Methionine Adenosyltransferase I/III Deficiency via the MAT1A Gene

Methionine adenosyltransferase (MAT) I/III deficiency is characterized by isolated persistent hypermethioninemia and occasionally unusual breath odor. Most individuals with isolated hypermethioninemia are free of major clinical difficulties, although rare cases of individuals with neurologic abnormalities, including intellectual impairment, increased tendon reflexes, dystonia, and nystagmus, have been reported (Mudd 2011; Chien et al. 2015). The product of MAT, S-adenosylmethionine (AdoMet), is a major methyl donor for a large number of biologically important compounds, including two liver-synthesized myelin phospholipids, phosphatidylcholine and sphingomyelin. In a review of 30 affected patients, 27 individuals were found to have normal intelligence and no neurological signs, while three patients were found to have intellectual impairment (Mudd et al. 1995). It has been reported that at least two individuals with complete absence of MATI/III activity developed brain demyelination at 11 years of age (Chamberlin et al. 1996). Although it has been suggested that MATI/III plays an essential role in maintaining myelin structure in the brain, not all patients with truncating pathogenic variants have neurologic involvement (Hazelwood et al. 1998). In a recent study, 32 out of 64 patients with MATI/III deficiency were reported to have some evidence of CNS abnormalities, and the authors suggest that patients with higher levels of methionine are more likely to present with CNS abnormalities (Chien et al. 2015).

Most cases of hypermethioninemia are initially detected by newborn screening, as high levels of serum methionine may serve as an indicator of hyperhomocysteinemia associated with cystathionine β-synthase deficiency. Although methionine S-adenosyltransferase deficiency usually does not require treatment (Andria et al. 2012), dietary therapy may help to maintain myelin structure in individuals with severe MAT I/III deficiency (Chamberlin et al. 1996; Hirabayashi et al. 2013). Treatment with supplemental AdoMet may help improve neurological development and myelination (Furujo et al. 2012).

Methionine adenosyltransferase (MAT) I/III deficiency is an autosomal genetic disorder caused by a deficiency of methionine adenosyltransferase I alpha. The disease is associated with pathogenic variants in the MAT1A gene located on chromosome 10q22. Pathogenic variants within the MAT1A gene encoding methionine adenosyltransferase I alpha are the only known cause of the disease, and nearly 60 different variants have been reported (Human Gene Mutation Database). Causative variants have been reported in all nine coding exons, with missense and nonsense variants serving as the main cause of disease.

Most MAT1A pathogenic variants show autosomal recessive inheritance, but autosomal dominant inheritance has also been reported. In all cases described to date, the autosomal dominant form of disease has been linked to heterozygosity for a single sequence variant, c.791G>A (p.Arg264His) (Chamberlin et al. 1997). In vitro studies suggest that residue 264 is involved in salt bridge formation that is essential for subunit dimerization, and the dominant effect of the R264 mutation is exerted by the formation of enzymatically inactive R264/H264 dimers (Chamberlin et al. 2000).

Most cases of hypermethioninemia are initially detected by newborn screening. Population screening suggests the incidence of MATI/III deficiency may be as high as 1 in 25,000 to 1 in 30,000 live births (Baric 2009). Methionine adenosyltransferase I/III deficiency can be found in ethnically diverse populations, including Europeans, Americans, Spaniards (Couce et al. 2013), Koreans (Kim et al. 2002), Taiwanese (Chien et al. 2005), and Japanese (Nagao et al. 2013).

The MAT1A gene is primarily expressed in the liver; it encodes an α1 subunit that can form two different isozymes, a homotetramer (MAT I) or homodimer (MAT III). MAT catalyzes the biosynthesis of S-adenosylmethionine (also known as AdoMet or SAM) from methionine and ATP (Catoni 1953). AdoMet is the source of methyl groups for most biological methylations and is important in both transmethylation and transsulfuration pathways.

A comprehensive review of the literature suggests that the clinical sensitivity of this test should be high. Of the 61 biochemically/enzymatically diagnosed patients for whom MAT1A gene sequencing was performed, 59 patients carried two pathogenic variants. One patient was reported to be heterozygous for a single variant, and one patient was reported with one sequencing variant and one multi-exonic deletion (Chien et al. 2015). This suggests a clinical sensitivity of ~98% for direct sequencing of the MAT1A gene. In addition, of 18 Spanish patients detected by newborn screening programs (Couce et al. 2013), 15 were reported to be heterozygous for the known R264H dominantly inherited variant, while two of the remaining three patients were compound heterozygous for two variants and the last patient was found to carry only a single heterozygous variant. This suggests a clinical sensitivity of ~95% for direct sequencing of the MAT1A gene.

This test provides full coverage of all coding exons of the MAT1A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).