) gene (OMIM 613381). CBS catalyzes the first step of the transsulfuration pathway that converts homocysteine (Hcy) into cystathionine (Cysta) via a number of co-substrates and mechanisms. Formation of Cysta by condensation of Hcy and cysteine (Cys) produces a molar equivalent of hydrogen sulfide (H2S). H2S plays important roles in cognitive and vascular functions. Clinically, patients with CBS deficiency present with vascular, ocular, neurological and skeletal impairments. Biochemically, CBS deficiency manifests with elevated Hcy and reduced concentration of Cysta in plasma and urine. A number of pathogenic variants of human CBS have been characterized by their residual enzymatic activity, but very few studies have examined H2S production by pathogenic CBS variants, possibly due to technical hurdles in H2S detection and quantification. We describe a method for the real-time, continuous quantification of H2S formed by wild-type and pathogenic variants of human recombinant CBS, as well as by fibroblast extracts from healthy controls and patients diagnosed with CBS deficiency. The method takes advantage of the specificity and high affinity of hemoglobin I of the clam Lucina pectinata toward H2S and is based on UV-visible spectrophotometry. Comparison with the gold-standard, end-point H2S quantification method employing monobromobimane, as well as correlations with CBS enzymatic activity determined by LC-MS/MS showed agreement and correlation, and permitted the direct, time-resolved determination of H2S production rates by purified human recombinant CBS and by CBS present in fibroblast extracts. Rates of H2S production were highest for wild-type CBS, and lower for pathogenic variants. This method enables the examination of structural determinants of CBS that are important for H2S production and its possible relevance to the clinical outcome of patients.

ObjectivesThis study aims to determine clusters of access to healthcare among adults with rare diseases in Switzerland, identify associated individual characteristics of access, and impact on health-related quality of life (HRQoL).MethodsSwiss adults (N = 341) diagnosed with a rare disease completed an online survey including the Perception of Access to Healthcare Questionnaire (PAHQ) and Short Form Health Survey (SF-12). We employed partition around medoids algorithm to identify patient clusters based on the PAHQ. Various sociodemographic/disease-related factors and HRQoL were assessed.ResultsWe identified two patient clusters: higher (n = 227) and lower access (n = 114). Significantly associated with lower access were an unstable disease course (p < 0.05), increased number of misdiagnoses (p < 0.05), and diseases affecting the nervous system (p < 0.01). Membership in the lower access cluster was significantly associated with worse HRQoL (p < 0.05).ConclusionFindings highlight the need for comprehensive assessment of healthcare access in adults with rare diseases and identifies potential targets for tailored interventions.

Introduction Children represent a large and vulnerable patient group. However, the evidence base for most paediatric diagnostic and therapeutic procedures remains limited or is often inferred from adults. There is an urgency to improve paediatric healthcare provision based on real-world evidence generation. Digital transformation is a unique opportunity to shape a data-driven, agile, learning healthcare system and deliver more efficient and personalised care to children and their families. The goal of Paediatric Personalized Research Network Switzerland (SwissPedHealth) is to build a sustainable and scalable infrastructure to make routine clinical data from paediatric hospitals in Switzerland interoperable, standardised, quality-controlled, and ready for observational research, quality assurance, trials and health-policy creation. This study describes the design, aims and current achievements of SwissPedHealth.Methods and analysis SwissPedHealth was started in September 2022 as one of four national data streams co-funded by the Swiss Personalized Health Network (SPHN) and the Personalized Health and Related Technologies (PHRT). SwissPedHealth develops modular governance and regulatory strategies and harnesses SPHN automatisation procedures in collaboration with clinical data warehouses, the Data Coordination Center, Biomedical Information Technology Network, and other SPHN institutions and funded projects. The SwissPedHealth consortium is led by a multisite, multidisciplinary Steering Committee, incorporating patient and family representatives. The data stream contains work packages focusing on (1) governance and implementation of standardised data collection, (2) nested projects to test the feasibility of the data stream, (3) a lighthouse project that enriches the data stream by integrating multi-omics data, aiming to improve diagnoses of rare diseases and 4) engagement with families through patient and public involvement activities and bioethics interviews.Ethics and dissemination The health database regulation of SwissPedHealth was approved by the ethics committee (AO_2022-00018). Research findings will be disseminated through national and international conferences and publications in peer-reviewed journals, and in lay language via online media and podcasts.

OBJECTIVE:Children and adolescents with rare diseases face significant barriers when accessing healthcare. We aimed to assess and predict these barriers and investigate associations with health-related quality of life (HRQoL). METHOD:We conducted a cross-sectional survey of Swiss parents (N = 189) of children with rare diseases including the Barriers to Care Questionnaire (BCQ), containing six barriers and the Pediatric Quality of Life Inventory (PedsQL). Latent profile analysis (LPA) was used to uncover distinct classes, which were compared using chi-square tests and Mann-Whitney U tests. Relevant medical and sociodemographic class predictors were identified using Elastic Net regression, followed by regression analysis to investigate their role in predicting barriers to care and examine the effects of these classes on HRQoL. RESULTS:Two distinct groups were identified, a higher barriers class (59%) and a lower barriers class (41%). In the higher barriers class, participants showed elevated scores across all subscales and specifically on pragmatics and expectations. More barriers to care were linked to a nonstable disease course (OR = 2.27, p = .002) and a diagnosis after the age of 3 months (OR = 2.17, p = .006). Individuals in the higher barriers class exhibited more psychological comorbidities (p = .044), congenital malformations/deformations/chromosomal abnormalities (p=.042), and medical misdiagnoses (p = .006). Children in the higher barriers class had significantly lower PedsQL scores compared to the lower barriers class (p <.05). CONCLUSION:This study highlights the need for comprehensive assessment of barriers to pediatric care in rare diseases, offering potential entry points for targeted interventions.

Vitamin B12 (B12) deficiency (B12D) can have detrimental effects on early growth and development. The Austrian newborn screening (NBS) program targets inborn errors of cobalamin metabolism and also detects B12D. Of 59 included neonates with B12D suspected by NBS, B12D was not further investigated in 16 (27%) retrospectively identified cases, not confirmed in 28 (48%), and confirmed in 15 (25%) cases. NBS and recall biomarkers were recorded. Age at sampling of the dried blood spots for NBS and the 1st-tier methionine/phenylalanine ratio were the strongest parameters to predict B12D (67.4% correct allocations). No differences between cases with confirmed, unconfirmed, or unknown B12D or differences to norms were observed for growth and psychomotor development (Vineland III scales, phone interviews with parents of children between months 10 and 14 of life). B12 intake was below recommendations in most mothers. NBS can detect reduced intracellular B12 activity. No advantage of NBS detection and treatment regarding infant cognitive development or growth could be proven. Since conspicuous NBS findings cannot be ignored, and to prevent exposing newborns to invasive diagnostics, assessment of maternal B12 status during pregnancy seems advisable.

BackgroundNewborn bloodspot screening (NBS) for cystic fibrosis (CF) is important for early diagnosis and treatment. However, screening can lead to false-positive results leading to unnecessary follow-up tests and distress. This study evaluated the 11-year performance of the Swiss CF-NBS programme, estimated optimal cut-offs for immunoreactive trypsinogen (IRT), and examined how simulated algorithms would change performance.MethodsThe Swiss CF-NBS is based on an IRT–DNA algorithm with a second IRT (IRT-2) as safety net. We analysed data from 2011 to 2021, covering 959,006 IRT-1 analyses and 282 children with CF. We studied performance based on European Cystic Fibrosis Society (ECFS) standards including sensitivity, specificity, positive predictive value (PPV), false negative rate, and second heel-prick tests; identified optimal IRT cut-offs using receiver operating characteristics (ROC) curves; and calculated performance for simulated algorithms with different cut-offs for IRT-1, IRT-2, and safety net.ResultsThe Swiss CF-NBS showed excellent sensitivity (96 %, 10 false negative cases) but moderate PPV (25 %). Optimal IRT-1 and IRT-2 cut-offs were identified at 2.7 (>99th percentile) and 5.9 (>99.8th percentile) z-scores, respectively. Analysis of simulated algorithms showed that removing the safety net from the current algorithm could increase PPV to 30 % and eliminate >200 second heel-prick tests per year, while keeping sensitivity at 95 %.ConclusionThe Swiss CF-NBS program performed well over 11 years but did not achieve the ECFS standards for PPV (≥30 %). Modifying or removing the safety net could improve PPV and reduce unnecessary follow-up tests while maintaining the ECFS standards for sensitivity.

Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.

Im Jahr 2011 wurde das Neugeborenen-Screening für zystische Fibrose in der Schweiz eingeführt. Nach zehn Jahren ist es Zeit für einen Blick zurück auf das, was erreicht wurde, und für einen Ausblick auf weitere Optimierungen des Programms.

Le dépistage néonatal de la mucoviscidose a été introduit en Suisse en 2011. Dix ans plus tard, il est temps de jeter un regard sur ce qui a été accompli et d’envisager des optimisations supplémentaires du programme à l’avenir.

Chat generative pre-trained transformer (ChatGPT) is an advanced large language model (LLM) that uses deep learning techniques. The chatbot was first released in November 2022 by OpenAI, an artificial intelligence company based in San Francisco, and is currently one of the largest publicly available LLMs.1 Numerous potential applications of ChatGPT or other LLMs in science and medicine include identification of research topics and assisting health care professionals in clinical and laboratory diagnosis. In the field of medical science, where accuracy and credibility are essential, it is necessary to carefully weigh the risks and benefits associated with using LLMs in scientific publishing.2 If you ask ChatGPT (Version 3.5, on July 17, 2023) to summarise the "risk and potential of ChatGPT in medical scientific publications" in two to three sentences, the answer is: "Using ChatGPT in the publication of medical science poses risks such as potential inaccuracies, limited context understanding, lack of domain-specific knowledge, and ethical concerns regarding authorship. However, it also offers chances for assistance in literature review, idea generation, collaborative writing, and facilitating the dissemination of knowledge to a broader audience. Researchers should exercise caution, verify information independently, and consult domain experts to mitigate risks and maximise the benefits of using ChatGPT in medical science publication." This summary sums up quite nicely the risks and potential of using ChatGPT in scientific publishing. It is becoming clear that we need clear rules for dealing with this fairly new development. The advantages for authors are quite obvious. LLMs can support the writing process by providing suggestions for sentence structure, grammar, and style and thus help improve the clarity and readability of scientific manuscripts. This may be particularly helpful to non-native speakers of English, potentially democratising scientific writing. Researchers could also use it to explore different perspectives, design experimental plans, or consider alternative approaches to a problem. However, the associated risks need to be clear to every author. ChatGPT generates responses based on patterns it has learned from training data, but it may provide factually inaccurate or misleading information and answers may not be evidence-based. LLMs do not have real-time context awareness, which means they may not fully understand the specific context, potentially leading to misinterpretation or incorrect conclusions. The training data for ChatGPT are not publicly available, leading to a lack of transparency. Further, the training dataset is limited to information available in 2021,1 so ChatGPT is not up to date on the latest research. Finally, a significant limitation is ChatGPT's inability to cite its sources; if researchers use LLMs to produce content for publication without proper acknowledgement or transparency, this raises ethical issues related to plagiarism, authorship, and scientific integrity. What is the correct way to use this new application in scientific writing? Journal editors, researchers, and publishers are now debating the place of such tools in the published literature, and whether it is appropriate to cite the bot as an author. Some preprint servers allow inclusion of ChatGPT as a co-author,3 but this has been rejected by the editors-in-chief of Nature and Science since ChatGPT cannot bear responsibility for the content and authenticity of scientific studies and thus does not meet the criteria for a study author.4 This rule has been correspondingly applied by most scientific journals and is also the position of the Editorial Team of the JIMD. Nevertheless, transparency regarding the utilisation of ChatGPT or other LLMs in a study or manuscript, including a clear indication of its use in the materials and methods section, is currently mandatory for all scientific journals. As we navigate the uncharted waters of incorporating ChatGPT or other LLMs into publications in medical science, we must proceed cautiously, fully aware of both the risks and opportunities of their integration into scientific writing. The potential for inaccuracies and the ethical implications of their implementation cannot be ignored. The challenge will be to embrace this evolution and, by combining the strengths of human expertise with their technical capabilities, maximise the overall potential while maintaining the highest standards of accuracy, transparency, and integrity. For now, further scrutiny of AI generated text in scientific writing is needed. We hope the readership of the Journal of Inherited Metabolic Disease will consider these issues and contribute to the debate.

Organic acidurias or acidaemias (OADs), such as glutaric aciduria type 1, methylmalonic, propionic and isovaleric aciduria, are a group of inherited metabolic diseases whose common biochemical hallmark is the accumulation of non-amino mono-, di- and tricarboxylic acids called “organic acids.” The majority of OADs is caused by deficient mitochondrial breakdown of coenzyme A-activated carbonic acids, resulting in mitochondrial dysfunction with subsequent energy impairment, oxidative stress, impaired mitophagy and altered post-translational protein acylation,1 and, finally, acute and/or chronic dysfunction of organs with a high energy demand.2 Research into OADs has advanced diagnosis and therapy for affected individuals, reducing mortality and morbidity. Since the 1990s, some OADs have been included in newborn screening programmes, enabling preclinical detection and early initiation of therapy. A variety of treatment strategies has been established, ranging from dietary restriction of precursor amino acids, cofactor treatment and transient emergency treatment to solid organ (liver and kidney) transplantation. Innovative strategies such as mRNA therapy and gene replacement therapy are currently under development or evaluated in clinical trials. Furthermore, longitudinal observation of large patient cohorts has improved our knowledge about natural history and disease variants, molecular genetics has elucidated the underlying genetic defects of OADs, and the development of guidelines has used available evidence to direct diagnosis, therapy and follow-up of individuals with OADs. Despite this progress, the long-term clinical outcome in individuals with OADs is not always favourable, pathomechanisms are far from being fully understood, and the current status of early prediction of disease severity, evidence-based risk stratification and personalised therapy leave room for improvement. Since much progress has been made but important gaps still hamper the transition of OADs to precision medicine, we have decided to dedicate a special issue of the Journal of Inherited Metabolic Disease to OADs and invited key experts in the field to share their insights into future directions in this fascinating field of inherited metabolic diseases and to prepare the ground for predictive, preventative, personalised and participatory medicine for OADs. This themed issue of the Journal of Inherited Metabolic Disease kicks off with a contribution from Schuurmans et al.3 in which a literature-based up-to-date genetic landscape of GCDH pathogenic variants is provided and potential genotype–phenotype correlations in glutaric aciduria type 1 are explored using novel combinatorial methods. Complementary to this study, Yuan et al.4 investigate the predictive power of combining in silico and in vitro modelling with real-world data from longitudinal observational studies for glutaric aciduria type 1. In the following articles, the themed issue focuses on the recent progress in elucidating pathomechanisms and exploiting this knowledge for targeted therapy. McCorvie et al.5 discuss the complex cooperation of transporters, enzymes and chaperones that are required for the generation and delivery of cobalamin, a cofactor for two human enzymes. This is followed by Ramon et al.6 demonstrating how cellular and computational models help to decipher environmental and metabolic interactions in methylmalonic aciduria, suggesting a compensatory role for increased anaplerosis through glutamine. Next, Head et al.7 outline how precise knowledge about pathophysiology in methylmalonic aciduria has enabled the development of targeted therapy. Since conservative therapy does not prevent disease progression and the manifestation of irreversible organ dysfunction in individuals with methylmalonic and propionic aciduria, two articles presented by Martinelli et al.8 and Chakrapani et al.9 focus on safety, efficacy and timing of solid organ transplantation as well as neurological outcome following transplantation. In the final articles, the themed issue explores the importance of evidence-based guidelines for individuals with rare disorders such as OADs. Boy et al.10 present the third revision of recommendations for glutaric aciduria type 1, developed by an international group of experts and patient representatives. Finally, Forny et al.11 demonstrate how guideline development can guide clinical research (et vice versa), enabling a steady improvement of our knowledge base and the level of evidence of recommendations for these rare diseases. Taken together, the collection of papers in this special issue of the Journal of Inherited Metabolic Disease is a rich source of knowledge and expertise on OADs and will hopefully provide new insights and inspiration for future research and clinical studies.

Since Sackett et al. stated that ‘Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients’, randomised clinical trials (RCTs) and meta-analysis have become established as the cornerstone of evidence-based practice.1 However, such studies remain challenging for ultra-rare disorders including the 1500 or so known inherited metabolic diseases (IMDs).2 RCTs in such patient populations are frequently underpowered3 and are also confounded by genetic variability between affected individuals, variable pre-treatment manifestations, a lack of standard of care comparators and dearth of clinically relevant outcome measures.4 Frequently, treatment effects can be assessed through comparisons with well-characterised historical cases, and the JIMD is dedicated to publishing comprehensive cohort studies for IMDs with detailed clinical, functional and genetic data. In the absence of data from RCTs, clinical practice guidelines established by experts in the field using standardised methodology can help to guide evidence-based practice. Guidelines are important tools for our care of, and advocacy for, children and adults with (ultra)rare IMDs. In contrast to more common disorders, for which there is often a wealth of data from clinical studies, the evidence base for IMDs is limited, and recommendations for diagnosis and management are often based on expert consensus. Increasingly, such consensus is accomplished using methodology, such as the Delphi approach, although this is by no means uniform.5 The more recent GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation6) may be more suitable for the rare disease field, as it partially accounts for the above described challenges. Recognising the variable limitations, guidelines published in peer-reviewed journals set a standard for multiple stakeholders, including clinicians, researchers, health services, regulatory agencies and patient advocacy groups. A published guideline can facilitate access to services or therapies, provide directions for clinical researchers and be accepted as standard of care by agencies. In a special online issue of the journal accompanying this editorial, we bring together a collection of guidelines and position papers published in the Journal of Inherited Metabolic Disease. These include guidelines for the management of organic acidurias,7-9 urea cycle disorders,10 cobalamin-related remethylation disorder,11 galactosaemia,12 congenital disorders of glycosylation,13-16 acute porphyria,17 phenylketonuria,18 pyridoxine-dependent epilepsy19 and mitochondrial neurogastrointestinal encephalomyopathy,20 as well as guidelines for neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy21 and for safe drug prescribing in primary mitochondrial disorders.22 We hope that collating these high-quality clinical practice guidelines will be an invaluable resource to aid our readership in improving the diagnosis and treatment of patients with IMDs and help them to optimise care pathways. Guidelines must be dynamic; recommendations must be amended to reflect the growth in our understanding of the disorder. It must always be borne in mind that guidelines are intended as a tool to provide direction to their readers based on the sum of knowledge and experience at the time of publication. They are neither set in stone, nor immutable, and should not replace clinical judgement, or responsibility. ‘It's about integrating individual expertise with the best external evidence’—Sackett's words of wisdom from almost three decades ago continue to resonate.1 The authors declare no conflicts of interest.

INTRODUCTION:The goal of this study was to investigate the hair cortisol concentration (HCC) in healthy and ill cows and their newborn calves. A total of 40 cows and their 42 newborn calves were divided into two groups: group 1 consisted of 19 clinically healthy cows and their 20 newborn calves, and group 2 comprised 21 cows that had had a chronic illness in the third trimester of gestation and their 22 newborn calves. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) system was used to measure the HCC in hair samples that were collected from the cows and calves on the day the calves were born. In both groups, the mean HCCs of the calves was significantly higher than that of the cows (group 1, 31,0 vs. 0,6 pg/mg; group 2, 19,4 vs. 0,8 pg/mg; P.