Mudd's disease (MAT I/III deficiency): a survey of data for MAT1A homozygotes and compound heterozygotes

Abstract

Background: This paper summarizes the results of a group effort to bring together the worldwide available data on patients who are either homozygotes or compound heterozygotes for mutations in MAT1A. MAT1A encodes the subunit that forms two methionine adenosyltransferase isoenzymes, tetrameric MAT I and dimeric MAT III, that catalyze the conversion of methionine and ATP to S-adenosylmethionine (AdoMet). Subnormal MAT I/III activity leads to hypermethioninemia. Individuals, with hypermethioninemia due to one of the MAT1A mutations that in heterozygotes cause relatively mild and clinically benign hypermethioninemia are currently often being flagged in screening programs measuring methionine elevation to identify newborns with defective cystathionine β-synthase activity. Homozygotes or compound heterozygotes for MAT1A mutations are less frequent. Some but not all, such individuals have manifested demyelination or other CNS abnormalities.

Purpose of the study: The goals of the present effort have been to determine the frequency of such abnormalities, to find how best to predict whether they will occur, and to evaluate the outcomes of the variety of treatment regimens that have been used. Data have been gathered for 64 patients, of whom 32 have some evidence of CNS abnormalities (based mainly on MRI findings), and 32 do not have such evidence.

Results and discussion: The results show that mean plasma methionine concentrations provide the best indication of the group into which a given patient will fall: those with means of 800 μM or higher usually have evidence of CNS abnormalities, whereas those with lower means usually do not. Data are reported for individual patients for MAT1A genotypes, plasma methionine, total homocysteine (tHcy), and AdoMet concentrations, liver function studies, results of 15 pregnancies, and the outcomes of dietary methionine restriction and/or AdoMet supplementation. Possible pathophysiological mechanisms that might contribute to CNS damage are discussed, and tentative suggestions are put forth as to optimal management.

Fig. 1

Mean plasma methionine values of untreated patients in the first months of life are plotted against mean ages at which samples were drawn. Red markers indicate patients with evidence of CNS abnormalities; green markers, patients without such evidence

Fig 2

Plasma methionine concentrations for patients on normal diets without (green) or with (red) evidence of CNS abnormalities. Green values are plotted against age at last report; red values, against age at which CNS abnormality was first found. Triangles indicate mean methionine values at ages ≥ 5 months; circles indicate mean methionine values at ages < 5 months (if values at older ages are not available; and plotted against age at last report)

Fig. 3

Plasma AdoMet as a function of plasma methionine. Symbols are the same as those used in Fig. 2. For each patient the mean plasma methionine concentration on normal diets at ages ≥ 5 months is plotted against the mean plasma AdoMet concentration on normal diets at ages ≥ 5 months. Patients without and with evidence of CNS abnormalities are shown, respectively, by red or green markers

Fig. 4

Values for plasma methionine and tHcy are plotted for individual samples from patients on normal diets. Red and green triangles and circles are used as in Fig. 2 to indicate either presence or absence of CNS abnormalities and ages either above or below 5 months