Elevated Plasma Methionine Research Articles

Genomic analysis of 9 infants with hypermethioninemia by whole-exome sequencing among in Henan, China

BackgroundHypermethioninemia is an inborn error of metabolism with elevated plasma methionine (Met) caused by methionine adenosyltransferase deficiency. Methionine adenosyltransferase (MAT) I/III deficiency is the most common cause of hypermethioninemia. Except for increased blood Met, most patients have no symptoms, but a small number have nervous system complications, including cognitive impairment and mental retardation. ObjectiveTo investigate the gene variation of patients with hypermethioninemia in newborns in Henan province. Methods9 cases of hypermethioninemia were screened for amino acids profile and acyl carnitine by tandem mass spectrometric (MS/MS) among 245 054 newborns. We performed whole-exome sequencing on 9 families of infants with hypermethioninemia. We identified mutated genes under different models of inheritance and further assessed these mutations through Sanger sequencing and association analysis. ResultsThe incidence of neonatal hypermethioninemia was 1:27 228 in Henan province. A total of ten mutations in the MAT1A gene in the 9 patients were identified, including nine reported mutations (c.1070C > T, c.895C > T, c.100 T > A, c.315C > A, c.529C > T, c.623A > C, c.407G > T, c.1066C > T, 867G > T) and one novel mutations (c.772G > C). c.772G > C was detected in 2 families and is the most common variant. 7 infants (7/9) with hypermethioninemia were genetically autosomal dominant, and 2 infants (2/9) with hypermethioninemia were genetically autosomal recessive. ConclusionOur findings expand the mutational spectrum of hypermethioninemia, with the description of one new mutation. They improve the understanding of the genetic background and clinical manifestation of MAT1A in Chinese patients.

Identification of three novel pathogenic mutations in cystathionine beta-synthase gene of Pakistani intellectually disabled patients.

Classical homocystinuria (HCU) is an autosomal recessive inborn error of metabolism, which is caused by the cystathionine-β-synthase (CBS: encoded by CBS) deficiency. Symptoms of untreated classical HCU patients include intellectual disability (ID), ectopia lentis and long limbs, along with elevated plasma methionine, and homocysteine. A total of 429 ID patients (age range: 1.6-23 years) were sampled from Northern areas of Punjab, Pakistan. Biochemical and genetic analyses were performed to find classical HCU disease in ID patients. Biochemically, nine patients from seven unrelated families were identified with high levels of plasma methionine and homocysteine. Targeted exonic analysis of CBS confirmed seven causative homozygous mutations; of which three were novel missense mutations (c.451G>T; p.Gly151Trp, c.975G>C; p.Lys325Asn and c.1039+1G>T splicing), and four were recurrent variants (c.451+1G>A; IVS4+1 splicing, c.770C>T; p.Thr257Met, c.808_810del GAG; p.Glu270del and c.752T>C; p.Leu251Pro). Treatment of patients was initiated without further delay with pyridoxine, folic acid, cobalamin, and betaine as well as dietary protein restriction. The immediate impact was noticed in behavioral improvement, decreased irritability, improved black hair color, and socialization. Overall, health outcomes in this disorder depend on the age and symptomatology at the time of treatment initiation. With personalized treatment and care, such patients can reach their full potential of living as healthy a life as possible. This screening study is one of the pioneering initiatives in Pakistan which would help to minimize the burden of such treatable inborn errors of metabolism in the intellectually disabled patients.

Analysis of five cases of hypermethioninemia diagnosed by neonatal screening.

Background Hypermethioninemia is a group of diseases with elevated plasma methionine (Met) caused by hereditary and non-hereditary factors, although it could also be caused by administration of the amino acid Met. Among these, the disease caused by methionine adenosyltransferase (MAT) I/III deficiency is the most common, and is characterized by persistent, isolated hypermethioninemia as well as slightly elevated homocysteine. S-adenosylmethionine is the product of Met, which can be used as a direct methyl donor of many substances, such as choline and nucleotide, and essential in the development of the body. Among the patients, most have no symptoms, and a small number have central nervous system complications with high levels of plasma Met, including mental retardation, cognitive impairment and special breathing odor. Methods In this study, five cases of MAT I/III deficiency were diagnosed and retrospectively analyzed among 220,000 newborns. Patients with high Met levels received a Met-restricted diet treatment. Results and conclusions MAT I/III deficiency is a common reason for Met elevation in neonatal screening by tandem mass spectrometry (MS/MS), which needs long-term follow-up except for these patients with explicitly benign mutations.

Reversible Cerebral White Matter Abnormalities in Homocystinuria.

Striking MRI brain changes resembling leukoencephalopathy are rarely seen in classical homocystinuria. Our case suggests that reversible white matter changes (WMC) are linked to elevated plasma methionine levels arising during treatment.A 6-year-old boy with learning difficulties and a normal MRI brain scan was diagnosed with homocystinuria (initial total homocysteine 344μmol/L and methionine 64μmol/L). At the age of 6.5years, he developed superior sagittal sinus (SSS) thrombosis. Antithrombotic and homocysteine-lowering treatments were started. Due to poor dietary compliance and betaine treatment, his methionine level reached 1,285μmol/L, and left side weakness developed. Repeat MRI scan revealed new confluent WMC in previously myelinated brain areas. Further 3-month treatment with tighter dietary control significantly dropped his methionine level (233μmol/L) with resolution of his neurological deficit and of radiological changes.We suggest a reversible toxicity from hypermethioninaemia as a possible source of cerebral WMC (secondary to a demyelinating process) in patients with homocystinuria. It highlights the importance of homocysteine-lowering treatment as a prevention and complete resolution of neurological complications. It also demonstrates the need to consider homocystinuria in a differential diagnosis of paediatric leukoencephalopathy.

Mechanistic basis of hypermethioninemia.

Hypermethioninemia is a condition defined as elevated plasma methionine levels and may be a consequence of different conditions that include non-genetic and genetic causes. In severe cases, hypermethioninemia may lead to development of neurological and hepatic impairments, but mechanisms are still not well elucidated. Therefore, this review aims to reunite the knowledge acquired about the methionine-induced brain and liver toxicity focusing on the results obtained by studies from patients, in vitro experiments, and in vivo animal models. In general, some studies have shown that methionine decreases Na+,K+-ATPase activity, induces oxidative stress, increases acetylcholinesterase activity, and leads to dendritic spine downregulation in brain. Concerning to liver, hypermethioninemia seems to provoke changesincell morphology, lipid accumulation, oxidative stress, inflammation, and ATP depletion. It is possible to infer that oxidative damage is one of the most important mechanisms responsible for methionine toxicity, since different studies showed that this amino acid induces oxidative stress in brain and liver tissues. Besides, reactive oxygen species may mediate other alterations induced by methionine, such as the reduction in brain Na+,K+-ATPase activity, and liver inflammation.

The effect of dietary modulation of sulfur amino acids on cystathionine β synthase-deficient mice.

Cystathionine β synthase (CBS) is a key enzyme in the methionine and cysteine metabolic pathway, acting as a metabolic gatekeeper to regulate the flow of fixed sulfur from methionine to cysteine. Mutations in the CBS gene cause clinical CBS deficiency, a disease characterized by elevated plasma total homocysteine (tHcy) and methionine and decreased plasma cysteine. The treatment goal for CBS-deficient patients is to normalize the metabolic values of these three metabolites using a combination of vitamin therapy and dietary manipulation. To better understand the effectiveness of nutritional treatment strategies, we have performed a series of long-term dietary manipulation studies using our previously developed Tg-I278T Cbs(-/-) mouse model of CBS deficiency and sibling Tg-I278T Cbs(+/-) controls. Tg-I278T Cbs(-/-) mice have undetectable levels of CBS activity, extremely elevated plasma tHcy, modestly elevated plasma methionine, and low plasma cysteine. They exhibit several easily assayable phenotypes, including osteoporosis, loss of fat mass, reduced life span, and facial alopecia. The diets used in these studies differed in the amounts of sulfur amino acids or sulfur amino acid precursors. In this review, we will discuss our findings and their relevance to CBS deficiency and the concept of gene-diet interaction.

Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias

There are now four genetic mouse models that induce hyperhomocyst(e)inemia by decreasing the activity of an enzyme involved in homocysteine metabolism: cystathionine beta-synthase, methylenetetrahydrofolate reductase, methionine synthase and methionine synthase reductase. While each enzyme deficiency leads to murine hyperhomocyst(e)inemia, the accompanying metabolic profiles are significantly and often unexpectedly, different. Deficiencies in cystathionine beta-synthase lead to elevated plasma methionine, while deficiencies of the remaining three enzymes lead to hypomethioninemia. The liver [S-adenosylmethionine]/[S-adenosylhomocysteine] ratio is decreased in mice lacking methylenetetrahydrofolate reductase or cystathionine beta-synthase, but unexpectedly increased in mice with deficiencies in methionine synthase or methionine synthase reductase. Folate pool imbalances are observed in complete methylenetetrahydrofolate reductase deficiency, where methyltetra-hydrofolate is a minor component, and in methionine synthase reductase deficiency, where methyltetrahydrofolate is increased relative to wild-type mice. These differences illustrate the potential diversity among human patients with hyperhomocyst(e)inemia, and strengthen the argument that the pathologies associated with the dissimilar forms of the condition will require different treatments.

Fibrillin-2 Defects Impair Elastic Fiber Assembly in a Homocysteinemic Chick Model

Homocysteinemia in humans is associated with vascular complications that increase the risk for atherosclerosis and stroke. Animal studies have shown that the disease is multifactorial and includes lesions associated with the elastin component of the extracellular matrix. In the following experiments we have used the aortas from rapidly growing chicks to assess the cause of the elastin defects resulting from homocysteinemia. Day-old chicks were fed diets containing varying amounts of DL-methionine, DL-homocysteine, homocysteine thiolactone or DL-cysteine for periods up to 9 wk. Three weeks after feeding 2% DL-methionine the plasma methionine was elevated > 20-fold, whereas plasma homocysteine was more than 3-fold normal plasma values. The aortas showed severe histopathology, evidenced by the pronounced separation of elastic lamellae with marked smooth muscle proliferation and, in some instances, aneurysms. There was no evidence of decreased desmosine content or a significant reduction in lysyl oxidase in the aortas from the treated groups compared to those from controls. Increasing other dietary factors such as the vitamins required for methionine metabolism had no effect on the development of the vascular lesions. Twenty to 30% of the chicks fed the high methionine diets exhibited severe neurological problems, expressed as tonic contractions or seizures. Electron microscopy revealed disordered aortic elastic fibrils, associated with either an absence of or disrupted assembly of microfibrils. Immunohistochemical studies demonstrated a loss of fibrillin-2 immunoreactivity in the aortas of chicks fed 2% methionine. The studies suggest that elevated plasma methionine or its metabolites disrupt normal microfibril configuration, leading to the assembly of aberrant elastic fibers.

Amelioration of Ethionine Toxicity in the Chick

Several chick bioassays were conducted to evaluate means of ameliorating ethionine toxicity. Supplementing a corn-soy diet marginally deficient in sulfur amino acids (methionine + cystine) with .075% D,L-ethionine reduced weight gain in 8-day-old chicks by 70% compared to gains of unsupplemented controls. Dietary addition of .50% DL-methionine prevented reduction in weight gain and feed intake resulting from ethionine supplementation whereas feeding supplemental L-cystine was without effect. Supplementation of the ethionine-containing diet with either choline or betaine ameliorated the growth depression, although neither compound was able to completely overcome the toxic effects of ethionine. Dietary ethionine did not affect plasma levels of free methionine or cystine but did increase plasma free glycine 6-fold. Dietary addition of .50% DL-methionine caused normalization of plasma glycine levels whereas it elevated plasma methionine concentration. Although results suggested the possibility of ethionine-induced serine or threonine deficiency, dietary additions of .75% L-serine or .75% L-threonine failed to improve chick weight gain. These studies suggest that ethionine, in addition to affecting transsulfuration and transmethylation activity, may exert specific effects on certain amino acids in tissue pools.

D-Methionine Utilization During Parenteral Nutrition in Adult Rats

D-Methionine, present in some parenteral solutions, is poorly utilized by man. To evaluate some of the factors affecting utilization, methionine isomer excretion was measured in rats treated with two different parenteral regimens: total parenteral nutrition and protein sparing therapy. Within each regimen, nutrient solutions differing only in methionine isomer composition were compared. Eight rats on the total parenteral nutrition regimen were infused with a 33% glucose--2.8% amino acid solution at a rate providing 100% of energy requirement. Four rats received the parenteral sulution containing L-methionine, and four the solution containing DL-methionine. Eight additional rats on a protein sparing regimen were infused with an amino acid solution (8.5%) at a rate to provide 25% of energy requirement. Four rats were infused with a solution containing L-methionine, and four with a solution containing DL-methionine. Total methionine content of livers was not affected by differences in methionine isomer. Infusion of the solution containing DL-methionine significantly increased plasma methionine levels during protein sparing therapy, with the increase representing accumulation of the D-isomer. Rats receiving protein sparing therapy had significantly higher liver methionine levels than rats receiving total parenteral nutrition. Although rats infused with the solution containing DL-methionine had elevated plasma methionine levels during protein sparing therapy, urinary methionine losses were small, as were losses of methionine sulfoxide and alpha-keto-gamma-methiolbutyrate. In contrast to humans, adult rats utilized more than 99% of parenterally administered D- or L-methionine.

Thiols and Hepatic Coma

The plasma concentrations of methane and ethane thiols have been determined during the course of acute liver failure by a gas-chromatographic technique, and a prognostic evaluation is possible using this analysis. Further, the effects of some therapeutic measures, notably hemoperfusion, on the thiol levels have been investigated. It is concluded that these toxins, which are to a large extent covalently protein-bound, are extremely difficult to remove in an extracorporeal liver support system. Since the cause of the pathological thiol concentrations is probably the elevated plasma methionine levels associated with severe liver disease, it is suggested that the most hopeful course of action against the accumulation of thiols in the body might be a preventative therapy involving the normalization of methionine at an early stage of the disease.

The Effect of Supplemental Glycine or Threonine on the Elevated Plasma Methionine Concentration and the Decreased Feed Intake of Chicks Fed the Methionine Excess Diet

The Effect of Supplemental Glycine or Threonine on the Elevated Plasma Methionine Concentration and the Decreased Feed Intake of Chicks Fed the Methionine Excess Diet

Cystine: a semi-essential amino acid in the newborn infant.

ABSTRACT. Pohlandt, F. (Department of Paediatrics, Section of Neonatology, University Hospital, Ulm, Federal Republic Germany). Cystine: a semi‐essential amino acid in the newborn infant. Acta Paediatr Scand63: 801, 1974.—The enzyme activities of the transsulfuration pathway (Cystine biosynthesis) are low or not measurable in the livers of human fetuses, premature and full‐term newborns. Cystine thus may be an essential amino acid in newborn infants. To test this suggestion, we studied the plasma amino acid concentrations in 20 premature and 7 full‐term infants treated for prematurity and/or respiratory distress syndrome by ion exchange columnchromatography. The infants received infusions of a 5% glucose‐electrolyte‐solution during the first two days of life. In premature newborns the plasma cystine concentrations markedly decreased within the first 12 hours of life (median <5 μmol/l) and remained low tlfereafter. In full‐term infants the plasma cystine concentrations decreased similarly. To rule out the possibility that these low plasma cystine concentrations were the result of a reduced cystine biosynthesis due to a lack of methionine, a substrate of transsulfuration pathway, we studied premature on infusion of a mixture of synthetic l‐amino acids free from cystine. Despite elevated plasma methionine concentrations (median 113.4 μnol/l) the plasma cystine concentrations remained very low. Cystine, therefore, can be considered a semi‐essential amino acid in the newborn infant and should be supplied to newborns receiving balanced parenteral nutrition.

HOMOCYSTINURIA, AN ERROR IN THE METABOLISM OF METHIONINE

A new inborn error of metabolism was found in two mentally retarded children. The excretion of homocystine was accompanied in one boy by ectopia lentis, failure to thrive, poor developmental milestones, thrombo embolic phenomena, methioninuria, decreased excretion of taurine, and elevated plasma methionine. The second patient had normal plasma methionine levels, and a nearly normal amino acid pattern in the urine other than homocystine. Loading tests using methionine, serine, and homocystine failed to alter plasma amino acid levels and did not provide any information on the nature of the metabolic defect in sulfur amino acid metabolism. The two children had different abnormalities in methionine metabolism or they had the same metabolic defect but in different degrees of severity.