LabMed

Hypermethioninemia

At a Glance

Hypermethioninemia is a finding of an elevated methionine on plasma amino acids analysis. The differential for methionine elevations includes homocystinuria caused by cystathionine β-synthase deficiency (CBS), methionine S-adenosyltransferase deficiency (MAT), glycine N-methyltransferase deficiency, S-adenosylhomocysteine hydrolase deficiency, and acquired or inherited liver disease. This chapter focuses primarily on narrowing this differential and MAT deficiency. (See the chapter on Homocystinuria for further description of CBS deficiency.)

Methionine S-Adenosyltransferase Deficiency (MAT) is an inherited disorder of metabolism of the amino acid methionine. Methionine, homocysteine, and cysteine are all sulfur-containing amino acids linked by a methylation cycle.

MAT is most commonly inherited in an autosomal recessive manner because of to two abnormal copies of the MAT1A gene; a dominant form has also been reported but is not discussed here. Autosomal recessive inheritance means the individual has inherited two abnormal copies of the MAT1A gene (each gene containing a mutation). Both parents of an individual with MAT are carriers and do not manifest any symptoms of disease.

Most individuals with MAT have been identified through newborn screening, and the vast proportion of them has not exhibited any clinical symptoms of disease. Individuals may have a “boiled cabbage” smell in to their urine or sweat. The few reported symptomatic individuals have exhibited abnormal white matter myelination on MRI or neurological decline, but the significance and role of hypermethioninemia is not clear. Ascertainment bias may be a factor with these reports. No clinical intervention or treatment is thought to be necessary.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Methionine is routinely measured on quantitative plasma amino acids analysis.

Plasma total homocysteine levels should be measured, because only free homocysteine is able to be detected by amino acid chromatography.

When the diagnosis is uncertain, electrolytes, liver function tests, complete blood count (CBC), plasma acylcarnitines, and serum methylmalonic acid or urine organic acids should be performed.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

Elevations of methionine are very common in liver disease. Prematurity of the liver enzymes may cause a pattern of elevated methionine and tyrosine.

Methionine and tyrosine are typically elevated in multiple forms of acquired and inherited liver disease.

Acquired disease may include viral hepatitis, bacterial infection, acetaminophen overdose, herbal medicines, or mushroom poisoning.

Additional inherited liver diseases, such as Tyrosinemia, Homocystinuria, galactosemia, hereditary fructose intolerance, lysosomal storage disease, urea cycle disorders, mitochondrial DNA depletion disorders, neimann-pick type C disease, and congenital disorders of glycosylation should also be considered.

Elevations of methionine may also be seen after infusion of parenteral nutrition (TPN), often with many other nonspecific elevations of other amino acids included in the TPN bag.

What Lab Results Are Absolutely Confirmatory?

Confirmatory DNA sequencing of MAT1A is clinically available and may be useful as a diagnosis when attempting to exclude other causes of hypermethioninemia.

Enzyme analysis has been reported in a research setting.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Currently, there are no known clinical consequences of this disease. Treatments have been reported with methionine-restrict diets and supplemental S-adenosylmethionine in symptomatic cases.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications - OTC drugs or Herbals - that might affect the lab results?

If isolated elevations of methionine are detected, clinical correlation with the ordering physician is necessary to ensure other causes of Hypermethioninemia have been excluded.

If elevated methionine is detected, the chromatogram must be reviewed to examine free homocysteine, as it may be missed if at low levels. Infants with isolated elevated methionine levels may be on methionine-enriched formulas. Newborns with mildly elevated levels should have them repeated within a few weeks or months to see if levels were transiently elevated because of prematurity of liver enzymes.

Methionine coelutes with homocitrulline, which can be elevated in Hyperammonemia-Hyperornithinemia-Homocitrullinemia syndrome. It can be differentiated, as ornithine and glutamine will also be elevated.

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