Methionine Adenosyltransferase I/iii Deficiency

A number sign (#) is used with this entry because methionine adenosyltransferase (MAT) I/III deficiency is caused by homozygous, compound heterozygous, or heterozygous mutation in the MAT1A gene (610550) on chromosome 10q22.

Description

Methionine adenosyltransferase deficiency is an inborn error of metabolism resulting in isolated hypermethioninemia. Most patients have no clinical abnormalities, although some with the autosomal recessive form have have neurologic abnormalities (Mudd et al., 2003; Kim et al., 2016).

Clinical Features

Gaull and Tallan (1974) reported a female infant with hypermethioninemia detected by newborn screening. Liver biopsy showed a deficiency of methionine adenosyltransferase. A case reported earlier in abstract may have represented this disorder (Hug et al., 1968). Mudd et al. (2003) reported follow-up of the patient reported by Gaull and Tallan (1974). She had completely normal physical and mental development with persistently increased serum methionine levels associated with decreased MAT activity (11% of control values). She had 4 pregnancies beginning at age 23 years. Three pregnancies and children were completely normal; 1 pregnancy resulted in fetal arrest at 10 weeks' gestation and termination, which the authors did not believe was related to the metabolic abnormality. Of note, the patient ingested 2 large eggs daily during the pregnancies to ensure adequate choline delivery to the fetuses.

Finkelstein et al. (1975) observed a male infant ascertained in newborn screening because of hypermethioninemia. At 32 months the child was clinically normal with persistently elevated serum methionine levels. At that time, liver biopsy showed decreased MAT activity. Gout et al. (1977) reported an affected infant in France who had growth retardation, anorexia, digestive disturbances, and a strong smell of 'boiled cabbage' in urine and sweat. At 6-year follow-up, psychomotor and growth developments were excellent on a low-methionine diet, although hypermethioninemia persisted. Liver biopsy showed abnormal kinetics of methionine adenosyltransferase.

Gaull et al. (1981) reported 4 children with hypermethioninemia identified in a neonatal mass screening program. Hepatic methionine adenosyltransferase was decreased to 7.8 to 17.5% of normal controls (mean 11.4%). Electron microscopy of the liver showed increased smooth endoplasmic reticulum, decreased rough endoplasmic reticulum, and increased lysosomes; short breaks in the outer mitochondrial membranes were present to a variable extent. Despite the persistent hypermethioninemia, all 4 children appeared well. In each case the parents were well and unrelated. Gaull et al. (1981) suggested that normal activity of extrahepatic MAT may explain the benign clinical phenotype.

Gahl et al. (1987) reported a 31-year-old man with MAT deficiency, the oldest reported patient at that time. Although he was clinically normal, a long-distance runner, teacher, and father of 3, he had fetid breath, greatly elevated plasma methionine, and met-sulfoxides of 46 micromoles. The bad breath was shown to be due to the presence of unusually large amounts of dimethylsulfide (Gahl et al., 1988). Hazelwood et al. (1998) provided follow-up of this patient. He had normal neurologic status with no evidence of demyelination on MRI. He also had mild aortic regurgitation attributed to rheumatic fever.

Surtees et al. (1991) reported an unusual case of MAT deficiency in an individual with persistent hypermethioninemia who developed abnormal neurologic symptoms and brain demyelination. The patient responded favorably to AdoMet therapy.

Mudd et al. (1995) reviewed the clinical and biochemical features of 30 patients with isolated hypermethioninemia, some of whom had previously been reported. Two patients reported by Gout et al. (1977) and Gaull et al. (1981) with documented MAT deficiency were 24 and 20 years old, respectively, and had no neurologic or intellectual impairment despite persistent increased serum methionine. Twenty-seven patients had normal intelligence and no neurologic signs; 3 had mental retardation or decreased IQ, 2 of whom had neurologic signs. The most severely affected girl had mental retardation, dystonia, and evidence of myelination arrest on MRI; however, she had a brother with dystonia and verbal difficulties who had normal serum methionine. In the patients as a whole, methionine transamination metabolites accumulated abnormally only when plasma methionine concentrations exceeded 300-350 microM and did so more markedly after 0.9 years of age. Mudd et al. (1995) noted that limitation of dietary methionine intake could moderate the abnormal elevations of both methionine and its transamination metabolites in isolated persistent hypermethioninemia, but concluded that dietary restriction is not usually necessary.

Inheritance

Methionine adenosyltransferase deficiency is usually inherited as an autosomal recessive trait (Ubagai et al., 1995). However, in the parents of a patient, Gaull et al. (1981) detected decreased enzyme activity in the father (55% of control values) and normal values in the mother. Another father and mother had moderately impaired plasma methionine tolerance curves following oral loads of methionine. The authors raised the possibility of multiple allelic forms of the enzyme and higher activities in human females (as has been demonstrated by Natori (1963) in rats).

Blom et al. (1992) observed a clinically benign form of persistent hypermethioninemia with probable dominant inheritance in 3 generations of a family. Methionine loading of 2 affected family members demonstrated a diminished ability to catabolize methionine but the activities of MAT and cystathionine beta-synthase were not decreased in fibroblasts from 4 affected family members. Fibroblast methylenetetrahydrofolate reductase (MTHFR; 607093) activity and its inhibition by S-adenosylmethionine were also normal, indicating normal regulation of homocysteine remethylation. Serum folate concentrations were not increased. Blom et al. (1992) speculated that since the hepatic and fibroblast isoenzymes of MAT are determined by different genes, the biochemical findings in this family might represent mutation in the structural gene for the hepatic isoenzyme.

In a review of 30 affected patients and their families, Mudd et al. (1995) found that most had autosomal recessive inheritance; the pattern in 1 family was consistent with autosomal dominant inheritance. The authors speculated that since adult hepatic MAT exists normally as either dimers or tetramers of identical subunits, a mutant subunit might negatively affect the activity of a normal subunit with which it is associated. Depending on the strength of this interaction, MAT activity in liver of a heterozygote could vary sufficiently to result in recessive or dominant inheritance.

Molecular Genetics

In 3 unrelated patients with MAT deficiency, Ubagai et al. (1995) identified homozygous or compound heterozygous mutations in the MAT1A gene (610550.0001-610550.0004). Two of the patients had been reported by Gaull et al. (1981). Ubagai et al. (1995) used site-directed mutagenesis and transient expression assays to demonstrate that the mutations partially inactivated MAT activity.

In a 43-year-old man with isolated hypermethioninemia reported by Gahl et al. (1987), Hazelwood et al. (1998) identified a homozygous truncating mutation in the MAT1A gene (610550.0008). Chamberlin et al. (1996) identified the same mutation in a girl with MAT deficiency without neurologic abnormalities. Hazelwood et al. (1998) noted that not all patients with truncating mutations in the MAT1A gene have neurologic involvement.

In affected members of 2 families with autosomal dominant inheritance of persistent hypermethioninemia (Blom et al., 1992; Mudd et al., 1995), Chamberlin et al. (1997) identified a heterozygous mutation in the MAT1A gene (R264H; 610550.0007). Cotransfection studies showed that the R264/R264H heterodimers were enzymatically inactive, thus providing an explanation for dominant inheritance in these families.

Kim et al. (2002) reported 2 Korean sisters with MAT1A mutations leading to MAT I/III deficiency. Both girls had normal growth and development and no mental retardation, neurologic abnormalities, or other clinical problems. One was identified by newborn screening and the other during the course of family studies.

Genotype/Phenotype Correlations

In 2 patients with complete MAT deficiency and neurologic features reported by Surtees et al. (1991) and Mudd et al. (1995), Chamberlin et al. (1996) identified homozygous truncating mutations in the MAT1A gene (610550.0005; 610550.0006). The results suggested that complete absence of MAT activity may result in neurologic signs and symptoms and that MAT is required to maintain myelin structure in the brain. However, not all patients with truncating mutations have neurologic involvement (see 610550.0008 and Hazelwood et al., 1998).

History

Methionine adenosyltransferase deficiency was identified when mass screening of neonates for hypermethioninemia was instituted to detect homocystinuria (236200). Other causes of neonatal hypermethioninemia include tyrosinemia (276700), prematurity, particularly of hepatic cystathionase combined with consumption of high-methionine-containing bovine milk, and neonatal hepatitis (Meny et al., 1978). Other forms of hypermethioninemia, with or without associated myopathy, have also been reported (Gaull et al., 1981).