Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake

A diagnostic trap

S. Harvey Mudd, Nancy Braverman, Martin Gilbert Pomper, Kamer Tezcan, Jonathan Kronick, Parul Jayakar, Cheryl Garganta, Mary G. Ampola, Harvey L. Levy, Shawn E. McCandless, Hobart Wiltse, Sally P. Stabler, Robert H. Allen, Conrad Wagner, Marlene W. Borschel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)6-16
Number of pages11
JournalMolecular Genetics and Metabolism
Volume79
Issue number1
DOIs
StatePublished - May 1 2003

Fingerprint

Hyperhomocysteinemia
Methionine
Cystathionine
Homocystinuria
Magnetic resonance imaging
Brain Edema
Metabolites
Assays
Protein Hydrolysates
Plasmas
Inferior Colliculi
S-Adenosylmethionine
Fibroblasts
Cerebral Cortex
Brain Stem
Adenosine Triphosphatases
Hypermethioninemia
Brain
Eating
Glucose

Keywords

  • Cerebral edema
  • Cystathionine
  • Diet
  • Homocysteine
  • Hyperhomocysteinemia
  • Hypermethioninemia
  • Infant
  • Inferior colliculi
  • Methionine
  • S-adenosylmethionine

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Endocrinology, Diabetes and Metabolism

Cite this

Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake : A diagnostic trap. / Mudd, S. Harvey; Braverman, Nancy; Pomper, Martin Gilbert; Tezcan, Kamer; Kronick, Jonathan; Jayakar, Parul; Garganta, Cheryl; Ampola, Mary G.; Levy, Harvey L.; McCandless, Shawn E.; Wiltse, Hobart; Stabler, Sally P.; Allen, Robert H.; Wagner, Conrad; Borschel, Marlene W.

In: Molecular Genetics and Metabolism, Vol. 79, No. 1, 01.05.2003, p. 6-16.

Research output: Contribution to journalArticle

Mudd, SH, Braverman, N, Pomper, MG, Tezcan, K, Kronick, J, Jayakar, P, Garganta, C, Ampola, MG, Levy, HL, McCandless, SE, Wiltse, H, Stabler, SP, Allen, RH, Wagner, C & Borschel, MW 2003, 'Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: A diagnostic trap', Molecular Genetics and Metabolism, vol. 79, no. 1, pp. 6-16. https://doi.org/10.1016/S1096-7192(03)00066-0
Mudd, S. Harvey ; Braverman, Nancy ; Pomper, Martin Gilbert ; Tezcan, Kamer ; Kronick, Jonathan ; Jayakar, Parul ; Garganta, Cheryl ; Ampola, Mary G. ; Levy, Harvey L. ; McCandless, Shawn E. ; Wiltse, Hobart ; Stabler, Sally P. ; Allen, Robert H. ; Wagner, Conrad ; Borschel, Marlene W. / Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake : A diagnostic trap. In: Molecular Genetics and Metabolism. 2003 ; Vol. 79, No. 1. pp. 6-16.
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AU - Mudd, S. Harvey

AU - Braverman, Nancy

AU - Pomper, Martin Gilbert

AU - Tezcan, Kamer

AU - Kronick, Jonathan

AU - Jayakar, Parul

AU - Garganta, Cheryl

AU - Ampola, Mary G.

AU - Levy, Harvey L.

AU - McCandless, Shawn E.

AU - Wiltse, Hobart

AU - Stabler, Sally P.

AU - Allen, Robert H.

AU - Wagner, Conrad

AU - Borschel, Marlene W.

PY - 2003/5/1

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N2 - 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.

AB - 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.

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KW - Homocysteine

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KW - Methionine

KW - S-adenosylmethionine

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