Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap

doi:10.1016/S1096-7192(03)00066-0

Molecular Genetics and Metabolism

Volume 79, Issue 1, May 2003, Pages 6-16

https://doi.org/10.1016/S1096-7192(03)00066-0 Get rights and content

Abstract

Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine β-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na⁺,K⁺-ATPase is inhibited by methionine and related metabolites.

Introduction

We describe an unusual series of events involving a cluster of 10 infants in whom it was realized within a relatively short period, beginning in April 1999, that they had unexplained elevations of plasma methionine, in almost all cases accompanied by modest elevation of plasma total homocysteine (tHcy). For several, cystathionine β-synthase (CBS) deficiency had been considered or tentatively diagnosed. A puzzling aspect of these cases was that among the eight screened as newborns for hypermethioninemia, the result for six was considered normal, and only marginally, at most, elevated in two others. Further uncertainty arose when CBS activities in fibroblast extracts, studied in four patients, were reported to be normal; when several methionine-related metabolites in addition to tHcy were found also to be grossly elevated, producing evidence against CBS deficiency and other known causes of hypermethioninemia; and, lastly when, at a time studies of the first of these patients to be extensively investigated were still underway, his elevations of plasma methionine and related metabolites decreased without apparent cause to close to their normal ranges. An explanation of these facts became apparent when dietary histories revealed that during periods of hypermethioninemia nine of these infants had been receiving the same protein hydrolysate formula, a hypoallergenic preparation recommended for infants with food allergies or colic due to protein sensitivity. For approximately 3 years (between May 1998 and February 2001) this formula had had a higher methionine content than previously. This paper reports case histories of these infants, together with the results of metabolite measurements and other studies that eliminate known genetic abnormalities as the cause of the hypermethioninemia. The results also strongly support the concurrence of increased methionine intake and the abnormal metabolite elevations. We report also a 10th infant who, while receiving a greatly increased methionine intake from a total parenteral nutrition (TPN) solution, developed similar metabolic abnormalities. Because two of these children had abnormal brain MRI studies while hypermethioninemic, we discuss the possible cause and effect relationship between severe hypermethioninemia and development of cerebral edema. Also described are the metabolite studies that can help distinguish the causes of infantile hypermethioninemia.

Section snippets

Methods

Patients were ascertained by virtue of having elevated plasma methionine concentrations. The authors provided clinical information on their patients, obtained, when possible, previously drawn plasma samples for assays of diagnostic metabolites, and furnished data on dietary methionine intakes. The latter were usually estimated retrospectively based on approximate formula intakes and methionine concentrations (in mg/L) specified by the manufacturers of each product (Table 1). Methionine intakes

Case histories

Patients 1–9, each of whom received Formula A during the period from May 1998 to February 2001 when its methionine content had been increased, are presented sequentially according to their dates of birth. Case histories are provided to clarify the sequence of events and the reasons for the changes in diets and clinical management. None of the babies in question had a known family history of genetic disease in parents or siblings. Plasma concentrations of methionine and related metabolites are

The etiology of the hypermethioninemia and helpful diagnostic steps

Although the timing of the ascertainment of the nine Formula A-related patients and the fact that their hypermethioninemia occurred when they were placed on the methionine-fortified formula and was absent on normal diets are strong indications that increased methionine intake was a major factor in causing their hypermethioninemia, in some individuals methionine normalized (patient 5) or markedly diminished (patients 6–8) with further growth and development while they were still on Formula A.

Acknowledgements

We thank Howard Fistal (Miami Children’s Hospital, Miami, FL) for ascertaining the methionine intake of Patient 10 while she was on Nephramine, Louis Sokoloff (NIMH, Bethesda, MD) and Wayne Albers (NINDS, Bethesda, MD) for helpful discussions, Andrew Morris (Great Ormond Street Hospital for Children, London, UK), Sabine Scholl and A.M. Das (Medizinische Hochschule, Hannover, Germany) for information about patients, David Worsley (Connecticut Department of Health, Hartford, CT) for information

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Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.
Methionine restriction leads to hyperhomocysteinemia and alters hepatic H<inf>2</inf>S production capacity in Fischer-344 rats
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Although hyperhomocysteinemia is a known risk factor of cardiovascular and neurological diseases (Kang et al., 1992; Ravaglia et al., 2005), there is an ongoing debate in favour of the concept that homocysteine might not be directly related to cardiovascular disease rather it might be an indicator of unhealthy condition which can lead to cardiovascular disease (Cleophas et al., 2000). Therefore, hyperhomocysteinemia in MR animals is in apparent discord with the lifespan increasing effect of MR. Homocysteine is a metabolic intermediate between methionine and cysteine, therefore elevation of homocysteine levels with high methionine intake is expected (Mudd et al., 2003); however, hyperhomocysteinemia with the limited dietary intake of sulphur amino acids in a MR diet seems to conflict with conventional expectations (Gürdöl, 2010). Further complicating understanding of how MR may alter metabolism, recently it was hypothesized that increased flux in the pathway that converts homocysteine to cysteine was associated with the elevated H2S production in several animal models of increased longevity by dietary restriction, including MR in rodents (Hine et al., 2015).
Dietary methionine restriction (MR) increases lifespan in several animal models. Despite low dietary intake of sulphur amino acids, rodents on MR develop hyperhomocysteinemia. On the contrary, MR has been reported to increase H₂S production in mice. Enzymes involved in homocysteine metabolism also take part in H₂S production and hence, in this study, the impact of MR on hyperhomocysteinemia and H₂S production capacity were investigated using Fischer-344 rats assigned either a control or a MR diet for 8 weeks. The MR animals showed elevated plasma homocysteine accompanied with a reduction in liver cysteine content and methylation potential. It was further found that MR decreased cystathionine-β-synthase (CBS) activity in the liver, however, MR increased hepatic cystathionine-γ-lyase (CGL) activity which is the second enzyme in the transsulfuration pathway and also participates in regulating H₂S production. The relative contribution of CGL in H₂S production increased concomitantly with the increased CGL activity. Additionally, hepatic mercaptopyruvate-sulphur-transferase (MPST) activity also increased in response to MR. Taken together, our results suggest that reduced CBS activity and S-Adenosylmethionine availability contributes to hyperhomocysteinimia in MR animals. Elevated CGL and MPST activities may provide a compensatory mechanism for maintaining hepatic H₂S production capacity in response to the decreased CBS activity.
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Homocystinuria due to cystathionine beta synthase (CBS) deficiency presents with a wide clinical spectrum. Treatment by the enteral route aims at reducing homocysteine levels by using vitamin B6, possibly methionine-restricted diet, betaine and/or folate and vitamin B₁₂ supplementation. Currently no nutritional guidelines exist regarding parenteral nutrition (PN) under acute conditions.
Exhaustive literature search was performed, in order to identify the relevant studies describing the pathogenesis and nutritional intervention of adult classical homocystinuria requiring PN. Description of an illustrative case of an adult female with CBS deficiency and intestinal perforation, who required total PN due to contraindication to enteral nutrition.
Nutritional management of decompensated classical homocystinuria is complex and currently no recommendation exists regarding PN composition. Amino acid profile and monitoring of total homocysteine concentration are the main tools enabling a precise assessment of the severity of metabolic alterations. In case of contraindication to enteral nutrition, compounded PN will be required, as described in this paper, to ensure adequate low amounts of methionine and others essential amino acids and avoid potentially fatal toxic hypermethioninemia.
By reviewing the literature and reporting successful nutritional management of a decompensated CBS deficiency using tailored PN with limited methionine intake and n-3 PUFA addition, we would like to underscore the fact that standard PN solutions are not adapted for CBS deficient critical ill patients: new solutions are required. High methionine levels (>800 μmol/L) being potentially neurotoxic, there is an urgent need to improve our knowledge of acute nutritional therapy.
Moderate hyperhomocysteinemia induced by short-term dietary methionine overload alters bone microarchitecture and collagen features during growth
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In general, hyperhomocysteinemia is increasingly appreciated as a risk factor for various diseases, including osteoporosis. However, its effects in non-adults remain largely unknown. Our aim was to determine whether dietary-caused increased homocysteine levels have deleterious effects on bone structure during growth.
We developed a model of moderate hyperhomocysteinemia caused by short-term methionine nutritional overload in growing rats. 30-days-old male Wistar albino rats were randomly assigned to either experimental group subject to a 30-days hypermethionine diet or control group. High-resolution 3D assessment of bone geometry and microarchitecture, as well as fluorescence spectroscopic analysis of bone matrix were performed.
Short-term moderate hyperhomocysteinemia (~ 30 μmol/L) achieved in the study notably affected bone and cartilage characteristics. Parameters of the cortical bone geometry in the experimental group indicated peculiar reorganization of the bone cross-section. Trabecular bone microarchitecture was especially sensitive to hyperhomocysteinemia showing clearly negative bone balance in the experimental group (almost 30% reduced bone volume, mainly due to ~ 25% decrease in trabecular number as well as markedly reduced trabecular connections). Fluorescent spectroscopy of bone matrix revealed multiple alterations to collagen spectra due to homocysteine accumulation in bone, indicative of broken collagenous cross-links.
Given that appropriate accrual of bone mass during growth has important effects on the risk of osteoporosis in adulthood, understanding the skeletal effects of dietary-induced hyperhomocysteinemia in non-adults is essential for interpreting its importance as a modifiable risk factor for osteoporosis and improving programs to preserve/re-establish bone health.
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Stopping Parenteral Nutrition for 3 Hours Reduces False Positives in Newborn Screening
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Citation Excerpt :
The question is complex. Very high methionine attributable to dietary causes has been shown to be potentially dangerous in a few cases.24 The situation related to PN and NBS is different, though.
To evaluate effects of holding parenteral nutrition (PN) for 3 hours prior to newborn screening (NBS) on false-positive NBS rate for amino acids (AAs) in very low birth weight (VLBW) infants (birth weight <1500 g).
We analyzed data from 12 567 consecutive births in 1 hospital between May 2010 and June 2013. VLBW infants were stratified into 3 groups: (1) infants without PN before NBS (no-PN group); (2) infants with early PN running at the time of NBS (early-PN group); and (3) infants with early-PN that were temporarily replaced by dextrose-containing intravenous fluid 3 hours prior to NBS (stop-PN group). We compared the false-positive rate for AA and cost effectiveness between the groups.
The false-positive rate for AA among 413 VLBW infants was significantly higher than infants with birth weight >1500 g (7.62% vs 0.05%; P < .001). There were no false-positive results for AA in the no-PN group. The false-positive rate for AA in the stop-PN group (2/65) was significantly lower than the early-PN group (29/245) (3.1% vs 11.8%; P = .037). The stop-PN group was more cost effective than early-PN group, saving $17.27 per infant screened ($5.53 vs $22.80) or $192.54 for each false-positive result for AA averted. Further reductions in inconclusive samples were also noted.
VLBW and early-PN are significant factors for false-positive results for AA. Holding PN containing AAs for 3 hours before NBS collection is a practical and cost-effective method to significantly reduce the false-positive rate for AA in VLBW infants.

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Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap

Abstract

Introduction

Section snippets

Methods

Case histories

The etiology of the hypermethioninemia and helpful diagnostic steps

Acknowledgements

Blood

Metabolism

Analyt. Biochem.

Metabolism

J. Pediatr.

Energy

Screening for “inborn errors of metabolism” in the newborn infant—a multiple test program

Birth Defects

Rapid diagnosis of homocystinuria and other hypermethioninemias from newborns’ blood spots by tandem mass spectrometry

Clin. Chem.

Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency

FASEB J.

The plasma aminogram. I. Influence of the level of protein intake and a comparison of whole protein and amino acid diets

Pediatr. Res.