Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

BACKGROUND: Remethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions. OBJECTIVE: To summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management. DATA SOURCES: Review, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach. KEY RECOMMENDATIONS: We strongly recommend measuring plasma total homocysteine in any patient presenting with the combination of neurological and/or visual and/or haematological symptoms, subacute spinal cord degeneration, atypical haemolytic uraemic syndrome or unexplained vascular thrombosis. We strongly recommend to initiate treatment with parenteral hydroxocobalamin without delay in any suspected remethylation disorder; it significantly improves survival and incidence of severe complications. We strongly recommend betaine treatment in individuals with MTHFR deficiency; it improves the outcome and prevents disease when given early

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

"Classical organic acidurias": diagnosis and pathogenesis.

Organic acidurias are inherited metabolic diseases due to the deficiency of an enzyme or a transport protein involved in one of the several cellular metabolic pathways devoted to the catabolism of amino acids, carbohydrates or lipids. These deficiencies result in abnormal accumulation of organic acids in the body and their abnormal excretion in urine. More than 65 organic acidurias have been described; the incidence varies, individually, from 1 out of 10,000 to[1 out of 1000,000 live births. Collectively, their incidence approximates 1 out of 3000 live births. Among these disorders, methyl malonic aciduria, propionic aciduria, maple syrup urine disease and isovaleric aciduria are sometimes referred to as classical organic acidurias. In this review, we focused on the basic GC–MS-based methodologies employed in the diagnosis of classical organic acidurias and provided updated reference values for the most common involved organic acids. We also attempted to provide the most recent updates on the pathogenetic bases of these diseases

Serum metabolomic profiles suggest influence of sex and oral contraceptive use.

Background The effects of sex and oral contraceptives (OCs) on blood metabolites have been scarcely studied. Considering the widespread use of OCs and the fact that protocol designs for clinical trials emphasise the use of contraception for women of childbearing potential, we examined if OCs and sex affect the serum levels of the physiologically relevant amino acids, carnitine and acylcarnitines, using metabolomics approaches. Methods Thirty-five healthy adult men and 67 women aged between 20 and 47 years were enrolled. They were drug free with the exception of women taking cyclic format OCs that contained ethinylestradiol and different progestins. OC-free women were analysed during the first ten days of their menstrual cycles, and amino acids, free carnitine and acylcarnitines were measured using HPLC or LC/MS/MS. Results The serum levels of alanine, serine, aspartic acid, arginine and taurine were not significantly different among the analysed groups. Men had significantly higher leucine, isoleucine, methionine, phenylalanine, asparagine, glutamine + glutamate, and histidine than women who did not use OCs, while tryptophan was significantly lower in men. OC use significantly decreased the levels of glycine, proline, glutamine + glutamate, lysine, hydroxyproline and ornitine when compared with non-user women. The level of free carnitine was higher in men than in women; in addition, OC use further reduced the levels of carnitine in women although the reduction is not significant. Total esterified carnitines were higher in untreated women when compared with that of men and OC users. Globally, the effect of OCs and sex was specific for the individual esterified carnitine. The observed metabolic changes were not attributable to renal or hepatic functions or to differences in body weight. Conclusion The assessed parameters were specifically influenced by sex, highlighting the need to have reference values for women and men. The major novelty of this study is the demonstration that OCs specifically change the profiles of serum amino acids and carnitine, which suggests that OC users and non-users should be represented in clinical trials

Maternal VitaminB12 deficiency detected in expanded newborn screening

Introduzione: La disponibilità di nuove tecnologie come la spettrometria di massa tandem ha contribuito enormemente al numero di errori congeniti del metabolismo che possono essere diagnosticati. Infatti, grazie ai programmi di screening metabolico esteso sin dalle prime ore di vita di un neonato, è possibile identificare malattie che possono in tal modo essere trattate precocemente, prima che sintomi clinici, spesso potenzialmente letali, si manifestino. Non esiste però un consenso universale sul pannello più opportuno di patologie da sottoporre a screening (1). Nella Regione Campania si effettua da alcuni anni un progetto pilota di screening neonatale allargato che coinvolge un numero limitato di centri nascita Scopo dello studio e metodi: In questo lavoro abbiamo confrontato l’incidenza, nel periodo 2007-2014, dei disordini metabolici diagnosticati mediante screening metabolico con quella dei disordini individuati nella popolazione dei pazienti per i quali è stato richiesto il dosaggio di aminoacidi e acilcarnitine sulla base di un sospetto clinico. Lo scopo era quello di valutare quanti dei pazienti nati nello stesso periodo in Campania e identificati dopo l’insorgenza dei sintomi clinici avrebbero potuto beneficiare di una diagnosi alla nascita. Risultati e conclusioni: Nel corso della nostra esperienza 26 su 45466 neonati (1:1749) sono stati i casi positivi identificati allo screening neonatale: 5 difetti di acil-CoA deidrogenasi a catena media (MCAD), 3 metilmalonico acidemia (MMA), 7 difetti di vitamina B12 secondari a carenza materna (2), 1 propionico acidemia (PA), 1 isovalerico acidemia, 1 beta-chetotiolasi (βKT), 1 difetto di isobutirril-CoA deidrogenasi, 1 difetto di acil-CoA deidrogenasi a catena corta/ramificata, 1 difetto di 3-metil-crotonil-CoA carbossilasi, 1 difetto di cistationina beta-sintetasi, 2 fenilchetonuria, 1 difetto di carnitina secondario a carenza materna, 1 formiminoglutammico aciduria. Una diagnosi (MCAD) ha consentito l’identificazione della patologia in un fratello asintomatico di 18 mesi che non era stato sottoposto allo screening. Ventisei diagnosi su 2545 (1:98) sono state invece eseguite nel nostro laboratorio su pazienti per i quali il dosaggio degli aminoacidi e delle acilcarnitine in spettrometria di massa tandem era stato richiesto su base clinica. Nell’ambito delle diagnosi post sintomatiche 14/26 sono state effettuate su pazienti nati dopo dell’inizio del progetto di screening metabolico allargato: 5 MMA, 1 PA, 1 βKT, 2 iperglicinemia non chetotica, 1 encefalopatia etilmalonica, 1 difetto di metilene-tetraidrofolato reduttasi, 2 difetti di 3-idrossi-acil-CoA deidrogenasi a catena lunga, 1 difetto di proteina trifunzionale mitocondriale. In conclusione, i dati ottenuti sottolineano la numerosità delle diagnosi effettuate in mancanza di screening, quando ormai il difetto metabolico si è tradotto in un danno d’organo, in uno stadio in cui il potenziale effetto della terapia è compromesso e ribadiscono l’importanza dello screening neonatale quale unico protocollo per la tempestiva diagnosi di malattie del metabolismo. 1- Watson MS. et al, Pediatrics 2006; 117: S296-307. 2- Scolamiero E. et al, Clin Biochem. 2014 doi: 10.1016/j.clinbiochem.2014.08.020 [Epub ahead of print