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Background: Newborn bloodspot screening identifies presymptomatic babies who are affected by genetic or congenital conditions. Each year, around 10,000 parents of babies born in England are given a positive newborn bloodspot screening result for one of nine conditions that are currently screened for. Despite national guidance, variation exists regarding the approaches used to communicate these results to families; poor communication practices can lead to various negative sequelae. Objectives: Identify and quantify approaches that are currently used to deliver positive newborn bloodspot screening results to parents (phase 1). Develop (phase 2), implement and evaluate (phase 3) co-designed interventions for improving the delivery of positive newborn bloodspot screening results. Quantify the resources required to deliver the co-designed interventions in selected case-study sites and compare these with costs associated with current practice (phase 3). Design: This was a mixed-methods study using four phases, with defined outputs underpinned by Family Systems Theory. Setting: All newborn bloodspot screening laboratories in England (n = 13). Participants: Laboratory staff and clinicians involved in processing or communicating positive newborn bloodspot screening results, and parents of infants who had received a positive or negative newborn bloodspot screening result. Interventions: Three co-designed interventions that were developed during phase 2 and implemented during phase 3 of the study. Main outcome measure: Acceptability of the co-designed interventions for the communication of positive newborn bloodspot screening results. Results: Staff were acutely aware of the significance of a positive newborn bloodspot screening result and the impact that this could have on families. Challenges existed when communicating results from laboratories to relevant clinicians, particularly in the case of congenital hypothyroidism. Clinicians who were involved in the communication of positive newborn bloodspot screening results were committed to making sure that the message, although distressing for parents, was communicated well. Despite this, variation in communication practices existed. This was influenced by many factors, including the available resources and lack of clear guidance. Although generally well received, implementation of the co-designed interventions in practice served to illuminate barriers to acceptability and feasibility. The interventions would not influence NHS expenditure and could be cost neutral when delivered by teleconsultations. Limitations: Participants with a pre-existing interest in this topic may have been more likely to self-select into the study. The researchers are experienced in this field, which may have biased data collection and analysis. COVID-19 hindered implementation and related data collection of the co-designed interventions. Conclusions: There was variation in the processes used to report positive newborn bloodspot screening results from newborn bloodspot screening laboratories to clinical teams and then to families. The various practices identified may reflect local needs, but more often reflected local resource. A more consistent ‘best practice’ approach is required, not just in the UK but perhaps globally. The co-designed interventions represent a starting point for achieving this. Future work: Future work should include a national evaluation study with predefined outcomes, accompanied by an economic evaluation, to assess the acceptability, feasibility and usability of the co-designed interventions in practice nationally. Trial registration: This trial is registered as ISRCTN15330120. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 19. See the NIHR Journals Library website for further project information.

Abstract Background Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI). Results In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered. Conclusion The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies.

Rare diseases, such as inherited metabolic diseases, have been identified as a health priority within the European Union more than 20 years ago and have become an integral part of EU health programs and European Reference Networks. Having the potential to pool data, to achieve sufficient sample size, to overcome the knowledge gap on rare diseases and to foster epidemiological and clinical research, patient registries are recognized as key instruments to evidence-based medicine for individuals with rare diseases. Patient registries can be used for multiple purposes, such as (1) describing the natural history and phenotypic diversity of rare diseases, (2) improving case definition and indication to treat, (3) identifying strategies for risk stratification and early prediction of disease severity (4), evaluating the impact of preventive, diagnostic, and therapeutic strategies on individual health, health economics, and the society, and (5) informing guideline development and policy makers. In contrast to clinical trials, patient registries aim to gather real-world evidence and to achieve generalizable results based on patient cohorts with a broad phenotypic spectrum. In order to develop a consistent and sustained framework for rare disease registries, uniform core principles have been formulated and have been formalized through the European Rare Disease Registration Infrastructure. Adherence to these core principles and compliance with the European general data protection regulations ensures that data collected and stored in patient registries can be exchanged and pooled in a protected environment. To illustrate the benefits and limitations of patient registries on rare disease research this review focuses on inherited metabolic diseases. [ABSTRACT FROM AUTHOR]

• Genetic screening can be used to identify a broader spectrum of diseases and is not limited to traditional biochemical screening diseases. • Genetic screening can identify positive cases of diseases and can eliminate false positives caused by multiple factors. • The targeted capture-based NGS method is more suitable for newborn genetic screening compared to multiplex PCR-NGS. • Newborn genetic screening combined with traditional biochemical screening can maximize the role of NBS. Newborn screening can detect around 40 different diseases based on biochemical indicators and has resulted in the improved quality of life for children suffering from genetic diseases. However, NBS is limited as it does not cover all genetic diseases in newborns and has high rates of false positives and negatives. Genetic screening can be used to address the shortcomings of traditional biochemical screening, however, the comprehensive clinical value of genetic screening is yet to be systematically studied. In this study, we used two different genetic screening methods to examine 200 cases of NBS. We found that genetic screening can be used to identify a broader spectrum of diseases and is not limited to traditional biochemical screening diseases; it can identify positive cases of disease and can eliminate false positives caused by multiple factors such as pathogenic variants carrier or the mode of childbirth. Genetic screening has shortened the time to diagnosis and reduced the costs of testing. Furthermore, we found that the biochemical detection results were limited when patients simultaneously carried multiple pathogenic mutations. Our research provisionally demonstrates the necessity, feasibility and significance of clinical genetic screening in newborns and provides a solid basis for future clinical developments. [ABSTRACT FROM AUTHOR]

Understanding the genetic architecture of metabolic epilepsies is of paramount importance, both to current clinical practice and for the identification of further research directions. The main goals of our study were to identify the scope of metabolic epilepsies and to investigate their clinical presentation, diagnostic approaches and treatments. The International Classification of Inherited Metabolic Disorders and IEMbase were used as a basis for the identification and classification of metabolic epilepsies. Six hundred metabolic epilepsies have been identified, accounting for as much as 37% of all currently described inherited metabolic diseases (IMD). Epilepsy is a particularly common symptom in disorders of energy metabolism, congenital disorders of glycosylation, neurotransmitter disorders, disorders of the synaptic vesicle cycle and some other IMDs. Seizures in metabolic epilepsies may present variably, and most of these disorders are complex and multisystem. Abnormalities in routine laboratory tests and/or metabolic testing may be identified in 70% of all metabolic epilepsies, but in many cases they are non-specific. In total, 111 metabolic epilepsies (18% of all) have specific treatments that may significantly change health outcomes if diagnosed in time. Although metabolic epilepsies comprise an important and significant group of disorders, their real scope and frequency may have been underestimated. [ABSTRACT FROM AUTHOR]

Abstract The ongoing coronavirus disease 2019 (COVID-19) pandemic has caused disruption in all aspects of daily life, including the management and treatment of rare inherited metabolic disorders (IMDs). To perform a preliminary assessment of the incidence of COVID-19 in IMD patients and the impact of the coronavirus emergency on the rare metabolic community between March and April 2020, the European Reference Network for Hereditary Metabolic Diseases (MetabERN) has performed two surveys: one directed to patients’ organizations (PO) and one directed to healthcare providers (HCPs). The COVID-19 incidence in the population of rare metabolic patients was lower than that of the general European population (72.9 × 100,000 vs. 117 × 100,000). However, patients experienced extensive disruption of care, with the majority of appointments and treatments cancelled, reduced, or postponed. Almost all HCPs (90%) were able to substitute face-to-face visits with telemedicine, about half of patients facing treatment changes switched from hospital to home therapy, and a quarter reported difficulties in getting their medicines. During the first weeks of emergency, when patients and families lacked relevant information, most HCPs contacted their patients to provide them with support and information. Since IMD patients require constant follow-up and treatment adjustments to control their disease and avoid degradation of their condition, the results of our surveys are relevant for national health systems in order to ensure appropriate care for IMD patients. They highlight strong links in an interconnected community of HCPs and PO, who are able to work quickly and effectively together to support and protect fragile persons during crisis. However, additional studies are needed to better appreciate the actual impact of COVID-19 on IMD patients’ health and the mid- and long-term effects of the pandemic on their wellbeing.

Rare diseases, such as inherited metabolic diseases, have been identified as a health priority within the European Union more than 20 years ago and have become an integral part of EU health programs and European Reference Networks. Having the potential to pool data, to achieve sufficient sample size, to overcome the knowledge gap on rare diseases and to foster epidemiological and clinical research, patient registries are recognized as key instruments to evidence-based medicine for individuals with rare diseases. Patient registries can be used for multiple purposes, such as (1) describing the natural history and phenotypic diversity of rare diseases, (2) improving case definition and indication to treat, (3) identifying strategies for risk stratification and early prediction of disease severity (4), evaluating the impact of preventive, diagnostic, and therapeutic strategies on individual health, health economics, and the society, and (5) informing guideline development and policy makers. In contrast to clinical trials, patient registries aim to gather real-world evidence and to achieve generalizable results based on patient cohorts with a broad phenotypic spectrum. In order to develop a consistent and sustained framework for rare disease registries, uniform core principles have been formulated and have been formalized through the European Rare Disease Registration Infrastructure. Adherence to these core principles and compliance with the European general data protection regulations ensures that data collected and stored in patient registries can be exchanged and pooled in a protected environment. To illustrate the benefits and limitations of patient registries on rare disease research this review focuses on inherited metabolic diseases.

Isobutyryl-CoA dehydrogenase deficiency (IBDHD, MIM: #611283) is a rare autosomal recessive hereditary disease, which is caused by genetic mutations of acyl-CoA dehydrogenase (ACAD) 8 and associated with valine catabolism. Here, tandem mass spectrometry (MS/MS) was applied to screen 302,993 neonates for inherited metabolic diseases (IMD) in Ningbo of China from 2017 to 2020. The results suggest that 198 newborns (0.7‰) were initially screened positive for IBDHD with C4-Carnitine, and 27 cases (0.1‰) were re-screened positive. Genetic diagnosis was performed on 21 of the 27 cases. Seven compound heterozygous variations, three biallelic variations, and one heterozygous variation of ACAD8 were found with a pathogenicity rate of 33.3% (7/21). In addition, seven biallelic variations, one heterozygous variation of acyl-CoA dehydrogenase short chain (ACADS), and one biallelic variation of acyl-CoA dehydrogenase short/branched chain (ACADSB) was detected. Further research showed that ACAD8 mutations of 11 IBDHD cases distributed in six different exons with total 14 mutation sites. Five of which were known suspected pathogenic sites (c.286G > A, c.553C > T, c.1000C > T, c.409G > A, c.500del) and six were novel mutation sites: c.911A > T, c.904C > T, c.826G > A, c.995T > C, c.1166G > A, c.1165C > T. This finding enriched the mutation spectrum of ACAD8 in IBDHD. [ABSTRACT FROM AUTHOR]

Mitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health. [ABSTRACT FROM AUTHOR]

Abstract Background Inherited metabolic diseases (IMD) are complex medical conditions. Thanks to improvements in diagnosis and treatment, a growing number of pediatric IMD patients reach adulthood. Thus, clinical care of adults with IMD has emerged as a new and challenging reality. This purpose of this study of adults with IMD in an adult metabolic clinic at two academic hospitals (Lausanne and Geneva) was to help inform decisions on the future organization of health care for this group of patients. Methods All adult patients with a biochemical and/or genetic diagnosis of IMD followed at the clinics were included in the study. Electronic patient records were reviewed for clinical features, diagnostic studies, treatment and long-term outcome. Data of undiagnosed patients referred for suspected IMD were analyzed separately. Results 126 patients were included in the study. The most prevalent group of diseases was small molecules disorders with 82 (65%) patients, followed by energy defects disorders with 29 (23%) patients and complex molecules disorders with 15 (12%) patients. Overall, 64% of patients were diagnosed before, and 36% after the age 16 years. Among the 126 cases, 51% suffered from medical complications. 79% of the patients were receiving a specific treatment for their disease. Among the 138 undiagnosed patients referred for suspicion of IMD, investigations lead to a genetic diagnosis in 24 (17%) patients. 19 had confirmation of an IMD, 5 were found to have another genetic condition. Conclusions This retrospective study reveals significant features of adult IMD cohort. The disorders are heterogeneous, and there is no one-size-fits-all approach – treatment must be tailored to fit each specific disorder in each individual patient. Even patients who are followed at the dedicated clinic are not protected from metabolic decompensations and/or chronic organ-specific complications. While it is commonly assumed that patients with IMD are more stable once they become adults, our data show that the diseases continue to exact a lifelong toll. A coordinated monitoring of target organs by a multidisciplinary team is needed. To ensure that the success in diagnosis and treatment of individuals with IMD is sustained, there is a clear requirement for adequately staffed adult IMD clinics.

Abstract Background The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases. Methods At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN’s clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data. Results As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method – 0% missing). Discussion Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability.

Isobutyryl-CoA dehydrogenase deficiency (IBDHD, MIM: #611283) is a rare autosomal recessive hereditary disease, which is caused by genetic mutations of acyl-CoA dehydrogenase (ACAD) 8 and associated with valine catabolism. Here, tandem mass spectrometry (MS/MS) was applied to screen 302,993 neonates for inherited metabolic diseases (IMD) in Ningbo of China from 2017 to 2020. The results suggest that 198 newborns (0.7‰) were initially screened positive for IBDHD with C4-Carnitine, and 27 cases (0.1‰) were re-screened positive. Genetic diagnosis was performed on 21 of the 27 cases. Seven compound heterozygous variations, three biallelic variations, and one heterozygous variation of ACAD8 were found with a pathogenicity rate of 33.3% (7/21). In addition, seven biallelic variations, one heterozygous variation of acyl-CoA dehydrogenase short chain (ACADS), and one biallelic variation of acyl-CoA dehydrogenase short/branched chain (ACADSB) was detected. Further research showed that ACAD8 mutations of 11 IBDHD cases distributed in six different exons with total 14 mutation sites. Five of which were known suspected pathogenic sites (c.286G > A, c.553C > T, c.1000C > T, c.409G > A, c.500del) and six were novel mutation sites: c.911A > T, c.904C > T, c.826G > A, c.995T > C, c.1166G > A, c.1165C > T. This finding enriched the mutation spectrum of ACAD8 in IBDHD.

Parents increasingly utilise the internet to obtain information on health practices, but the quality of online information about screening for inherited metabolic diseases (IMD) needs to be improved. A content analysis examined how IMD blood and urine tests were described online in local healthcare sectors between May and June 2021. Among the nine resources, four were blood test providers and five were urine test providers. All mentioned the test benefits and procedures. Other information, such as false-positive/negative or risk of pain, was infrequently mentioned. The descriptions of urine tests are advertised as outperforming blood tests and can be purchased from commercial laboratory sites without medical guidance. Two urine test providers claimed no false results were reported. A few commercial advertisements highlighted the simplicity of the urine test and potentially overstated the invasiveness of the blood test. We found that some advertisements described IMD as “silent killers” and emphasised the advantage of getting “reassurance” in controlling the child’s developmental health and well-being. To better protect the parents, or broadly, the public interest, regulatory and oversight measures on the urine tests should be implemented to promote the proper use of genetic tests. Without timely regulation and oversight, the incorrect descriptions might create a public misconception about utilising these commercial laboratory tests to inform health decisions.

Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene-disease lists from gNBS studies, evaluating gene-disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237-889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene-disease pairs, and the total number of exclusive gene-disease pairs was positively correlated with the total number of genes included per study. While most pairs receive "Definitive" or "Strong" ClinGen classifications, some are labeled as "Refuted" (n = 5) or "Disputed" (n = 28), particularly in genetic cardiac diseases. Importantly, 17%-48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene-disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options. [ABSTRACT FROM AUTHOR]

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years of age of UCDs due to a deficiency in one of the 6 enzymes (arginase, ASL, ASS, CPS1, NAGS, OTC) or the two transporters (ORNT1 or citrin). Seventy‐one patients were included (68% female, 32% male). The diagnosis was made in the context of (a) a metabolic decompensation (42%), (b) family history (55%), or (c) chronic symptoms (3%). The median age at diagnosis was 33 years (range 16‐86). Eighty‐nine percent of patients were diagnosed with OTC deficiency, 7% CPS1 deficiency, 3% HHH syndrome and 1% argininosuccinic aciduria. For those diagnosed during decompensations (including 23 OTC cases, mostly female), 89% required an admission in intensive care units. Seven deaths were attributed to UCD—6 decompensations and 1 epilepsy secondary to inaugural decompensation. This is the largest cohort of UCDs diagnosed in adulthood, which confirms the triad of neurological, gastrointestinal and psychiatric symptoms during hyperammonemic decompensations. We stress that females with OTC deficiency can be symptomatic. With 10% of deaths in this cohort, UCDs in adults remain a life‐threatening condition. Physicians working in adult care must be aware of late‐onset presentations given the implications for patients and their families. [ABSTRACT FROM AUTHOR]

Background: Many surveys have been performed over the years to assess the medical and social requirements of patients with a rare disease, but no studies have focused specifically on patients in Europe or with an inherited metabolic disease (IMD). To obtain a comprehensive overview of the social and psychological status and needs of IMD patients, especially in Europe, the European Reference Network for Hereditary Metabolic Disorders (MetabERN) has performed a dedicated survey among its metabolic patients.Results: A total of 924 patients and caregivers responded to the questionnaire. Most participants were from 25 European countries, with Spain, Italy, and Germany being the most represented; only eight participants were extra-European. The survey showed that most social assistance services, from free educational/development services for those with intellectual disability to transition from childhood to adult care and job placement support, are available for a limited number of patients or are unknown to the majority of patients or their parents/caregivers. Similarly, psychological assistance for the patient or the parent/caregiver is available for a small fraction of respondents, despite the fact that the majority considers this type of support necessary for both the patient and the caregiver. In addition, for most IMD patients local specialised or emergency medical assistance is lacking, although national clinical pathways are defined, and medical professionals of reference are readily available when needed. Lastly, while most national health services in Europe cover all or part of the expenses for medications, medical devices, food supplements, dietary integrators, physiotherapy, and speech therapy, significant gaps in the economic support for healthcare and other expenses still exist.Conclusions: Overall, our survey reveals a widespread lack of social, psychological, and economic support for IMD patients in Europe. More needs to be done to provide daily assistance to IMD patients in order to alleviate the burden on caregivers and to allow patients to become independent and productive adults. Where support is actually available locally or nationally, most IMD patients are not aware of it, so an active dissemination of this information among the metabolic community is essential. [ABSTRACT FROM AUTHOR]

Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. Currently, liver transplantation is the only curative option available for many liver diseases. Gene therapy represents a valuable approach to treatment. The liver plays a central role in a myriad of essential metabolic functions, making it an attractive organ for gene therapy; hepatocytes comprise the most relevant target. To date, viral vectors constitute the preferred approach to targeting hepatocytes with genes of therapeutic interest. Alternatively, mRNA-based therapy offers a number of comparative advantages. Clinical and preclinical studies undertaken to treat inherited metabolic diseases affecting the liver, cirrhosis and fibrosis, hepatocellular carcinoma, hepatitis B, and cytomegalovirus using lipid nanoparticle-encapsulated mRNAs that encode the therapeutic or antigenic protein of interest are discussed.

Correct identification and quantification of different sterol biomarkers can be used as a first-line diagnostic approach for inherited metabolic disorders (IMD). The main drawbacks of current methodologies are related to lack of selectivity and sensitivity for some of these compounds. To address this, we developed and validated two sensitive and selective assays for quantification of six cholesterol biosynthesis pathway intermediates (total amount (free and esterified form) of 7-dehydrocholesterol (7-DHC), 8-dehydrocholesterol (8-DHC), desmosterol, lathosterol, lanosterol and cholestanol), two phytosterols (total amount (free and esterified form) of campesterol and sitosterol) and free form of two oxysterols (7-ketocholesterol (7-KC) and 3β,5α,6β-cholestane-triol (C-triol). For quantification of four cholesterol intermediates we based our analytical approach on sterol derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). Quantification of all analytes is performed using UPLC coupled to an Orbitrap high resolution mass spectrometry (HRMS) system, with detection of target ions through full scan acquisition using positive atmospheric pressure chemical ionization (APCI) mode. UPLC and MS parameters were optimized to achieve high sensitivity and selectivity. Analog stable isotope labeled for each compound was used for proper quantification and correction for recovery, matrix effects and process efficiency. Precision (2.4%–12.3% inter-assay variation), lower limit of quantification (0.027 nM–50.5 nM) and linearity (5.5 μM (R2 0.999) – 72.3 μM (R2 0.997)) for phyto- and oxysterols were determined. The diagnostic potential of these two assays in a cohort of patients (n = 31, 50 samples) diagnosed with IMD affecting cholesterol and lysosomal/peroxisomal homeostasis is demonstrated. [Display omitted] • Quantification of sterols in plasma is important in the field of IMD. • UPLC-Orbitrap-HRMS methods were developed and validated. • PTAD derivatization was used for quantification of desmosterol, lanosterol, 7/8-DHC. • Developed methods are highly sensitive, selective and need 100–125 μL plasma. • 190 control samples and 50 samples from patients with IMD were studied. [ABSTRACT FROM AUTHOR]

Abstract Adult metabolic medicine (AMM) is an expanding medical subspecialty, due to the increasing number of adult patients with inherited metabolic diseases (IMD). However, a formal training and postgraduate education in this field is not available in the majority of countries. Existing adult metabolic specialists (AMS) come from many different backgrounds. The aim of this survey was to assess the state of play as regards education and training in AMM worldwide. Members of the Society for the Study of Inborn Error of Metabolism adult metabolic group (n = 89) were asked to take part in this survey. Forty‐two AMS (47.2%) from 18 different countries completed the questionnaire. The most common specialties were internal medicine (38.1%), endocrinology (26.2%), genetics (21.4%), and neurology (21.4%). Ninety‐five percent of respondents considered that practical clinical experience had contributed importantly for their professional development, while only 27% felt the same for formal academic education. The current state of available education and training was judged as generally poor or fair (73% of the respondents). The most suggested ways of improving education and training in AMM were: to facilitate international internships; to implement courses on adult‐IMD; and to create a formal academic education. The skills considered most important for AMS were: recognition of signs and symptoms of diseases, knowledge of the available treatments, and ability to perform a correct follow up. In conclusion, worldwide, current available education and training in AMM is considered inadequate. This survey emphasizes the need for development of new, formal training opportunities to improve knowledge, and competence in this rapidly expanding field.

Abstract Background We describe early health services utilization for children diagnosed with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency through newborn screening in Ontario, Canada, relative to a screen negative comparison cohort. Methods Eligible children were identified via newborn screening between April 1, 2006 and March 31, 2010. Age-stratified rates of physician encounters, emergency department (ED) visits and inpatient hospitalizations to March 31, 2012 were compared using incidence rate ratios (IRR) and incidence rate differences (IRD). We used negative binomial regression to adjust IRRs for sex, gestational age, birth weight, socioeconomic status and rural/urban residence. Results Throughout the first few years of life, children with MCAD deficiency (n = 40) experienced statistically significantly higher rates of physician encounters, ED visits, and hospital stays compared with the screen negative cohort. The highest rates of ED visits and hospitalizations in the MCAD deficiency cohort occurred from 6 months to 2 years of age (ED use: 2.1–2.5 visits per child per year; hospitalization: 0.5–0.6 visits per child per year), after which rates gradually declined. Conclusions This study confirms that young children with MCAD deficiency use health services more frequently than the general population throughout the first few years of life. Rates of service use in this population gradually diminish after 24 months of age.

(1) Background: Phenotypic diversity and long-term health outcomes of individuals with urea cycle disorders (UCDs) have been described in detail. However, there is limited information on the burden on affected families. (2) Methods: To evaluate the family burden in parents with children suffering from UCDs, we used validated questionnaires. Socio-demographic characteristics were evaluated, and an adapted version of the Parental Need Scale for Rare Diseases questionnaire was used. The survey was conducted in families of UCD patients cared for at the University Children’s Hospital Heidelberg. (3) Results: From April to November 2021, 59 participants were interviewed (mothers n = 34, fathers n = 25). The affected patients most frequently suffered from ornithine transcarbamylase deficiency (OTC-D) (female n = 12, male n = 12), followed by argininosuccinate synthetase deficiency (ASS-D, n = 13) and argininosuccinate lyase deficiency (ASL-D, n = 8). About one-third of the participants were “dissatisfied” or “extremely dissatisfied” with health professionals’ disease knowledge. In addition, 30% of the participants reported a medium or high need for “additional information on the development of their children”, and 44% reported a medium or high need “for information on available services”. A majority of 68% reported a need for additional support regarding services such as support groups (42%) or psychological counseling (29%). (4) Conclusions: Our study indicates that there is an unmet need for sufficient information about the development of children with UCDs, as well as for information about available support services for families with UCD patients. Furthermore, the results highlight the importance of establishing or improving family-centered care approaches. This pilot study may serve as a template for the assessment of the family burden associated with other inherited metabolic diseases.

Summary: We describe a case of a 21 years old woman affected by Citrullinemia type 1- Arginosuccinate Synthase deficiency (ASSD)-who underwent a SARS CoV2 infection during the first phase of pandemic burst in Italy. She had no symptoms of infection nor a metabolic crisis.After recovery from SARS CoV2, she experienced a worsening in their epilepsy despite therapy, with one/two crisis a week.

Background: Following the broad application of new analytical methods, more and more pathophysiological processes in previously unknown diseases have been elucidated. The spectrum of clinical presentation of rare inherited metabolic diseases (IMDs) is broad and ranges from single organ involvement to multisystemic diseases. With the aim of overcoming the limited knowledge about the natural course, current diagnostic and therapeutic approaches, the project has established the first unified patient registry for IMDs that fully meets the requirements of the European Infrastructure for Rare Diseases (ERDRI).Results: In collaboration with the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), the Unified European registry for Inherited Metabolic Diseases (U-IMD) was established to collect patient data as an observational, non-interventional natural history study. Following the recommendations of the ERDRI the U-IMD registry uses common data elements to define the IMDs, report the clinical phenotype, describe the biochemical markers and to capture the drug treatment. Until today, more than 1100 IMD patients have been registered.Conclusion: The U-IMD registry is the first observational, non-interventional patient registry that encompasses all known IMDs. Full semantic interoperability for other registries has been achieved, as demonstrated by the use of a minimum common core data set for equivalent description of metabolic patients in U-IMD and in the patient registry of the European Rare Kidney Disease Reference Network (ERKNet). In conclusion, the U-IMD registry will contribute to a better understanding of the long-term course of IMDs and improved patients care by understanding the natural disease course and by enabling an optimization of diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: The gangliosidoses are rare inherited diseases that result in pathologic accumulation of gangliosides in the central nervous system and other tissues, leading to severe and progressive neurological impairment and early death in the childhood forms. No treatments are currently approved for the gangliosidoses, and development of treatments is impaired by limited understanding of the natural history of these diseases. Objective: The objective of this study is to improve understanding of the juvenile gangliosidoses phenotypes and the late-infantile phenotypic subtype. Methods: Through a prospective natural history study of subjects with juvenile GM1- and GM2-gangliosidosis, a timeline of clinical changes was developed for the classic juvenile phenotypes and the late-infantile phenotypes and results of serial neurodevelopmental testing was analyzed. Results: Several candidate ‘outcome measures’ were identified: changes in ambulation and verbalization skills, the communication domain from neurodevelopmental testing and the caregiver-reported socialization domain. Conclusions: The most common symptoms leading caregivers to seek a genetic diagnosis were changes in ambulation and verbalization.

Acute intoxication‐type inborn errors of metabolism (IT‐IEM) such as urea cycle disorders and non‐acute IT‐IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and – in acute diseases – metabolic decompensations nevertheless. Research on the subjective burden of IT‐IEM remains sparse. Studies with appropriate sample sizes are needed to make valid statements about health‐related quality of life (HrQoL) in children and adolescents with IT‐IEM. Six international metabolic centres contributed self‐reports and proxy reports of HrQoL (assessed with the Paediatric Quality of Life Inventory) to the final data set (n = 251 patients; age range 2.3‐18.8 years). To compare HrQoL of the patient sample with norm data and between acute and non‐acute IT‐IEM, t tests were conducted. To examine the influence of child age, sex, diagnosis and current dietary treatment on HrQoL, multiple linear regression analyses were conducted. Self‐reports and proxy reporst showed significantly lower HrQoL total scores for children with IT‐IEM compared to healthy children. Current dietary treatment significantly predicted lower proxy reported total HrQoL. Children with non‐acute IT‐IEM reported significantly lower psychosocial health and emotional functioning than children with acute IT‐IEM. The patient sample showed significantly impaired HrQoL and a diet regimen remains a risk factor for lower HrQoL. Differences in HrQoL between acute and non‐acute IT‐IEM subgroups indicate that factors beyond symptom severity determine the perception of disease burden. Identifying these factors is of crucial importance to develop and implement appropriate interventions for those in need. [ABSTRACT FROM AUTHOR]

Background: Neonatal screening for inherited metabolic diseases (IMDs) has been revolutionized by tandem mass spectrometry (MS/MS). This study aimed to enhance neonatal screening for IMDs using machine learning (ML) techniques., Methods: The study involved the analysis of a comprehensive dataset comprising 309,102 neonatal screening records collected in the Ningbo region, China. An advanced ML system model, encompassing nine distinct algorithms, was employed for the purpose of predicting the presence of 31 different IMDs. The model was compared with traditional cutoff schemes to assess its diagnostic efficacy. Additionally, 180 suspected positive cases underwent further evaluation., Results: The ML system exhibited a significantly reduced positive rate, from 1.17% to 0.33%, compared to cutoff schemes in the initial screening, minimizing unnecessary recalls and associated stress. In suspected positive cases, the ML system identified 142 true positives with high sensitivity (93.42%) and improved specificity (78.57%) compared to the cutoff scheme. While false negatives emerged, particularly in heterozygous carriers, our study revealed the potential of the ML system to detect asymptomatic cases., Conclusion: This research provides valuable insights into the potential of ML in pediatric medicine for IMD diagnosis through neonatal screening, emphasizing the need for accurate carrier detection and further research in this domain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Yang, Ding, Zhang, Hu, Zhuang, Wang, Wu, Chen and Li.)

Parents need to constantly monitor their children with inherited metabolic diseases (IMDs) and have difficulty coordinating care. The aim of this descriptive study was to determine the symptoms and problems in children with IMDs and factors affecting caregiver burden. The study was conducted in a pediatric hospital. The study sample consisted of 47 mothers of children with IMDs. Data were collected using a descriptive characteristics form (DCF), a data collection form related to symptoms and problems (DCFSP), and a caregiver burden inventory (CBI). The most common specific problems were hepatomegaly (36.2%), developmental delay (27.7%), and muscle weakness (14.9%). Mothers' CBI mean total score was 30.23 ± 19.65. Mothers whose children were partially or completely dependent had significantly higher scores than others. Mothers who expressed the family income status as "an expenses more than income" had higher CBI scores. Understanding the problems of children with IMD and factors effecting caregiver burden of mothers can help health-care professionals to identify patients' and their families' needs and facilitate the development of nursing interventions for effective care and reduction of caregiver burden. These results can be used to improve the nursing care of children with IMDs and their families. [ABSTRACT FROM AUTHOR]

We surveyed individuals with inherited metabolic diseases (IMDs) or their caregivers to explore experiences with genetic testing. Pursuit of knowledge, benefit to science, clinician recommendations, cascade testing, and cost were important considerations for pursuing genetic testing. Knowledge about inheritance patterns was limited, even for those who had received genetic testing. Future studies should further examine knowledge of IMDs and genetic testing among families, and factors that impact clinicians' decisions to offer genetic testing for IMDs.

Background: Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. Inborn errors of metabolism (IEMs) constitute a group of more than 1,000 monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease, resulting in either accumulation of toxic metabolites and/or shortage of energy and building blocks for the cells. Many IEMs are amenable to treatment with the potential to improve outcomes. With this literature review we aim to create an overview of IEMs presenting with PIND in children, to aid clinicians in accelerating the diagnostic process.Methods: We performed a PubMed search on IEMs presenting with PIND in individuals aged 0–18 years. We applied stringent selection criteria and subsequently derived information on encoding genes, pathways, clinical and biochemical signs and diagnostic tests from IEMbase (www.iembase.org) and other sources.Results: The PubMed search resulted in a total of 2,152 articles and a review of references added another 19 articles. After applying our selection criteria, a total of 85 IEMs presenting with PIND remained, of which 57 IEMs were reported in multiple unrelated cases and 28 in single families. For 44 IEMs (52%) diagnosis can be achieved through generally accessible metabolic blood and urine screening tests; the remainder requires enzymatic and/or genetic testing. Treatment targeting the underlying pathophysiology is available for 35 IEMs (41%). All treatment strategies are reported to achieve stabilization of deterioration, and a subset improved seizure control and/or neurodevelopment.Conclusions: We present the first comprehensive overview of IEMs presenting with PIND, and provide a structured approach to diagnosis and overview of treatability. Clearly IEMs constitute the largest group of genetic PIND conditions and have the advantage of detectable biomarkers as well as amenability to treatment. Thus, the clinician should keep IEMs at the forefront of the diagnostic workup of a child with PIND. With the ongoing discovery of new IEMs, expanded phenotypes, and novel treatment strategies, continuous updates to this work will be required.

Resumen: Introducción: El fallo hepático agudo (FHA) secundario a enfermedades metabólicas hereditarias (EMH) es una enfermedad grave infrecuente de mal pronóstico. La intervención temprana puede salvar vidas. Objetivo: Describir la presentación clínica, la investigación y la evolución de FHA asociado a EMH en niños pequeños. Material y métodos: Estudio retrospectivo realizado en una unidad terciaria de cuidados intensivos neonatales y pediátricos, por un período de 27 años. Se analizaron los registros médicos de todos los niños hasta 2 años de edad, hospitalizados por FHA y con etiología metabólica documentada. Resultados: De los 34 casos de ALF, 18 se asociaban a EMH: galactosemia (4), síndrome de depleción del ADN mitocondrial (SDM) (3), deficiencia de ornitina transcarbamilasa (3), defectos congénitos de la glucosilación (2), tirosinemia tipo 1 (2), deficiencia de 3-hidroxi-acil-CoA deshidrogenasa de cadena larga (1), intolerancia hereditaria a la fructosa (1), aciduria metilmalónica clásica (1) y citrulinemia tipo 1 (1). La edad mediana fue de 1,3 meses. En el 67% de los casos se había observado al menos un síntoma o signo indicativo de EMH con anterioridad (vómitos, fallo de medro, hipotonía o retraso del desarrollo). Los signos físicos más frecuentes en el momento del ingreso fueron: hepatomegalia (72%), ictericia (67%) y encefalopatía (44%). Los niveles analíticos pico fueron: razón internacional normalizada media, 4,5; lactato mediano, 5 mmol/L; bilirrubina media, 201 μmol/L; alanina aminotransferasa (ALT) mediana, 137 UI/L; y amonio mediano, 177 μmol/L. Un paciente fue remitido para trasplante de hígado en contexto de FHA (MSD). La tasa de mortalidad fue del 44%. Discusión: La identificación de EMH como causa frecuente de FHA permitió el uso de medidas terapéuticas específicas y un asesoramiento familiar apropiado. Sus manifestaciones clínicas particulares y niveles moderados de ALT y bilirrubina pueden llevar a sospechar esta condición. Abstract: Introduction: Pediatric acute liver failure (ALF) due to inherited metabolic diseases (IMD) is a rare life-threatening condition with a poor prognosis. Early intervention may be lifesaving. Objective: To describe clinical presentation, investigation and outcomes of ALF related to IMD in young children. Material and methods: Retrospective review of the medical records of children aged up to 24 months, admitted to a tertiary pediatric and neonatal Intensive Care Unit during a 27-year period, fulfilling the ALF criteria, with documented metabolic etiology. Results: From 34 ALF cases, 18 were related to IMD: galactosemia (4), mitochondrial DNA depletion syndrome (MDS) (3), ornithine transcarbamilase deficiency (3), congenital defects of glycosylation (2), tyrosinemia type 1 (2), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (1), hereditary fructose intolerance (1), classic methylmalonic aciduria (1) and citrulinemia type 1 (1). The median age was 1.3 months. At least one previous suggestive sign/symptom of IMD (vomiting, failure to thrive, hypotonia or developmental delay) was observed in 67% of the cases. The most common physical signs at admission included: hepatomegaly (72%), jaundice (67%) and encephalopathy (44%). The peak laboratorial findings were: mean international normalizad ratio 4.5, median lactate 5 mmol/L, mean bilirubin 201 μmol/L, median alanine aminotransferase (ALT) 137 UI/L and median ammonia 177 μmol/L. One patient was submitted to liver transplant in ALF context (MSD). The mortality rate was 44%. Discussion: The identification of IMD as a frequent cause of ALF allowed specific therapeutic measures and adequate family counselling. Particular clinical features and moderated ALT and bilirubin levels can lead to its suspicion.

Propionic Acidemia (PA) is a rare inherited metabolic disorder caused by the enzymatic block of propionyl-CoA carboxylase with the consequent accumulation of propionic acid, which is toxic for the brain and cardiac cells. Since a considerable amount of propionate is produced by intestinal bacteria, interest arose in the attempt to reduce propionate-producing bacteria through a monthly antibiotic treatment of metronidazole. In the present study, we investigated the gut microbiota structure of an infant diagnosed at 4 days of life through Expanded Newborn Screening (NBS) and treated the child following international guidelines with a special low-protein diet, specific medications and strict biochemical monitoring. Microbiota composition was assessed during the first month of life, and the presence of Bacteroides fragilis, known to be associated with propionate production, was effectively decreased by metronidazole treatment. After five antibiotic therapy cycles, at 4 months of age, the infant was supplemented with a daily mixture of three bifidobacterial strains, known not to be propionate producers. The supplementation increased the population of bifidobacteria, with Bifidobacterium breve as the dominating species; Ruminococcus gnavus, an acetate and formate producer, was also identified. Metabarcoding analysis, compared with low coverage whole metagenome sequencing, proved to capture all the microbial biodiversity and could be the elected tool for fast and cost-effective monitoring protocols to be implemented in the follow up of rare metabolic disorders such as PA. Data obtained could be a possible starting point to set up tailored microbiota modification treatment studies in the attempt to improve the quality of life of people affected by propionic acidemia.

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Background: Laboratory investigations of cerebrospinal fluid (CSF) are essential when suspecting an inborn error of metabolism (IEM) involving neurological features. Available tests are currently performed on different analytical platforms, requiring a large sample volume and long turnaround time, which often delays timely diagnosis. Therefore, it would be preferable to have an "one‐instrument" targeted multi‐metabolite approach. Method: A liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) platform, based on two different methods for analysing 38 metabolites using positive and negative electrospray ionisation modes, was established. To allow for platform extension, both methods were designed to use the same CSF sample preparation procedure and to be run on the same separation column (ACE C18‐PFP). Results: Assessment of the LC‐MS/MS platform methods was first made by analytical validation, followed by the establishment of literature‐based CSF cut‐off values and reference ranges, and by the measurement of available samples obtained from patients with confirmed diagnoses of aromatic l‐amino acid decarboxylase deficiency, guanidinoacetate methyltransferase deficiency, ornithine aminotransferase deficiency, cerebral folate deficiency and methylenetetrahydrofolate reductase deficiency. Conclusion: An extendable targeted LC‐MS/MS platform was developed for the analysis of multiple metabolites in CSF, thereby distinguishing samples from patients with IEM from non‐IEM samples. Reference concentrations for several biomarkers in CSF are provided for the first time. By measurement on a single analytical platform, less sample volume is required (200 μL), diagnostic results are obtained faster, and preanalytical issues are reduced. Synopsis: LC‐MS/MS platform for CSF analysis consisting of two differentially designed methods. [ABSTRACT FROM AUTHOR]

Background: The Canadian Inherited Metabolic Diseases Research Network (CIMDRN) is a pan-Canadian practice-based research network of 14 Hereditary Metabolic Disease Treatment Centres and over 50 investigators. CIMDRN aims to develop evidence to improve health outcomes for children with inherited metabolic diseases (IMD). We describe the development of our clinical data collection platform, discuss our data quality management plan, and present the findings to date from our data quality assessment, highlighting key lessons that can serve as a resource for future clinical research initiatives relating to rare diseases.Methods: At participating centres, children born from 2006 to 2015 who were diagnosed with one of 31 targeted IMD were eligible to participate in CIMDRN's clinical research stream. For all participants, we collected a minimum data set that includes information about demographics and diagnosis. For children with five prioritized IMD, we collected longitudinal data including interventions, clinical outcomes, and indicators of disease management. The data quality management plan included: design of user-friendly and intuitive clinical data collection forms; validation measures at point of data entry, designed to minimize data entry errors; regular communications with each CIMDRN site; and routine review of aggregate data.Results: As of June 2019, CIMDRN has enrolled 798 participants of whom 764 (96%) have complete minimum data set information. Results from our data quality assessment revealed that potential data quality issues were related to interpretation of definitions of some variables, participants who transferred care across institutions, and the organization of information within the patient charts (e.g., neuropsychological test results). Little information was missing regarding disease ascertainment and diagnosis (e.g., ascertainment method - 0% missing).Discussion: Using several data quality management strategies, we have established a comprehensive clinical database that provides information about care and outcomes for Canadian children affected by IMD. We describe quality issues and lessons for consideration in future clinical research initiatives for rare diseases, including accurately accommodating different clinic workflows and balancing comprehensiveness of data collection with available resources. Integrating data collection within clinical care, leveraging electronic medical records, and implementing core outcome sets will be essential for achieving sustainability. [ABSTRACT FROM AUTHOR]

Background: Progressive intellectual and neurological deterioration (PIND) is a rare but severe childhood disorder characterized by loss of intellectual or developmental abilities, and requires quick diagnosis to ensure timely treatment to prevent possible irreversible neurological damage. Inborn errors of metabolism (IEMs) constitute a group of more than 1,000 monogenic conditions in which the impairment of a biochemical pathway is intrinsic to the pathophysiology of the disease, resulting in either accumulation of toxic metabolites and/or shortage of energy and building blocks for the cells. Many IEMs are amenable to treatment with the potential to improve outcomes. With this literature review we aim to create an overview of IEMs presenting with PIND in children, to aid clinicians in accelerating the diagnostic process. Methods: We performed a PubMed search on IEMs presenting with PIND in individuals aged 0–18 years. We applied stringent selection criteria and subsequently derived information on encoding genes, pathways, clinical and biochemical signs and diagnostic tests from IEMbase (www.iembase.org) and other sources. Results: The PubMed search resulted in a total of 2,152 articles and a review of references added another 19 articles. After applying our selection criteria, a total of 85 IEMs presenting with PIND remained, of which 57 IEMs were reported in multiple unrelated cases and 28 in single families. For 44 IEMs (52%) diagnosis can be achieved through generally accessible metabolic blood and urine screening tests; the remainder requires enzymatic and/or genetic testing. Treatment targeting the underlying pathophysiology is available for 35 IEMs (41%). All treatment strategies are reported to achieve stabilization of deterioration, and a subset improved seizure control and/or neurodevelopment. Conclusions: We present the first comprehensive overview of IEMs presenting with PIND, and provide a structured approach to diagnosis and overview of treatability. Clearly IEMs constitute the largest group of genetic PIND conditions and have the advantage of detectable biomarkers as well as amenability to treatment. Thus, the clinician should keep IEMs at the forefront of the diagnostic workup of a child with PIND. With the ongoing discovery of new IEMs, expanded phenotypes, and novel treatment strategies, continuous updates to this work will be required. [ABSTRACT FROM AUTHOR]

• The α-Gal A/lysoGb3 ratio is a promising marker of Fabry disease in females. • A correlation between lysoGb3 concentration and age was found. • LysoGb3 levels were different between asymptomatic/symptomatic FD female patients. Fabry disease (FD [MIM:301500]) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene. Deficient activity of its product, lysosomal enzyme α-galactosidase A (α-Gal A), leads to excessive accumulation of glycosphingolipids in cells of multiple organs. The establishing of the diagnosis is challenge in female patients because of milder clinical manifestation and normal α-Gal A activity. The globotriaosylsphingosine (lysoGb3) is described as a more sensitive diagnostic biomarker for females with pathogenic mutation in the GLA gene. Thus, the aim of this study is to improve the biochemical diagnostic efficiency for FD in females. Here we report the α-Gal A/lysoGb3 ratio as the novel biochemical criteria for diagnosis of female patients with FD, using dried blood spots (DBS) as test samples. It showed 100% sensitivity in distinguishing our group of 35 female patients from control (n = 140). Whereas measurement of α-Gal A and lysoGb3 alone showed 8.6% and 74.4% respectively. A new approach of using the ratio of α-Gal A activity to lysoGb3 concentration in DBS may provide a more accurate screening tool for identification of FD females. [ABSTRACT FROM AUTHOR]

Abstract Background Inherited metabolic diseases (IMD) are a large group of rare single-gene disorders that are typically diagnosed early in life. There are important evidence gaps related to the comparative effectiveness of therapies for IMD, which are in part due to challenges in conducting randomized controlled trials (RCTs) for rare diseases. Registry-based RCTs present a unique opportunity to address these challenges provided the registries implement standardized collection of outcomes that are important to patients and their caregivers and to clinical providers and healthcare systems. Currently there is no core outcome set (COS) for studies evaluating interventions for paediatric IMD. This protocol outlines a study that will establish COS for each of two relatively common IMD in children, phenylketonuria (PKU) and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Methods This two-part study is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative. Part 1 includes a rapid review and development of an evidence map to identify a comprehensive listing of outcomes reported in past studies of PKU and MCAD deficiency. The review follows established methods for knowledge synthesis, including a comprehensive search strategy, two stages of screening citations against inclusion/exclusion criteria by two reviewers working independently, and extraction of important data elements from eligible studies, including details of the outcomes collected and outcome measurement instruments. The review findings will inform part 2 of our study, a set of Delphi surveys to establish consensus on the highest priority outcomes for each condition. Healthcare providers, families of children with PKU or MCAD deficiency, and health system decision-makers will be invited to participate in two to three rounds of Delphi surveys. The design of the surveys will involve parents of children with IMD who are part of a family advisory forum. Discussion This protocol is a crucial step in developing the capacity to launch RCTs with meaningful outcomes that address comparative effectiveness questions in the field of paediatric IMD. Such trials will contribute high-quality evidence to inform decision-making by patients and their family members, clinicians, and policy-makers.

Kidney disease is a global health burden with high morbidity and mortality. Causes of kidney disease are numerous, extending from common disease groups like diabetes and arterial hypertension to rare conditions including inherited metabolic diseases (IMDs). Given its unique anatomy and function, the kidney is a target organ in about 10% of known IMDs, emphasizing the relevant contribution of IMDs to kidney disease. The pattern of injury affects all segments of the nephron including glomerular disease, proximal and distal tubular damage, kidney cyst formation, built-up of nephrocalcinosis and stones as well as severe malformations. We revised and updated the list of known metabolic etiologies associated with kidney involvement and found 190 relevant IMDs. This represents the 14th of a series of educational articles providing a comprehensive and revised list of metabolic differential diagnoses according to system involvement. [ABSTRACT FROM AUTHOR]

At any age, respiratory manifestations are a major cause of increased morbidity and mortality of inherited metabolic diseases (IMDs). Type and severity are extremely variable, this depending on the type of the underlying disorder. Symptoms and signs originating from upper or lower airways and/or thoracic wall and/or respiratory muscles involvement can occur either at presentation or in the late clinical course. Acute respiratory symptoms can trigger metabolic decompensation which, in turn, makes airway symptoms worse, creating a vicious circle. We have identified 181 IMDs associated with various types of respiratory symptoms which were classified into seven groups according to the type of clinical manifestations affecting the respiratory system: (i) respiratory failure, (ii) restrictive lung disease, (iii) interstitial lung disease, (iv) lower airway disease, (v) upper airway obstruction, (vi) apnea, and (vii) other. We also provided a list of investigations to be performed based on the respiratory phenotypes and indicated the therapeutic strategies currently available for IMD-associated airway disease. This represents the thirteenth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement. [ABSTRACT FROM AUTHOR]

Inborn errors of metabolism (IEM) are inherited conditions caused by genetic defects in enzymes or cofactors. These defects result in a specific metabolic fingerprint in patient body fluids, showing accumulation of substrate or lack of an end-product of the defective enzymatic step. Untargeted metabolomics has evolved as a high throughput methodology offering a comprehensive readout of this metabolic fingerprint. This makes it a promising tool for diagnostic screening of IEM patients. However, the size and complexity of metabolomics data have posed a challenge in translating this avalanche of information into knowledge, particularly for clinical application. We have previously established next-generation metabolic screening (NGMS) as a metabolomics-based diagnostic tool for analyzing plasma of individual IEM-suspected patients. To fully exploit the clinical potential of NGMS, we present a computational pipeline to streamline the analysis of untargeted metabolomics data. This pipeline allows for time-efficient and reproducible data analysis, compatible with ISO:15189 accredited clinical diagnostics. The pipeline implements a combination of tools embedded in a workflow environment for large-scale clinical metabolomics data analysis. The accompanying graphical user interface aids end-users from a diagnostic laboratory for efficient data interpretation and reporting. We also demonstrate the application of this pipeline with a case study and discuss future prospects.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease.

Introduction: Mucopolysaccharidoses (MPS) constitute a group of progressive and multisystemic inherited metabolic diseases that profoundly affect both the mental health of patients and the wellbeing of their families. This study aims to evaluate the impact of MPS on family functioning and related factors., Methods and Results: Twenty-five patients with MPS, including types I ( n  = 4), II ( n  = 11), IIIB ( n  = 2), IVA ( n  = 3), and VI ( n  = 5), and their families participated in this study. The mean patient age was 13 years [standard deviation (SD): 7.7 years]. Behavioral and emotional problems were noted in 9.1% of all patients. While the type of MPS did not directly influence mental problems, the presence of neuronal involvement did ( p  = 0.006). Patients with MPS III exhibited difficulties primarily in emotional areas, conduct, hyperactivity, and peer problems. Importantly, both patients with MPS II and those with MPS III experienced a significant impact on communication [mean scores for communication domain: MPS II, 35.6 (SD: 24.3); MPS III, 35.0 (SD: 22.6)]; poorer communication was directly linked to worse adaptive behavior ( p  = 0.012), and worse adaptive behavior was associated with lower quality of life ( p  = 0.001). Quality of life and caregiver burden among family members did not significantly differ across MPS types; however, higher caregiver burden was negatively associated with quality of life ( p  = 0.002). Concerning family functioning, the most impacted domains included independence, intellectual/cultural orientation, activity/recreation, and expressiveness. Domain scores did not vary based on MPS type, treatment, or neurological involvement. Quality-of-life scores were positively associated with the cultural/intellectual domain score., Conclusion: The impacts of quality of life and family extend beyond clinical characteristics and MPS type, strongly influenced by patient cognition and communication, as well as type of family functioning, especially those with greater cultural/intellectual skills of their family members. A multidisciplinary approach addressing the broader needs of individuals with MPS becomes essential. Techniques aimed at improving communication, including prompt interventions such as speech therapy and augmentative and alternative communication strategies, can contribute to overall family functioning improvement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Valle, Bara, Furlin, Santos and Cordeiro.)

Background: Early diagnosis of inherited metabolic diseases (IMDs) is important because treatment may lead to reduced mortality and improved prognosis. Due to their diversity, it is a challenge to diagnose IMDs in time, effecting an emerging need for a comprehensive test to acquire an overview of metabolite status. Untargeted metabolomics has proven its clinical potential in diagnosing IMDs, but is not yet widely used in genetic metabolic laboratories. Methods: We assessed the potential role of plasma untargeted metabolomics in a clinical diagnostic setting by using direct infusion high resolution mass spectrometry (DI-HRMS) in parallel with traditional targeted metabolite assays. We compared quantitative data and qualitative performance of targeted versus untargeted metabolomics in patients suspected of an IMD ( n = 793 samples) referred to our laboratory for 1 year. To compare results of both approaches, the untargeted data was limited to polar metabolites that were analyzed in targeted plasma assays. These include amino acid, (acyl)carnitine and creatine metabolites and are suitable for diagnosing IMDs across many of the disease groups described in the international classification of inherited metabolic disorders (ICIMD). Results: For the majority of metabolites, the concentrations as measured in targeted assays correlated strongly with the semi quantitative Z-scores determined with DI-HRMS. For 64/793 patients, targeted assays showed an abnormal metabolite profile possibly indicative of an IMD. In 55 of these patients, similar aberrations were found with DI-HRMS. The remaining 9 patients showed only marginally increased or decreased metabolite concentrations that, in retrospect, were most likely to be clinically irrelevant. Illustrating its potential, DI-HRMS detected additional patients with aberrant metabolites that were indicative of an IMD not detected by targeted plasma analysis, such as purine and pyrimidine disorders and a carnitine synthesis disorder. Conclusion: This one-year pilot study showed that DI-HRMS untargeted metabolomics can be used as a first-tier approach replacing targeted assays of amino acid, acylcarnitine and creatine metabolites with ample opportunities to expand. Using DI-HRMS untargeted metabolomics as a first-tier will open up possibilities to look for new biomarkers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Willems, van der Ham, Schiebergen-Bronkhorst, van Aalderen, de Barse, De Gruyter, van Hoek, Pras-Raves, de Sain-van der Velden, Prinsen, Verhoeven-Duif and Jans.)

In the last decade, the gene therapy (GT) field experienced a renaissance, thanks to crucial understandings and innovations in vector design, stem cell manipulation, conditioning protocols, and cell/vector delivery. These efforts were successfully coupled with unprecedented clinical results of the trials employing the newly developed technology and with the novel establishment of academic–industrial partnerships. A renewed and strengthened interest is rising in the development of gene-based approaches for inherited neurometabolic disorders with severe neurological involvement. Inherited metabolic disorders are monogenetic diseases caused by enzymatic or structural deficiencies affecting the lysosomal or peroxisomal metabolic activity. The metabolic defect can primarily affect the central nervous system, leading to neuronal death, microglial activation, inflammatory demyelination, and axonal degeneration. This review provides an overview of the GT strategies currently under clinical investigation for neurometabolic lysosomal and peroxisomal storage diseases, such as adrenoleukodystrophy and metachromatic leukodystrophy, as well as novel emerging indications such as mucopolysaccharidoses, gangliosidoses, and neuronal ceroid lipofuscinoses, with a comprehensive elucidation of the main features and mechanisms at the basis of a successful GT approach for these devastating diseases. [ABSTRACT FROM AUTHOR]