MAFLD: How is it different from NAFLD?

"Metabolic dysfunction-associated fatty liver disease (MAFLD)" is the term suggested in 2020 to refer to fatty liver disease related to systemic metabolic dysregulation. The name change from nonalcoholic fatty liver disease (NAFLD) to MAFLD comes with a simple set of criteria to enable easy diagnosis at the bedside for the general medical community, including primary care physicians. Since the introduction of the term, there have been key areas in which the superiority of MAFLD over the traditional NAFLD terminology has been demonstrated, including for the risk of liver and extrahepatic mortality, disease associations, and for identifying high-risk individuals. Additionally, MAFLD has been adopted by a number of leading pan-national and national societies due to its concise diagnostic criterion, removal of the requirement to exclude concomitant liver diseases, and reduction in the stigma associated with this condition. The current article explores the differences between MAFLD and NAFLD diagnosis, areas of benefit, some potential limitations, and how the MAFLD terminology has opened up new fields of research.

Regulatory Effects of N-3 PUFAs on Pancreatic ß-cells and Insulin-sensitive Tissues.

The N-3 polyunsaturated fatty acids (PUFAs) have a wide range of health benefits, including antiinflammatory effects, improvements in lipids metabolism and promoting insulin secretion, as well as reduction of cancer risk. Numerous studies support that N-3 PUFAs have the potentials to improve many metabolic diseases, such as diabetes, nonalcoholic fatty liver disease and obesity, which are attributable to N-3 PUFAs mediated enhancement of insulin secretion by pancreatic ß-cells and improvements in insulin sensitivity and metabolic disorders in peripheral insulin-sensitive tissues such as liver, muscles, and adipose tissue. In this review, we summarized the up-to-date clinical and basic studies on the regulatory effects and molecular mechanisms of N-3 PUFAs mediated benefits on pancreatic ß-cells, adipose tissue, liver, and muscles in the context of glucose and/or lipid metabolic disorders. We also discussed the potential factors involved in the inconsistent results from different clinical researches of N-3 PUFAs.

Trace elements in dried blood spots as potential discriminating features for metabolic disorder diagnosis in newborns.

Trace elements in dried blood spots (DBSs) from newborns were determined by laser ablation coupled with inductively coupled plasma mass spectrometry, and data were subjected to chemometric evaluation in an attempt to classify healthy newborns and newborns suffering from metabolic disorders. Unsupervised [principal component analysis (PCA) and cluster analysis (CA)] and supervised [linear discriminant analysis (LDA) and soft independent modeling by class analogy (SIMCA)] pattern recognition techniques were used as classification techniques. PCA and CA have shown a clear tendency to form two groups (healthy newborns and newborns suffering from metabolic disorders). LDA and SIMCA have predicted that 90.5% and 83.9% of originally grouped healthy newborn cases were correctly classified by LDA and SIMCA, respectively. In addition, these percentages were 97.6% (LDA) and 80.6% (SIMCA) for DBSs from newborns suffering from metabolic disorders. However, SIMCA has only detected one misclassified DBS from the healthy group, and the lower percentage is attributed to four DBSs from the healthy newborn group and five DBSs from newborns with disorders that were found as belonging to both categories (healthy newborns and newborns with disorders) in the training set. LDA also gave a percentage of grouped maple syrup urine disease (MSUD) cases correctly classified of 100%, although the percentage fells to 66.7% when classifying phenylketonuria (PKU) cases. Finally, essential elements such as Fe, K, Rb, and Zn were found to be matched (correlated) with the concentration of amino acids such as phenylalanine, valine, and leucine, biomarkers linked with MSUD and PKU diseases.

The Discovery of Endoplasmic Reticulum Storage Disease. The Connection between an H&E Slide and the Brain.

The revolutionary evolution in science and technology over the last few decades has made it possible to face more adequately three main challenges of modern medicine: changes in old diseases, the appearance of new diseases, and diseases that are unknown (mostly genetic), despite research efforts. In this paper we review the road travelled by pathologists in search of a method based upon the use of routine instruments and techniques which once were available for research only. The application to tissue studies of techniques from immunology, molecular biology, and genetics has allowed dynamic interpretations of biological phenomena with special regard to gene regulation and expression. That implies stepwise investigations, including light microscopy, immunohistochemistry, in situ hybridization, electron microscopy, molecular histopathology, protein crystallography, and gene sequencing, in order to progress from suggestive features detectable in routinely stained preparations to more characteristic, specific, and finally, pathognomonic features. Hematoxylin and Eosin (H&E)-stained preparations and appropriate immunohistochemical stains have enabled the recognition of phenotypic changes which may reflect genotypic alterations. That has been the case with hepatocytic inclusions detected in H&E-stained preparations, which appeared to correspond to secretory proteins that, due to genetic mutations, were retained within the rough endoplasmic reticulum (RER) and were deficient in plasma. The identification of this phenomenon affecting the molecules alpha-1-antitrypsin and fibrinogen has led to the discovery of a new field of cell organelle pathology, endoplasmic reticulum storage disease(s) (ERSD). Over fifty years, pathologists have wandered through a dark forest of complicated molecules with strange conformations, and by detailed observations in simple histopathological sections, accompanied by a growing background of molecular techniques and revelations, have been able to recognize and identify arrays of grotesque polypeptide arrangements.

The impact of COVID-19 on rare metabolic patients and healthcare providers: results from two MetabERN surveys.

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.

The risks of ubiquinone and ß-carotene deficiency and metabolic disorders in patients with oral cancer.

BACKGROUND: Cancer development is mediated by oxidative stress and inflammation, which may correlate with metabolic disorders. The aim of this study was to evaluate antioxidant vitamins status and metabolic parameters in patients with oral cancer according to tumor-node-metastasis (TNM) stages. METHODS: A total of 194 patients with oral cancer were enrolled in this study. The patients were stratified for four groups according to cancer stages and that the statistics are comparisons across these groups. The levels of antioxidant vitamins (ubiquinone, ß-carotene, vitamin A and E), metabolic parameters, oxidative stress, antioxidant enzymes activity, and inflammatory markers were measured. RESULTS: More than half of the subjects had high blood pressure, central obesity, hyperglycemia, and hyperlipidemia regardless of TNM stage. With regard to antioxidant vitamins status, 46 and 94% of patients had ß-carotene and ubiquinone deficiency, respectively. Patients in T3 and T4 stages had significantly lower antioxidant enzyme (catalase, p = 0.03) activity and higher inflammatory markers levels (high sensitivity C-reactive protein and interleukin-6, p < 0.01) than patients in the other stages. In addition, the level of ß-carotene was negatively associated with waist circumference, and ubiquinone was positively associated with the level of high-density lipoprotein cholesterol (p < 0.05). Higher ß-carotene and ubiquinone levels were negatively associated with hypertriglyceridemia and the risk of metabolic syndrome (p < 0.05). CONCLUSIONS: A high proportion of patients with oral cancer had ubiquinone or ß-carotene deficiency and metabolic disorders. The level of ubiquinone or ß-carotene was negatively associated with the risk of central obesity, hypertriglyceridemia, and metabolic syndrome. Since patients with oral cancer suffer from high oxidative stress and inflammation (particularly in the T3 and T4 stages), supplementation with antioxidant vitamins such as ubiquinone or ß-carotene could be preferentially applied.

A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement.

The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.

A multi-omics investigation of the molecular characteristics and classification of six metabolic syndrome relevant diseases.

Metabolic syndrome (MTS) is a cluster of concurrent metabolic abnormal conditions. MTS and its component metabolic diseases are heterogeneous and closely related, making their relationships complicated, thus hindering precision treatment. Methods: We collected seven groups of samples (group a: healthy individuals; group b: obesity; group c: MTS; group d: hyperglycemia, group e: hypertension, group f: hyperlipidemia; group g: type II diabetes, n=7 for each group). We examined the molecular characteristics of each sample by metabolomic, proteomic and peptidomic profiling analysis. The differential molecules (including metabolites, proteins and peptides) between each disease group and the healthy group were recognized by statistical analyses. Furthermore, a two-step clustering workflow which combines multi-omics and clinical information was used to redefine molecularly and clinically differential groups. Meanwhile, molecular, clinical, network and pathway based analyses were used to identify the group-specific biological features. Results: Both shared and disease-specific molecular profiles among the six types of diseases were identified. Meanwhile, the patients were stratified into three distinct groups which were different from original disease definitions but presented significant differences in glucose and lipid metabolism (Group 1: relatively favorable metabolic conditions; Group 2: severe dyslipidemia; Group 3: dysregulated insulin and glucose). Group specific biological signatures were also systematically described. The dyslipidemia group showed higher levels in multiple lipid metabolites like phosphatidylserine and phosphatidylcholine, and showed significant up-regulations in lipid and amino acid metabolism pathways. The glucose dysregulated group showed higher levels in many polypeptides from proteins contributing to immune response. The another group, with better glucose/lipid metabolism ability, showed higher levels in lipid regulating enzymes like the lecithin cholesterol acyltransferase and proteins involved in complement and coagulation cascades. Conclusions: This multi-omics based study provides a general view of the complex relationships and an alternative classification for various metabolic diseases where the cross-talk or compensatory mechanism between the immune and metabolism systems plays a critical role.

Metabolic cardiomyopathy in pediatrics.

Currently, the percentage of non-specific myocardial lesions of non-inflammatory genesis has significantly increased in the structure of cardiovascular diseases in children and adolescents. Cardiomyopathies are a cluster of myocardial diseases that have become more of interest by cardiologists, morphologists, geneticists, and cardiac surgeons. Cardiomyopathies in children are regarded as a severe pathology characterized by a progressive course, resistance to therapy, and result in an unfavourable prognosis. The current article presents data from international publications dedicated to cardiomyopathy diagnostics in children. This article deals with terminology issues in compliance with international disease classification, primary diagnostic criteria of non-coronary myocardium pathology, and modern methods of diagnostics and pharmacotherapy.

Neck Circumference and Its Association with Cardiometabolic Risk Factors in Pediatric Population.

Background and objectives: To identify the relationship between neck circumference (NC) and cardiometabolic risk factors in children. Materials and Methods: Children and adolescents 6-18 years old (n = 548) from five counties of San Luis Potosí, México were included. Data was collected for biological markers (glucose and lipid profile) and anthropometric and clinical measurements-weight, height, NC, waist circumference (WC), and blood pressure (BP). Body mass index (BMI) was calculated using Quetelet formula (kg/m2). Descriptive analysis, correlation tests, and receiver operating characteristic (ROC) analysis were performed. Results: NC was highly correlated with BMI and WC in both genders (p <0.0001). The most frequent risk factor was high BMI (38.7%). Sensitivity and specificity analysis of NC and high BMI showed an area under the ROC curve of 0.887. Conclusions: According to our findings, NC is a simple, low-cost, and non-invasive measurement, which has a high association with high BMI and increased WC.

The Adipokine Profile and the Cardiometabolic Risk in Non-Obese Young Adults

Background: Young, non-obese adults are considered at low risk for cardiometabolic diseases, although markers of an unhealthy metabolic state are not uncommon findings in this population. Adipose tissue dysfunction, evaluated by the adipokine profile, significantly influences lipid and glucose metabolism and low-grade systemic inflammation. Aims: To determine the relation between adipose tissue dysfunction and the already confirmed cardiometabolic risk indicators, including the atherogenic index of plasma, lipid accumulation product, homeostatic model assessment of insulin resistance, and the low-grade inflammation markers, namely, interleukin 6 and high-sensitivity C-reactive protein. Study Design: Cross-sectional study. Methods: We recruited 93 non-obese, healthy young adults. Anthropometric, lipid profile, inflammatory markers, and adipokines were measured. An abnormal adipokine profile (high leptin-to-adiponectin ratio) was considered as a marker of a dysfunctional adipose tissue. The correlation between the leptin-to-adiponectin ratio and the anthropometric measurements, atherogenic index of plasma, lipid accumulation product, homeostatic model assessment of insulin resistance, interleukin 6, and high-sensitivity C-reactive protein was determined. Results: We found a direct correlation between the abnormal adipokine profile and the cardiometabolic risk indicators mentioned above, except for the low-grade inflammatory markers. In the regression model derived from our data, the leptin-to-adiponectin ratio was best correlated with the unfavorable plasma lipid profile, as estimated by the atherogenic index of plasma (r=0.097, confidence interval=0.015-0.180, p=0.021). A significantly higher leptin-to-adiponectin ratio was found in the insulin-resistant group (p=0.012) and in the highest lipid accumulation product quartile (p=0.032). Conclusion: In a non-obese young population, the high rate of leptin-adiponectin may be a good predictor of cardiovascular and metabolic risk assessment.

Normal weight metabolically unhealthy phenotype in youth: Do definitions matter?

BACKGROUND: Normal weight metabolically unhealthy (NWMU) adults are at increased risk of cardiometabolic disease, however, little is known regarding NWMU children. OBJECTIVES: We examined the associations between existing definitions of NWMU in children aged 8 to 10 years and insulin sensitivity (IS) and secretion 2 years later. METHODS: Data stem from the Quebec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort of 630 Caucasian youth, 8 to 10 years old at baseline, with at least one obese biological parent. Of these, 322 normal weight children were classified as NWMU using four definitions. At 10 to 12 years, IS was measured with the Matsuda-insulin sensitivity index; insulin secretion was measured with the ratio of the area under the curve (AUC) of insulin to the AUC of glucose over a 2-hour oral glucose tolerance test. Multiple linear regression models were used. RESULTS: Because few children met the existing definitions of metabolic syndrome, associations were examined for less stringent definitions (eg, having two vs no risk factors). At baseline, IS was lower in NWMU children compared to children with no risk factors (virtually all definitions). Moreover, after 2 years, IS was 14.4-19.3% lower in NWMU children with one or more risk factors, and up to 29.7% lower in those with two or more risk factors compared to those with none. Insulin secretion was not predicted by components of the metabolic syndrome. CONCLUSION: Existing definitions of NWMU youth performed relatively similarly in predicting IS as youth entered puberty. Children with one or more components of metabolic syndrome-even when of normal weight-have significantly lower IS over time.

BioM2MetDisease: a manually curated database for associations between microRNAs, metabolites, small molecules and metabolic diseases.

BioM2MetDisease is a manually curated database that aims to provide a comprehensive and experimentally supported resource of associations between metabolic diseases and various biomolecules. Recently, metabolic diseases such as diabetes have become one of the leading threats to people's health. Metabolic disease associated with alterations of multiple types of biomolecules such as miRNAs and metabolites. An integrated and high-quality data source that collection of metabolic disease associated biomolecules is essential for exploring the underlying molecular mechanisms and discovering novel therapeutics. Here, we developed the BioM2MetDisease database, which currently documents 2681 entries of relationships between 1147 biomolecules (miRNAs, metabolites and small molecules/drugs) and 78 metabolic diseases across 14 species. Each entry includes biomolecule category, species, biomolecule name, disease name, dysregulation pattern, experimental technique, a brief description of metabolic disease-biomolecule relationships, the reference, additional annotation information etc. BioM2MetDisease provides a user-friendly interface to explore and retrieve all data conveniently. A submission page was also offered for researchers to submit new associations between biomolecules and metabolic diseases. BioM2MetDisease provides a comprehensive resource for studying biology molecules act in metabolic diseases, and it is helpful for understanding the molecular mechanisms and developing novel therapeutics for metabolic diseases. Database URL: http://www.bio-bigdata.com/BioM2MetDisease/.

Las enfermedades metabólicas del hígado / Metabolic liver diseases / Doenças metabólicas hepáticas

El hígado humano, órgano unitario con múltiples funciones vitales, ocupa una posición anatómica privilegiada y estratégica, que le permite recibir información del resto de los órganos y sistemas de la economía. Es posible estar ante una enfermedad hepática con probables complicaciones sistémicas o frente a trastornos extrahepáticos que pueden afectar el hígado. Tal es el caso de las alteraciones en el metabolismo de determinados sustratos que tienen un impacto directo en este órgano y que ocasionan enfermedades hepáticas diversas. Así, se mencionan entre otras: la deficiencia de alfa 1 antitripsina (glicoproteína) que produce colestasis neonatal y cirrosis hepática en adolescentes y adultos con potencial desarrollo de hepatocarcinoma, y la alteración del metabolismo de ciertos metales como el cobre y el hierro, los que al acumularse en el hígado (sobrecarga hepática), dan por resultado las enfermedades de Wilson y hemocromatosis, respectivamente. Estas enfermedades metabólicas, si bien son de baja frecuencia en Argentina, y algunas de ellas difícilmente diagnosticadas en todo el mundo, pueden derivar en una muerte temprana. Esta breve revisión tiene como objetivo enfatizar que las enfermedades metabólicas que afectan al hígado no son una rareza y que pueden presentarse en diversas formas, y así mimetizarse con otras hepatopatías. Lo importante es tenerlas siempre presente.

Human liver, an extraordinary organ with multiple vital functions, takes up a privileged anatomic position, whose strategic site enables it to receive information from the rest of the organism. It is possible to observe liver disease with probable systemic complications, or extrahepatic manifestations that can affect the liver.They could be overthrow metabolisms because of some substances with a direct impact on the gland leading to different liver diseases. Such is the case of Alpha 1 antitrypsin deficiency (a glycoprotein deficiency) which leads to neonatal colestasis and cirrhosis in young and adults, and potentially develop hepatocellular carcinoma. Copper and ironmetabolisms and their accumulation load the hepatocites as a result give rise to Wilson disease and hemochromatosis, respectively. These metabolic diseases, of less frequency in Argentina, are hard to be diagnosed world wide and can lead to premature death. This short revision is aimed at emphasizing that metabolic diseases are not rare and can mimicry different liver diseases.

O fígado humano, órgão unitário com múltiplas funções vitais, ocupa uma posição anatômica privilegiada e estratégica, o que lhe permite receber informações do resto dos órgãos e sistemas da economia. É possível estar diante de uma doença hepática com prováveis complicações sistêmicas ou perante distúrbios extra hepáticos que podem afetar o fígado. Tal é o caso das alterações no metabolismo de certos substratos que têm um impacto direto neste órgão, causando diversas doenças hepáticas. Deste modo, são mencionadas, dentre outras: a deficiência de alfa 1 antitripsina (glicoproteína) que produz colestase neonatal e cirrose hepática nos adolescentes e adultos com potencial desenvolvimento de hepatocarcinoma e a alteração do metabolismo de certos metais como o cobre e o ferro, os quais ao se acumularem no fígado (sobrecarga hepática), resultam nas doenças de Wilson e Hemocromatose, respectivamente. Estas doenças metabólicas, apesar de serem de baixa frequência na Argentina, e algumas delas dificilmente diagnosticadas em todo o mundo, podem levar à morte precoce. Esta breve revisão visa enfatizar que as doenças metabólicas que afetam o fígado não são uma raridade e podem se apresentar de várias formas, mimetizando-se com outras hepatopatias. O importante é que estejam sempre presentes.

Nueva mutación descrita en una mujer joven con esplenomegalia, diagnosticada de enfermedad de Niemann-Pick tipo C / New mutation in a young woman diagnosed with Niemann-Pick disease type C

Fundamento y objetivo: Describir una nueva variante molecular del Niemann-Pick tipo C (NPC) en una paciente de 27 años con esplenomegalia y abolición de reflejos osteotendinosos. Material y métodos: NPC1 es el principal gen mutado en el NPC. Presentamos un caso con una nueva mutación, p.N916S, no descrita previamente en pacientes con NPC. Resultados: p.N916S fue descrita como causa de la enfermedad de NPC por los programas predictivos Mutation Master, PolyPhen2 y SIFT. Conclusiones: p.N916S es una nueva mutación detectada como causa de NPC en una paciente sin síntomas neurológicos graves (AU)

Background and objective: To describe a new molecular variant of Niemann-Pick disease type C (NPC) in a 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes. Material and methods: NPC1 is the main gene with described mutation in NPC disease. Here we report a case with a new mutation, p.N916S, not described before in a patient diagnosed with NPC. Results: p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master, PolyPhen2 and SIFT. Conclusions: p.N916S is a new mutation detected as a cause of NPC disease in a patient without severe neurological symptoms (AU)

Safety profile of anakinra in the management of rheumatologic, metabolic and autoinflammatory disorders.

Anakinra is a biologic response modifier that competitively antagonises the biologic effects of interleukin-1, the ancestor pleiotropic proinflammatory cytokine produced by numerous cell types, found in excess in the serum, synovial fluid and any involved tissues of patients with many inflammatory diseases. The magnitude of the risk of different infections, including Mycobacterium tuberculosis (Mtb) infection, associated with the large use of anakinra in many rheumatologic, metabolic or autoinflammatory disorders is still unknown. In addition, it is unclear whether this effect is modified by the concomitant use of antirheumatic drugs and corticosteroids. The rates of development of Mtb disease in patients treated with anakinra due to rheumatoid arthritis, systemic autoinflammatory diseases, Schnitzler's syndrome, Behçet's disease, adult-onset Still disease, systemic juvenile idiopathic arthritis, gout and diabetes mellitus have been usually very low. However, clinicians must carefully weigh the benefits of biological drugs against their risks, particularly in patients prone to infections. Additional data are needed to understand whether this risk of Mtb infection and reactivation are representative of a class effect related to biologics or whether anakinra bears specifically an intrinsic lower risk in comparison with other biologic drugs.

A new coding system for metabolic disorders demonstrates gaps in the international disease classifications ICD-10 and SNOMED-CT, which can be barriers to genotype-phenotype data sharing.

Data sharing is essential for a better understanding of genetic disorders. Good phenotype coding plays a key role in this process. Unfortunately, the two most widely used coding systems in medicine, ICD-10 and SNOMED-CT, lack information necessary for the detailed classification and annotation of rare and genetic disorders. This prevents the optimal registration of such patients in databases and thus data-sharing efforts. To improve care and to facilitate research for patients with metabolic disorders, we developed a new coding system for metabolic diseases with a dedicated group of clinical specialists. Next, we compared the resulting codes with those in ICD and SNOMED-CT. No matches were found in 76% of cases in ICD-10 and in 54% in SNOMED-CT. We conclude that there are sizable gaps in the SNOMED-CT and ICD coding systems for metabolic disorders. There may be similar gaps for other classes of rare and genetic disorders. We have demonstrated that expert groups can help in addressing such coding issues. Our coding system has been made available to the ICD and SNOMED-CT organizations as well as to the Orphanet and HPO organizations for further public application and updates will be published online (www.ddrmd.nl and www.cineas.org).