Automated Screening for Three Inborn Metabolic Disorders: A Pilot Study

Background: Inborn metabolic disorders (IMDs) form a large group of rare, but often serious, metabolic disorders. Aims: Our objective was to construct a decision tree, based on classification algorithm for the data on three metabolic disorders, enabling us to take decisions on the screening and clinical diagnosis of a patient. Settings and Design: A non-incremental concept learning classification algorithm was applied to a set of patient data and the procedure followed to obtain a decision on a patient’s disorder. Materials and Methods: Initially a training set containing 13 cases was investigated for three inborn errors of metabolism. Results: A total of thirty test cases were investigated for the three inborn errors of metabolism. The program identified 10 cases with galactosemia, another 10 cases with fructosemia and the remaining 10 with propionic acidemia. The program successfully identified all the 30 cases. Conclusions: This kind of decision support systems can help the healthcare delivery personnel immensely for early screening of IMDs

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics.

Inborn errors of metabolism (IEMs) are a group of inherited diseases with variable incidences. IEMs are caused by disrupting enzyme activities in specific metabolic pathways by genetic mutations, either directly or indirectly by cofactor deficiencies, causing altered levels of compounds associated with these pathways. While IEMs may present with multiple overlapping symptoms and metabolites, early and accurate diagnosis of IEMs is critical for the long-term health of affected subjects. The prevalence of IEMs differs between countries, likely because different IEM classifications and IEM screening methods are used. Currently, newborn screening programs exclusively use targeted metabolic assays that focus on limited panels of compounds for selected IEM diseases. Such targeted approaches face the problem of false negative and false positive diagnoses that could be overcome if metabolic screening adopted analyses of a broader range of analytes. Hence, we here review the prospects of using untargeted metabolomics for IEM screening. Untargeted metabolomics and lipidomics do not rely on predefined target lists and can detect as many metabolites as possible in a sample, allowing to screen for many metabolic pathways simultaneously. Examples are given for nontargeted analyses of IEMs, and prospects and limitations of different metabolomics methods are discussed. We conclude that dedicated studies are needed to compare accuracy and robustness of targeted and untargeted methods with respect to widening the scope of IEM diagnostics

Nutrition process improvements for adult inpatients with inborn errors of metabolism using the i-PARIHS framework

This project aimed to implement consensus recommendations and innovations that improve dietetic services to promote timely referral to optimise nutritional management for adult inpatients with inborn errors of metabolism (IEM).The i-PARIHS framework was used to identify service gaps, implement innovations and evaluate the innovations within this single-site study. The constructs of this framework are: (i) review of the evidence; (ii) recognising patients and staff knowledge and attitudes; (iii) acknowledging the local context; and (iv) the facilitators role. This included a literature review and metabolic centre service comparisons to investigate dietetic referral and foodservice processes to inform the innovation. A 12-month chart audit (6 months retrospective and prospective of implemented innovation, respectively) to evaluate newly established dietetic referral and IEM nutrition provision procedures was also completed.The innovations implemented encompassed a clinical alert triggering urgent referral, nutrition sick day plans and metabolic diet and formula prescription via an 'alert' tab in electronic records. Eleven metabolic protein-restricted diets and nine formula recipes were introduced. Prior to the innovations, only 53% (n = 19/36) of inpatients with IEM were assessed by the dietitian and received appropriate nutrition within 24 hours. Following implementation of the innovations, 100% (n = 11/11) of inpatients with IEM received timely dietetic assessment and therapeutic nutrition.Implementation of innovations developed using the i-PARIHS framework is effective in timely notification of the metabolic dietitian of referrals. This ensures optimal nutritional management during admissions which is required in this group of high-risk patients

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders

INTRODUCTION: Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. METHODS AND RESULTS: The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. CONCLUSION: The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches

Rare disease landscape in Brazil : report of a successful experience in inborn errors of metabolism

Brazil is a country of continental dimensions, with many social inequalities. The latter are reflected on its health system, which comprises a large public component called SUS, a small paid health insurance component and a third very small private component, in which patients pay personally for medical services. Seventy five percent of the population depends on SUS, which thus far does not provide adequate coverage for genetic medical procedures. In 2014, SUS introduced the “Policy for the Integral Attention to Subjects with Rare Diseases”, establishing guidelines for offering diagnosis and treatment. The policy defines the two main axes, genetic and non-genetic rare diseases. In this fashion, public genetic services in SUS will be installed and funded not by themselves, but as part of the more general policy of rare diseases. Unfortunately, up to now this policy is still depending on financial allowances to be effectively launched. In this article, our intention was to describe activities developed in the area of inborn errors of metabolism by a Brazilian reference center. In spite of the lack of support of SUS, thousands of Brazilian families affected by rare genetic metabolic disorders, and many health professionals from all regions of Brazil, already have benefited from the services, training programs and research projects provided by this comprehensive center

Metabolomic Studies in Inborn Errors of Metabolism: Last Years and Future Perspectives

The inborn errors of metabolism (IEMs or Inherited Metabolic Disorders) are a heterogeneous group of diseases caused by a deficit of some specific metabolic pathways. IEMs may present with multiple overlapping symptoms, sometimes difficult delayed diagnosis and postponed therapies. Additionally, many IEMs are not covered in newborn screening and the diagnostic profiling in the metabolic laboratory is indispensable to reach a correct diagnosis. In recent years, Metabolomics helped to obtain a better understanding of pathogenesis and pathophysiology of IEMs, by validating diagnostic biomarkers, discovering new specific metabolic patterns and new IEMs itself. The expansion of Metabolomics in clinical biochemistry and laboratory medicine has brought these approaches in clinical practice as part of newborn screenings, as an exam for differential diagnosis between IEMs, and evaluation of metabolites in follow up as markers of severity or therapies efficacy. Lastly, several research groups are trying to profile metabolomics data in platforms to have a holistic vision of the metabolic, proteomic and genomic pathways of every single patient. In 2018 this team has made a review of literature to understand the value of Metabolomics in IEMs. Our review offers an update on use and perspectives of metabolomics in IEMs, with an overview of the studies available from 2018 to 2022

Newborn screening using tandem mass spectrometry: A systematic review

Objectives: To evaluate the evidence for the clinical effectiveness of neonatal screening for phenylketonuria (PKU) and medium-chain acyl-coA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (tandem MS). Study design: Systematic review of published research. Data sources: Studies were identified by searching 12 electronic bibliographic databases; conference proceedings and experts consulted. Results: Six studies were selected for inclusion in the review. The evidence of neonatal screening for PKU and MCAD deficiency using tandem MS was primarily from observational data of large-scale prospective newborn screening programmes and systematic screening studies from Australia, Germany and the USA. Tandem MS based newborn screening of dried blood spots for PKU and/or MCAD deficiency was shown to be highly sensitive (>93.220%) and highly specific (>99.971%). The false positive rate for PKU screening was less than 0.046% and for MCAD deficiency the false positive rate was less than 0.023%. The positive predictive values ranged from 20 to 32% and 19 to 100%, respectively. Conclusions: This review suggests that neonatal screening of dried blood spots using a single analytical technique (tandem MS) is highly sensitive and specific for detecting cases of PKU and MCAD deficiency, and provides a basis for modelling of the clinical benefits and potential costeffectiveness

Compounded drugs as an alternative to the therapeutical gaps of inborn errors of metabolism

Inborn errors of metabolism are rare disorders with few therapeutic options for their treatments, which can make patients suffer with complications. Therefore, compounded drugs might be a promising option given that they have the ability of meeting the patient’s specific needs, (i) identification of the main drugs described in the literature; (ii) proposal of compounding systems and (iii) calculation of the budgetary addition for the inclusion of these drugs into the Brazilian Unified Health System. The research conducted a literature review and used management data as well as data obtained from official Federal District government websites. The study identified 31 drugs for the treatment of inborn errors of metabolism. Fifty eight percent (58%) (18) of the medicines had their current demand identified, which are currently unmet by the local Health System. The estimated budget for the production of compounded drugs was of R$363,16.98 per year for approximately 300 patients. This estimated cost represents a budgetary addition of only 0.17% from the total of expenditures planned for drug acquirement. There is a therapeutic gap for inborn errors of metabolism and compounding pharmacies show potential in ensuring access to medicine therapy with a low-cost investment

Report on advances for pediatricians in 2018: allergy, cardiology, critical care, endocrinology, hereditary metabolic diseases, gastroenterology, infectious diseases, neonatology, nutrition, respiratory tract disorders and surgery.

This review reported notable advances in pediatrics that have been published in 2018. We have highlighted progresses in allergy, cardiology, critical care, endocrinology, hereditary metabolic diseases, gastroenterology, infectious diseases, neonatology, nutrition, respiratory tract disorders and surgery. Many studies have informed on epidemiologic observations. Promising outcomes in prevention, diagnosis and treatment have been reported. We think that advances realized in 2018 can now be utilized to ameliorate patient car

High-risk screening and diagnosis of inborn errors of metabolism : a practical guide for laboratories

Inborn errors of metabolism (IEM) are a large and heterogeneous group of genetic diseases. In most of these conditions, the presence of variants in specific genes leads to enzyme deficiencies that affect a particular metabolic step. The number of laboratories dedicated to the study of IEM is very limited worldwide, and its multiplication is urgently required for a more effective diagnosis. With the scarcity of specialized centers, the diagnosis of affected individuals comes too late or does not happen at all. Moreover, the biological samples have to travel long distances, compromising its quality and delaying still more the diagnosis. In this work, we suggest a practical guide for a basic biochemical laboratory to get involved in the study of IEM. This proposal was based on already described metabolic tests and involves the need of just a few, simple, and affordable instruments that can give an enormous quantity of information about the possible metabolic defect faced, such as a spectrophotofluorometer and a gas chromatography/mass spectrometry (GC/MS) instrument. The procedures proposed can be customized and adapted to particular needs and situations, which make it especially useful for developing countries