BackgroundRemethylation defects are rare inherited disorders in which impaired remethylation of homocysteine to methionine leads to accumulation of homocysteine and perturbation of numerous methylation reactions.ObjectiveTo summarise clinical and biochemical characteristics of these severe disorders and to provide guidelines on diagnosis and management.Data sourcesReview, evaluation and discussion of the medical literature (Medline, Cochrane databases) by a panel of experts on these rare diseases following the GRADE approach.Key recommendationsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9991-4) contains supplementary material, which is available to authorised users.

Glutamine synthetase plays a major role in ammonia detoxification, interorgan nitrogen flux, acid-base homeostasis, and cell signaling. We report on two unrelated newborns who had congenital human glutamine synthetase deficiency with severe brain malformations resulting in multiorgan failure and neonatal death. Glutamine was largely absent from their serum, urine, and cerebrospinal fluid. Each infant had a homozygous mutation in the glutamine synthetase gene (R324C and R341C). Studies that used immortalized lymphocytes expressing R324C glutamine synthetase (R324C-GS) and COS7 cells expressing R341C-GS suggest that these mutations are associated with reduced glutamine synthetase activity.

Neural tube defects (NTDs) are common complex congenital malformations resulting from failure of the neural tube closure during embryogenesis. It is established that folic acid supplementation decreases the prevalence of NTDs, which has led to national public health policies regarding folic acid. To date, animal studies have not provided sufficient information to establish the metabolic and/or genomic mechanism(s) underlying human folic acid responsiveness in NTDs. However, several lines of evidence suggest that not only folates but also choline, B12 and methylation metabolisms are involved in NTDs. Decreased B12 vitamin and increased total choline or homocysteine in maternal blood have been shown to be associated with increased NTDs risk. Several polymorphisms of genes involved in these pathways have also been implicated in risk of development of NTDs. This raises the question whether supplementation with B12 vitamin, betaine or other methylation donors in addition to folic acid periconceptional supplementation will further reduce NTD risk. The objective of this article is to review the role of methylation metabolism in the onset of neural tube defects.

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.

ABSTRACT:We investigated respiratory chain (RC), tricarboxylic acid cycle (TCA) enzyme activities, and oxidative stress in the tissues of six patients with organic aciduria (OA) presenting various severe complications to further document the role of mitochondrial OXPHOS dysfunction in the development of complications. Two children with propionic acidemia (PA), presenting a severe cardiomyopathy, and four with methylmalonic aciduria (MMA), who developed a neurologic disease (3/4) and renal failure (2/4), were followed. We measured RC and TCA cycle enzyme activity in patient tissues and assessed oxidative metabolism in fibroblasts in vitro. Various RC deficiencies were found in tissues of patients with PA and MMA. TCA cycle enzyme activities were normal when investigated and reactive oxygen species were decreased as well as detoxifying systems activities in the two patients tested. In conclusion, mitochondrial dysfunction was found in all investigated tissues of six patients with organic acidemia presenting with severe complications. Reactive oxygen species production and detoxification were decreased in fibroblast primary cultures. Our results bring further support for a role of secondary respiratory deficiency in the development of late multiorgan complications of these diseases. (Pediatr Res 66: 91-95, 2009) P ropionic aciduria (PA) and methylmalonic aciduria (MMA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids. PA results from mutations in the PCCA or PCCB genes, encoding the ␣ and ␤ subunits of propionyl-CoA carboxylase, respectively, which converts propionyl-CoA into methylmalonyl-CoA. MMA is caused by mutations in the MUT gene, encoding the methylmalonyl-CoA mutase (MCM), or more rarely in genes encoding the coenzyme adenosylcobalamin of MCM. MCM converts methylmalonyl-CoA into succinylCoA, an intermediate of the tricarboxylic acid cycle (TCA) cycle, which generates NADH used by the mitochondrial respiratory chain (RC).Organic acidurias (OA) usually present as an acute metabolic distress at birth, when the enzymatic deficiency is complete, or later in life, when the deficiency is less severe. As propionate is produced by the catabolism of branched-chain amino acids, fatty acids with a carbon odd-chain and the intestinal flora, the treatment is based on a strict low-protein diet associated with a sufficient caloric intake, carnitine, and antibiotics. However, despite the therapeutic improvements of the last 20 y (1), the overall outcome of patients with OA remains unsatisfying: reports are increasing of long-term complications, such as neurologic disorders by degeneration of the basal ganglia (2), progressive renal failure (3), acute pancreatitis (4,5), and cardiomyopathy (6). It is commonly believed that 2-methylcitrate, methylmalonic acid (MA), and other accumulated metabolites derived from propionate inhibit some mitochondrial enzymes and are toxic on multiple tissues. However, current treatments designed to limit the accumulation of toxins rema...

The ketogenic diet (KD) is an established treatment for refractory epilepsy, including some inflammation-induced epileptic encephalopathies. In a lipopolysaccharide (LPS)-induced fever model in rats, we found that animals given the KD for 14 days showed less fever and lower proinflammatory cytokine levels than control animals. However, KD rats exhibited a decrease in circulating levels of arachidonic acid and long-chain n-3 polyunsaturated fatty acids (PUFAs), suggesting that the anti-inflammatory effect of KD was probably not due to an increase in anti-inflammatory n-3 PUFA derivatives. These properties might be of interest in some conditions such as fever-induced refractory epileptic encephalopathy in school-aged children.

To date, epimutations reported in man have been somatic and erased in germlines. Here, we identify a cause of the autosomal recessive cblC class of inborn errors of vitamin B12 metabolism that we name “epi-cblC”. The subjects are compound heterozygotes for a genetic mutation and for a promoter epimutation, detected in blood, fibroblasts, and sperm, at the MMACHC locus; 5-azacytidine restores the expression of MMACHC in fibroblasts. MMACHC is flanked by CCDC163P and PRDX1, which are in the opposite orientation. The epimutation is present in three generations and results from PRDX1 mutations that force antisense transcription of MMACHC thereby possibly generating a H3K36me3 mark. The silencing of PRDX1 transcription leads to partial hypomethylation of the epiallele and restores the expression of MMACHC. This example of epi-cblC demonstrates the need to search for compound epigenetic-genetic heterozygosity in patients with typical disease manifestation and genetic heterozygosity in disease-causing genes located in other gene trios.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and