Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine

Abstract

This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15–21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4–8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½ months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma.

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

“…Sorbitol and myoinositol have not been reported previously to be changed in MDs. Elevated cystathionine was found in single patients with mtDNA depletion syndrome (Tadiboyina et al , ; Mudd et al , ), but not in blood samples of patients with Leigh syndrome (Thompson Legault et al , ), caused by a structural defect of the respiratory chain. Alanine is a standard blood biomarker in MDs (Haas et al , ), but is also found increased in other conditions, including sepsis, tetraspasticity, hyperinsulinism, chronic thiamine deficiency or as a side effect of valproic acid treatment (Thabet et al , ; Noguera et al , ; Thauvin‐Robinet et al , ; Morava et al , ).…”

Glycine N-Methyltransferase Deficiency: A Member of Dysmethylating Liver Disorders?

“…In this disorder, the methylation ratio is decreased due to highly elevated AdoHcy. Interestingly, high AdoMet and high methylation index were recently found also in hepatic mtDNA depletion syndromes with poor outcome (Mudd et al 2012).…”

Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: Evaluation of outcomes after liver transplantation

“…LT may, therefore, be more effective in patients with later onset. Table 5 summarizes 20 patients with MPV17 mutations who received LT 20,[25][26][27][28][29][30][31] , including nine patients from our cohort. Nine of these 20 patients (45.0%) survived after LT.…”