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Objective: Ornithine transcarbamylase deficiency (OTC-D) is an X-linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity-adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell-based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC-D (mOTC-D) as reported in the UCDC and E-IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC-D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC-D and could thus serve as a tool for severity- adjusted evaluation of therapeutic strategies and counselling patients and parents.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome. Fil: Hillert, Alicia. No especifíca; Fil: Anikster, Yair. No especifíca; Fil: Belanger Quintana, Amaya. No especifíca; Fil: Burlina, Alberto. No especifíca; Fil: Burton, Barbara K.. No especifíca; Fil: Carducci, Carla. No especifíca; Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Christodoulou, John. No especifíca; Fil: Dordevic, Maja. No especifíca; Fil: Desviat, Lourdes R.. No especifíca; Fil: Eliyahu, Aviva. No especifíca; Fil: Evers, Roeland A.F.. No especifíca; Fil: Fajkusova, Lena. No especifíca; Fil: Feillet, Francois. No especifíca; Fil: Bonfim Freitas, Pedro E.. No especifíca; Fil: Gizewska, María. No especifíca; Fil: Gundorova, Polina. No especifíca; Fil: Karall, Daniela. No especifíca; Fil: Kneller, Katya. No especifíca; Fil: Kutsev, Sergey I.. No especifíca; Fil: Leuzzi, Vincenzo. No especifíca; Fil: Levy, Harvey L.. No especifíca; Fil: Lichter Koneck, Uta. No especifíca; Fil: Muntau, Ania C.. No especifíca; Fil: Namour, Fares. No especifíca; Fil: Oltarzewsk, Mariusz. No especifíca; Fil: Paras, Andrea. No especifíca; Fil: Perez, Belén. No especifíca; Fil: Polak, Emil. No especifíca; Fil: Polyakov, Alexander V.. No especifíca; Fil: Porta, Francesco. No especifíca; Fil: Rohrbach, Marianne. No especifíca; Fil: Scholl Bürgi, Sabine. No especifíca; Fil: Spécola, Norma. No especifíca; Fil: Stojiljkovic, Maja. No especifíca; Fil: Shen, Nan. No especifíca; Fil: Santana da Silva, Luiz C.. No especifíca; Fil: Skouma, Anastasia. No especifíca; Fil: van Spronsen, Francjan. No especifíca; Fil: Stoppioni, Vera. No especifíca; Fil: Thöny, Beat. No especifíca; Fil: Trefz, Friedrich K.. No especifíca; Fil: Vockley, Jerry. No especifíca; Fil: Yu, Youngguo. No especifíca; Fil: Zschocke, Johannes. No especifíca; Fil: Hoffmann, Georg F.. No especifíca; Fil: Garbade, Sven F.. No especifíca; Fil: Blau, Nenad. No especifíca

INTRODUCTION: Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking.METHODS: This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions and translations.RESULTS: Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128(42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration 5 years. Convulsions, coma or death were not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in 9 different languages.DISCUSSION: Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD. This article is protected by copyright. All rights reserved.

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The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed.

The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed.

Η Στεφανιαία Αθηροσκλήρωση αποτελεί την κύρια αιτία νοσηρότητας και θνητότητας στον εκβιομηχανισμένο κόσμο, παρά την πρόσφατη και ενθαρρυντική μείωση των προσαρμοσμένων για την ηλικία ποσοστών θανάτου. Η κατ’ εξοχήν αθηρογόνος λιποπρωτεϊνη που έχει αποδειχθεί ο πιο σημαντικός παράγοντας κινδύνου για την εμφάνιση πρώιμης καρδιαγγειακής νόσου είναι η LDL. Η Οικογενής Υπερχο-ληστερολαιμία (familial hypercholesterolemia,FH) είναι κληρονομική διαταραχή του μεταβολισμού της χοληστερόλης που μεταβιβάζεται με τον αυτόσωμο επικρατούντα χαρακτήρα, οφείλεται σε μεταλλάξεις στο γονίδιο του LDL υποδοχέα και μπορεί να οδηγήσει σε πρώιμη αθηροσκλήρωση και στην εμφάνιση καρδιοαγγειακών συμβαμάτων σε ηλικία μικρότερη των 60 ετών. Η συχνότητα εμφάνισης της ομοζύγου μορφής είναι 1:1000000 και της ετερόζυγου 1:500 και σε ορισμένους πληθυσμούς 1:200. Η έκφραση του φαινοτύπου καθώς και η θεραπεία της ετερόζυγου οικογενούς Υπερχοληστερολαιμίας προκαλεί προβληματισμούς στη παιδική και εφηβική ηλικία. Γι’ αυτό πραγματοποιήθηκε μελέτη του ενδοθηλίου των αγγείων των παιδιών με Ετερόζυγο Οικογενή Υπερχοληστερολαιμία με τη βοήθεια απεικονιστικής μεθόδου (B-mode υπέρηχο) σε σχέση με το γονότυπο των ασθενών αυτών και τη θεραπεία που εδόθη.Καταρχάς από αρχικό πληθυσμό 222 παιδιών, μελετήθηκε το ενδοθήλιο σε 111 παιδιά από τα οποία 62 παιδιά ήταν φορείς της μετάλλαξης c.1646G>A(p.Gly528Asp)γνωστή ως Genoa και 49 φορείς της c.858C>A(p.Ser265Arg) γνωστής ως Greece 2,που είναι δύο από τις τρείς πιο συχνές μεταλλάξεις που έχουν ως τώρα βρεθεί στον Ελληνικό πληθυσμό. Σε αυτά πραγματοποιήθηκε λεπτομερής κλινική εξέταση, μέτρηση των λιπιδίων τους και ακολούθησε αγγειολογικός έλεγχος , με μέτρηση της FMD της δεξιάς βραχιονίου αρτηρίας και υπολογισμός του πάχους του έσω- μέσου χιτώνα του ενδοθηλίου(IMT) των καρωτίδων, μηριαίων αρτηριών και κοιλιακής αορτής. Ακολούθησε στατιστική ανάλυση των ευρημάτων, στην οποία φαίνεται ότι παρά τα υψηλότερα επίπεδα λιπιδίων που εμφανίζονται στα παιδιά φορείς της μετάλλαξης c.1646G>A(p.Gly528Asp)Genoa, δεν εμφανίστηκαν στατιστικά σημαντικές διαφορές στις μετρήσεις των FMD,και του πάχους του έσω- μέσου χιτώνα (IMT) των καρωτίδων, των μηριαίων και της κοιλιακής αορτής μεταξύ των δύο ομάδων. Σε περαιτέρω όμως διερεύνηση της πρώιμης αθηροσκλήρωσης σε σχέση με την αύξηση της ηλικίας βρέθηκε ότι στην μεγαλύτερη ηλικιακή ομάδα(10-14 ετών) η διαφορά των τιμών των λιπιδίων εξακολουθεί και παραμένει χειρότερη για τη μετάλλαξη Genoa, οι αγγειακοί δείκτες (FMD και μέση τιμή IMT καρωτίδων και μηριαίων) είναι καλύτεροι.Στη δεύτερη φάση της μελέτης, σε 86 από τον αρχικό πληθυσμό παιδιών εδόθη βάσει συγκεκριμένων κριτηρίων υπολιπιδαιμική αγωγή με Στατίνες ως μονοθεραπεία ή με τη προσθήκη Εζετιμίμπης και παρακολουθήθηκαν για ένα έτος. Εκτός από τη κλινική τους εξέταση, έγινε μέτρηση λιπιδίων και άλλων βιοχημικών δεικτών 2,4, 6 και 12 μήνες μετά την έναρξη της θεραπείας, ενώ αγγειολογικός έλεγχος έγινε πριν και επαναλήφθηκε ένα έτος μετά την έναρξη της φαρμακευτικής αγωγής. Μετά από στατιστική ανάλυση των δεδομένων της μελέτης επιβεβαιώθηκε οτι η θεραπεία των παιδιών με Ετερόζυγο Οικογενή Υπερχοληστερολαιμία με Στατίνες με ή χωρίς Εζετιμίμπη είναι αποτελεσματική ως προς τη μείωση των επιπέδων των λιπιδίων, τη βελτίωση της ενδοθηλιακής τους λειτουργίας χωρίς εμφάνιση σοβαρών επιπλοκών.Εκτός όμως από την LDL, σημαντική φαίνεται να είναι και η συμβολή των επιπέδων της HDL στο ενδοθήλιο των αγγείων καθώς η μεταβολή των επιπέδων της παίζει σημαντικό ρόλο στο πάχος του έσω μέσου χιτώνα του ενδοθηλίου των καρωτίδων, ανεξάρτητα από τις μεταβολές της LDL χοληστερόλης.Κρίνεται όμως αναγκαία η συνέχιση της παρακολούθησης των ασθενών που είναι σε θεραπεία για μεγαλύτερο χρονικό διάστημα, όπως και η αύξηση τους σε αριθμό ,ώστε τα αποτελέσματα της παραπάνω μελέτης να ισχυροποιηθούν.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.

Introduction Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and causes neurological manifestations because of excessive accumulation of phenylalanine (PHE). It can also affect adult patients who discontinue their treatment, even if they had been under adequate metabolic control during childhood. For that reason, it is recommended that PKU treatment should be continued throughout life and target PHE levels for adult patients should range between 120 and 600 μmol/L. Case report The authors present an adult patient with PKU who discontinued treatment and developed cognitive dysfunction because of high blood levels of PHE. Brain magnetic resonance imaging (MRI) of the patient was characteristic for PKU, presenting periventricular and callosal white matter hyperintensities in T2 and fluid-attenuated inversion recovery sequences, which were additionally associated with true restriction in diffusion-weighted imaging sequence, a far less recognized PKU neuroimaging feature. Discussion Cognitive dysfunction and psychiatric disorders can be present in adult patients with PKU who discontinue treatment and have poor PHE metabolic control. The presence of white matter hyperintensities in T2 and fluid-attenuated inversion recovery MRI-sequences is a well-described neuroimaging feature of PKU, but diffusion-weighted imaging sequence may also be reliable in detecting brain lesions in patients with PKU. PKU lesions should be considered in the differential diagnosis of true diffusion restriction in brain MRI of patients with PKU history or those who might have escaped newborn screening diagnosis but present neurocognitive dysfunction. Appropriate treatment for the management of PKU should be initiated for the reversal of the clinical and neuroimaging findings.

INTRODUCTION: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism and causes neurological manifestations because of excessive accumulation of phenylalanine (PHE). It can also affect adult patients who discontinue their treatment, even if they had been under adequate metabolic control during childhood. For that reason, it is recommended that PKU treatment should be continued throughout life and target PHE levels for adult patients should range between 120 and 600 μmol/L. CASE REPORT: The authors present an adult patient with PKU who discontinued treatment and developed cognitive dysfunction because of high blood levels of PHE. Brain magnetic resonance imaging (MRI) of the patient was characteristic for PKU, presenting periventricular and callosal white matter hyperintensities in T2 and fluid-attenuated inversion recovery sequences, which were additionally associated with true restriction in diffusion-weighted imaging sequence, a far less recognized PKU neuroimaging feature. DISCUSSION: Cognitive dysfunction and psychiatric disorders can be present in adult patients with PKU who discontinue treatment and have poor PHE metabolic control. The presence of white matter hyperintensities in T2 and fluid-attenuated inversion recovery MRI-sequences is a well-described neuroimaging feature of PKU, but diffusion-weighted imaging sequence may also be reliable in detecting brain lesions in patients with PKU. PKU lesions should be considered in the differential diagnosis of true diffusion restriction in brain MRI of patients with PKU history or those who might have escaped newborn screening diagnosis but present neurocognitive dysfunction. Appropriate treatment for the management of PKU should be initiated for the reversal of the clinical and neuroimaging findings. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research., Funding information: Spanish Government; Fundación Inocente Inocente, Grant/Award Number: MINECO BFU2017‐84264‐P; Center for International Business Education and Research, University of Illinois at Urbana‐Champaign‐ISCIII; the Swiss National Science Foundation, Grant/Award Number: SNF 320030_176088; Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen (APS)

© 2018 SSIEM, Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design., This publication arises from the project E-HOD that has received funding from the European Union in the framework of the Health Programme. VK and PJ were supported by Institutional Research Programme RVO/VFN64165.