Hypermethionemias …

Arushi Gahlot Saini MD DM MNAMS

Neurogenetic Disorders

Updated 09.12.2024
Released 06.06.2024
Expires For CME 09.12.2027

Hypermethioninemia

Author: Arushi Gahlot Saini MD DM MNAMS

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Editor: Deepa S Rajan MD

Hypermethioninemia

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Introduction

Overview

Hypermethioninemia is defined as an excess of methionine in the blood that occurs due to several reasons. The normal plasma concentration of methionine ranges from 13 to 45 μM (74). Being a rare disorder, its exact frequency is not known. Also, because the disorder remains asymptomatic in many individuals, the actual incidence may be difficult to determine. Primary (genetic) hypermethionemia is caused by pathogenic variations in the genes involved in the catabolism of methionine in the body, such as the MAT1A, GNMT, or AHCY genes. In addition, three other metabolic disorders cause hypermethioninemia: (1) classical homocystinuria due to cystathionine B-synthase (CBS) deficiency, (2) tyrosinemia type 1 due to fumaryl acetoacetate hydrolase deficiency, and (3) citrin deficiency (56). Secondary (nongenetic) hypermethioninemia is caused by liver disease, premature birth (with transient hypermethioninemia), or excessive dietary intake of methionine from consuming large amounts of protein or methionine-rich infant formula.

As an essential amino acid, methionine is essential for growth and development. Hypermethioninemia may remain asymptomatic, but pathological levels in the blood can lead to neurologic effects, such as myopathy, hypotonia, movement disorder (tremor, dystonia), and cognitive impairment; hematological effects, such as altered erythrocyte morphology with consequent splenic hemosiderosis; facial dysmorphism with abnormal teeth and hair; and gastrointestinal and hepatic effects with anorexia. Of these, the most concerning are the hepatic and neurologic effects of hypermethioninemia (91). The main mechanisms of damage include oxidative stress, decreasing Na+,K+-ATPase activity and dendritic spine density, and increasing acetyl cholinesterase activity. In the liver, hypermethioninemia also induces histopathological changes, lipid accumulation, inflammation, and ATP depletion.

This article primarily discusses the first three genetic causes of hypermethioninemia as the other metabolic disorders are discussed elsewhere. The author briefly alludes to the secondary causes of hypermethioninemia.

Key points

	• Methionine is an essential amino acid for growth and development.
	• Primary (genetic) hypermethioninemia is caused by pathogenic variations in three genes involved in methionine catabolism: MAT1A, GNMT, and AHCY.
	• Secondary hypermethioninemia is associated with three other metabolic disorders: classical homocystinuria, tyrosinemia type 1, and citrin deficiency.
	• Secondary (nongenetic) hypermethioninemia is also caused by liver disease, premature birth (with transient hypermethioninemia), or excessive dietary intake of methionine from consuming excess protein or methionine-rich infant formula.
	• Hypermethioninemia commonly remains asymptomatic, but pathological levels may lead to concerning hepatic and neurologic effects.

Historical note and terminology

The history of the three deficiencies is traced sequentially.

MAT I/III deficiency. Hypermethioninemia due to defects in the conversion of methionine to S-adenosyl methionine was first discovered in the early 1970s, soon after the introduction of newborn screening for classical homocystinuria. The earliest reports came from the United States (29) and France (31). Subsequently, MAT activity was found to be low in liver extracts of biopsied samples (29; 25; 30; 35; 28). During the same period, the three isoforms of the MAT enzyme were discovered in mammals, and MAT III was noted to have the highest Km for methionine (25; 79; 28; 44; 45; 30; 27). The amino acid sequence encoded by MAT1A was soon established (38; 02; 67) and, subsequently, pathogenic variants were identified (81; 15; 14; 36). Because the extent of the loss of MAT I activity relative to that of MAT III is not clearly defined by identification of the underlying variation in the MAT1A gene, it has been customary to characterize such patients as “MAT I/III deficient.”

GNMT deficiency. GNMT deficiency was discovered in humans in 2001 (59). A direct sequencing of the GNMT gene was carried out in 2002 (51) and confirmed the diagnosis in the initially suspected patients.

AHCY deficiency. AHCY deficiency is the most recently discovered genetic cause of human hypermethioninemia and was initially described in a young boy with slow psychomotor development, severe muscular hypotonia, elevated plasma transaminases and creatine kinase, and hypomyelination (07). In 2017, Baric and colleagues reevaluated the clinical spectrum of the disease in 10 previously reported patients. The authors stated that the disorder should be suspected in patients with any combination of myopathy with markedly increased CK activity, hypotonia, developmental delay, hypomyelination, behavioral problems, liver disease, coagulation disorders, strabismus, and fetal hydrops with brain abnormalities (08).

Clinical manifestations

Presentation and course

Hypermethioninemia may remain asymptomatic, but pathological levels can lead to neurologic effects, such as cerebral edema (especially at methionine concentrations above 1000 uM), myopathy, hypotonia, movement disorder (tremor, dystonia), and intellectual disability and cognitive impairment; hematological effects, such as altered erythrocyte morphology with consequent splenic hemosiderosis and facial dysmorphism with abnormal teeth and hair; and gastrointestinal and hepatic effects (steatosis, inflammation, and cholestasis), with anorexia (91). Of these, the most concerning are the hepatic and neurologic effects of hypermethioninemia.

Cerebral edema with abnormal brain MRI has been particularly noted with acute elevations of methionine (960 to 3000 mM) in patients with CBS deficiency and MAT I/III deficiency when given betaine to reduce homocysteine levels (11) and in infants with excessive dietary methionine intake (blood levels 2000 to 6800 mM) (57). The CNS abnormalities in these cases disappeared when plasma methionine levels were lowered. However, extreme hypermethioninemia can be fatal, as was seen in an adult woman participating in an experimental study that involved administration of an acute oral dose of methionine of 100 mg/kg, and who erroneously received a dose perhaps 10 times higher leading to acute hypermethioninemia (up to 5700 mM) and elevated plasma S-adenosyl methionine (1089 nM) (19). The acute CNS deterioration led to dementia, apnea, pulseless cardiorespiratory failure, and, ultimately, death a few days later secondary to aspiration pneumonia.

MAT I/III deficiency. These isoforms of the MAT enzyme are present in the hepatocytes and contribute to the whole-body S-adenosylmethionine homeostasis. This disorder presents as both autosomal dominant and recessive and is characterized by severe hypermethioninemia. The autosomal dominant form of MAT I/III deficiency is generally asymptomatic and is detected on newborn screening in dried blood spots (64). The autosomal recessive form is characterized by severe hypermethioninemia, slightly subnormal to normal S-adenosylmethionine, and slightly elevated homocysteine in blood. This form has neurologic manifestations seen in nearly half of the patients and characteristic vacuolating myelinopathy with involvement of both subcortical and deep white matter, especially when the plasma methionine concentrations exceed 800 umol/L. No laboratory or clinical signs of hepatopathy have been observed in this isoform (17). Some patients with hypermethioninemia due to proven MAT I/III deficiency, or with metabolic abnormalities typical of that deficiency, have objectionable breath odor due to the presence of dimethylsulfide (28). This compound is formed by the methionine transamination pathway in which methionine is converted successively to 4-methylthio-2-oxobutyrate, 3-methylthiopropionate, methanethiol, and dimethylsulfide. Several other extra-CNS manifestations have been reported with MAT deficiency, such as boiled cabbage odor (26), anorexia, digestive disturbances, growth retardation (31), vasculopathy possibly due to associated homocysteinemia, unexplained moderate hepatomegaly (48), acrodermatitis enteropathica with severe zinc deficiency (63), cleft lip and palate (15), and profound hearing loss (20).

MAT II deficiency. This isoform is ubiquitously expressed and provides S-adenosylmethionine for methylation reactions in tissues. No patients with biallelic mutations in the MAT2A gene have been described so far, and only heterozygous mutations have been detected as a low penetrance risk factor for developing thoracic aortic aneurysm (34). The mechanism of this association is unknown and seems unrelated to the methionine metabolism.

GNMT deficiency. This enzyme is expressed in both hepatic and non-hepatic tissues and maintains S-adenosylmethionine homeostasis by converting excess S-adenosylmethionine into S-adenosylhomocysteine and N-methylglycine (also known as sarcosine). Hence, besides hypermethioninemia, it is biochemically characterized by markedly elevated levels of S-adenosylmethionine and normal levels of S-adenosylhomocysteine. Its deficiency is an ultra-rare disease previously described in only five young patients until now (04; 06). The disorder is characterized by hepatomegaly and elevated aminotransferases. In mouse models, liver disease and hepatocellular carcinoma have been described (49; 84), but only mild hepatopathy and absence of neurologic manifestations have been described in humans.

AHCY deficiency. This ultra-rare disorder was reported in only 10 patients until now (05; 12; 37; 77). Biochemically, it is characterized by markedly elevated S-adenosylmethionine and S-adenosylhomocysteine levels, normal to moderately elevated homocysteine, and hypermethioninemia. Clinically, the disorder may manifest intrauterine as fetal hydrops, mild to severe myopathy resulting in respiratory failure, moderate to severe liver disease (elevated aminotransferases, low albumin levels, coagulopathy, and even hepatocellular carcinoma), developmental delay, and neuropsychiatric manifestations (87). Based on single cases, it has been observed that AHCY deficiency can remain asymptomatic in childhood, and the disorder can be associated with early-onset hepatocellular carcinoma in the third decade of life (77). The neuroradiological spectrum varies from delayed myelination and dilated ventricles to hypoplasia of the cerebellum, ventral pons, corpus callosum, and mega cisterna (32; 09). The severe myopathy associated with this condition is characterized by elevated creatine kinase. This is because S-adenosyl methionine is predominantly used for synthesis of phosphatidylcholine byphosphatidyl ethanolamine methyltransferase, and of creatine by guanidinoacetate methyltransferase (58), and inhibition of the production of these products contributes to the myopathy and hypotonia. An interesting presentation of reduced vision due to maculopathy in a pedigree has been reported in a member of a sibship affected with S-adenosylhomocysteine hydroplase deficiency (SAHH), possibly due to dual genetic disease CRB1-related retinopathy overlapping the ocular phenotype of SAHH deficiency (33).

Biological basis

Etiology and pathogenesis

Methionine is an essential sulfur-containing amino acid obtained exogenously from diet or endogenously from protein breakdown in the body.

Table 1. Methionine Function in The Body

	• Building block for several proteins and peptides.
	• Donation of its methyl group to other molecules, such as nucleic acids, histones, amino acids, and lipid derivatives.
	• Production of its derivative molecules cysteine, glutathione, carnitine, creatine, and taurine.
	• Antioxidant protection of proteins that they are part of, by forming a hydrophobic bond between their sulfur atoms and the rings of aromatic amino acids, which are more susceptible to oxidation by reactive species.
	• Protection of other protein residues by preferential oxidation of surface-exposed methionine residues to methionine sulfoxide by the reactive species, which may be reduced back by the enzyme methionine sulfoxide reductase.
(70)

Hypermethioninemia commonly has an autosomal recessive inheritance and may rarely be inherited in an autosomal dominant pattern.

The three genes involved in primary hypermethioninemia encode for enzymes involved in the multistep breakdown of methionine (46).

MAT1A. The MAT1A gene encodes for the enzyme methionine adenosyl transferase (MAT, EC 2.5.1.6), which converts methionine into S-adenosyl methionine (also known as S-adenosyl methionine) and tripolyphosphate. MAT1A encodes two liver-specific isoforms, I (homo-tetramer) and III (homo-dimer), whereas a second gene MAT2A encodes the nonhepatic isoform II of the enzyme. In fact, the MAT2A and MAT2B gene products combine to form the MAT II isoenzyme (a heterotrimeric complex consisting of a dimer of the MAT2A gene product plus the regulatory subunit encoded by the MAT2B gene).

GNMT. The GNMT gene encodes the enzyme glycine N-methyl transferase, which converts S-adenosylmethionine into S-adenosylhomocysteine.

AHCY. The AHCY gene encodes for the enzyme S-adenosylhomocysteine hydrolase (AHCY, EC 3.3.1.1), which converts S-adenosylhomocysteine into homocysteine, which may then be converted back into methionine or cysteine.

Metabolism of methionine via transmethylation pathway. The amino acid methionine is primarily metabolized in the liver by the enzyme methionine adenosyl transferase (encoded by the gene MAT1A), which has three isoforms. The isoforms I and III predominate in the adult liver, whereas isoform II predominates in the non-hepatic tissues, fetal liver, and hepatocellular carcinoma. This enzyme converts methionine into S-adenosylmethionine by transferring the adenosyl group from adenosine triphosphate. S-adenosylmethionine acts as a methyl donor in methylation reactions of nucleic acids, proteins, and lipids. S-adenosylmethionine is subsequently transmethylated into S-adenosylhomocysteine, which is then hydrolyzed by enzyme AHCY into homocysteine (60; 07). The N-methyl glycine (sarcosine) produced at this step has no known physiological role and is converted back to glycine by mitochondrial sarcosine dehydrogenase, with the partially oxidized methyl group entering the one-carbon folate coenzyme pool. The transmethylation pathway of methionine is vitally important for the production of S-adenosyl methionine, which yields homocysteine as an end product. The homocysteine is then metabolized by two different pathways: remethylation or transsulfuration.

Remethylation pathway. Two key enzymes function to catalyze the remethylation of homocysteine to methionine: (1) 5-methyltetrahydrofolate–homocysteine methyltransferase (MTR), commonly known as methionine synthase; and (2) betaine–homocysteine S-methyltransferase (BHMT). The enzyme methionine synthase (EC 2.1.1.13, a vitamin B12-dependent enzyme) regenerates methionine from homocysteine by transferring a methyl group to homocysteine. This methyl group is derived from the endogenous 5-methyltetrahydrofolate (5-methyl-THF), which is formed during the metabolism of folic acid. For this remethylation reaction, there exists a salvage pathway that functions when toxins impair the function of the enzyme methionine synthase. In this salvage pathway, the enzyme BHMT transfers the methyl group from betaine (derived from choline) to homocysteine, forming methionine and N, N-dimethyl glycine (DMG). This pathway is the primary pathway for methionine metabolism in the cerebral tissue.

Transsulfuration pathway. Two key enzymes of this pathway are cystathionine B-synthase (CBS) and cystathionine gamma-lyase (CTH, also known as gamma-cystathionase). Both enzymes use pyridoxal 5-phosphate (PLP) as a cofactor, making transsulfuration sensitive to vitamin B6 status. The enzyme CBS (EC 4.2.1.22, a vitamin B6-dependent enzyme) condenses serine with homocysteine to form cystathionine. Cystathionine is then converted to alpha-ketobutyrate and cysteine by the enzyme gamma-cystathionase, another B6-depenent enzyme. Cysteine is the precursor of glutathione, an important antioxidant for the liver, making the transsulfuration pathway vital to the body. Initially, it was believed that there was an absence of the enzyme gamma-cystathionase in the brain, hence, transsulfuration was incomplete leading to accumulation of cystathionine in the brain. However, subsequent evidence by Vitvitsky and colleagues showed the existence of a functional transsulfuration pathway in human neurons and astrocytes and in the mouse brain, suggesting that this may contribute to the protection under oxidative stress conditions through brain glutathione synthesis (86).

Thus, the normal metabolic flow can be remembered as methionine to S-adenosylmethionine to S-adenosylhomocysteine to homocysteine to cystathionine (56).

Chemical hypermethioninemia in young mice has been shown to cause oxidative damage and reduction of antioxidant enzyme activity in the brain, kidney, and liver (22). Acute hypermethioninemia has also been shown to impair redox homeostasis and acetyl cholinesterase activity in the hippocampus, striatum, and cerebellum of young rats. The following are proposed biochemical and molecular mechanisms in primary hypermethioninemia.

MAT I/III deficiency. Animal models show decreased S-adenosyl methionine content in the liver of MAT I/III–deficient mice that leads to lower phosphatidylcholine and sphingomyelin synthesis and to decreased secretion of triglycerides and increased secretion of apoB and of lipid-poor VLDL (65). Decreased liver synthesis of phosphatidylcholine/sphingomyelin results in reduced availability of these compounds for brain myelination (15), whereas decreased S-adenosyl methionine and glutathione in the liver result in overexpression of the number of oncogenes and acute phase inflammatory markers (50), activation of caspase 3 and 8 (53), and expansion of liver stem cells. Human studies showed normal to decreased blood S-adenosyl methionine and S-adenosylhomocysteine, normal sarcosine, and elevated tHcy (74). Additionally, hypermethioninemia has been shown to induce memory deficits and morphological changes in the hippocampus of young rats, thus, elucidating some of the chronic effects of hypermethioninemia (72).

GNMT deficiency. Animal models show GNMT-deficient mice with markedly elevated S-adenosyl methionine in the liver, which leads to increased synthesis of phosphatidylcholine and depletion of phosphatidyl ethanolamine, with resulting abnormal diglyceride and triglyceride metabolism (55). Elevated S-adenosyl methionine also leads to activation of NF-κB, STAT3, and cyclin signaling pathways (84) and decreased activity of enzymes involved in gluconeogenesis and glycogenolysis (49).

SAHH deficiency. Animal studies show SAHH as a tumor suppressor. Hence, decreased SAAH activity leads to hepatocellular carcinoma (47). Administration of SAHH inhibitor leads to elevated S-adenosylhomocysteine, upregulation of ERK1/2, and increased proliferation of vascular smooth muscle cell proliferation resulting in enhanced atherosclerosis (52). S-adenosyl methionine is a major metabolite accumulating in SAHH deficiency and has been shown to cause disturbance of redox homeostasis and reduction of Na+, K+-ATPase activity, leading to impaired neurotransmission in cerebral cortex supernatants of adolescent rats (89).

Brain edema and coma associated with extremely high methionine concentrations are probably due to a direct toxic effect of methionine on sodium/potassium ATPase (Na+/K+ ATPase) (56; 73) and less likely due to the osmotic effect of betaine on the brain (42; 68).

Differential diagnosis

Confusing conditions

Mutations in the genes encoding the remethylation enzymes or in genes needed for methyl cobalamin or tetrahydrofuran synthesis result in elevated concentrations of homocysteine along with low methionine concentrations. Specifically, hypermethioninemia is seen in the following conditions or scenarios.

Transient hypermethioninemia. Transient hypermethioninemia has been noted in normal birthweight, full-term babies whose dietary intakes of methionine were unusually high, or in very low birthweight babies on normal diets. Mild transient hypermethioninemia may also occur in normal babies on normal diets; however, at least some of these may also have an underlying MAT1A heterozygosity (23).

Liver disease. Liver disease has been associated with hypermethioninemia in some subsets of patients.

CBS deficiency. Homocystinuria due to CBS deficiency was the first genetic condition shown to cause hypermethioninemia in 1962 (60). The details of this condition are described elsewhere. It is characterized by dislocation of the optic lenses, intellectual disability, early thromboembolic events, and skeletal abnormalities, including osteoporosis, genu valgum, and thinning and lengthening of the long bones (66; 41; 88). The hypermethioninemia in CBS deficiency is attributed to the excessive remethylation of the accumulated homocysteine upstream of the metabolic block. Remethylation occurs by both methyl-tetrahydrofuran and betaine-dependent pathways (43). In addition to combined hyperhomocystinemia and hypermethioninemia in CBS deficiency, there is additionally significant elevation of both S-adenosylhomocysteine and S-adenosyl methionine. The elevation of S-adenosylhomocysteine is due to the reversible activity of AHCY, and the equilibrium favors S-adenosylhomocysteine formation in conditions when homocysteine is high (56). On the other hand, reasons for S-adenosyl methionine elevation are inhibition by S-adenosylhomocysteine of methyltransferases using S-adenosyl methionine and the tendency of S-adenosyl methionine to rise when methionine is high and MAT I/III activity is normal. Additionally, there is a low level of plasma cystathionine and total plasma cysteine.

Tyrosinemia type I or fumaryl acetoacetate hydrolase (FAH) deficiency. The disorder is characterized by liver failure, neurologic crises, rickets, and hepatocellular carcinoma. The earliest clinical features include severe liver involvement, vomiting, and diarrhea, and later patients present with growth failure, hypophosphatemia with rickets, and proximal renal tubular defects. If untreated, death occurs by the end of the first decade. The biochemical characteristics of hypermethioninemia (independent of tyrosine elevation) are secondary to generalized liver dysfunction (69) or inhibition of MAT III by fumarylacetoacetate (82). The distinction can be made by the distinct clinical, biochemical, and genetic picture.

Citrin deficiency. Citrin is a mitochondrial solute carrier protein active as an aspartate–glutamate exchanger. First identified in 1999, its deficiency has been linked to pathogenic variants in the SLC25A13 gene. Citrin deficiency manifests in two clinical forms: (1) neonatal intrahepatic cholestasis (NICCD), and (2) late-onset adult-onset type II citrullinemia (CTLN2). Hypermethioninemia is frequently seen in NICCD but not in CTLN2. Elevations of methionine are often accompanied by elevations of galactose, citrulline, threonine, tyrosine, phenylalanaine lysine, and arginine. All these abnormalities tend to normalize by the end of infancy and commonly do not require specific treatment.

Associated or underlying disorders

ADK deficiency. ADK deficiency is caused by pathogenic variants in the ADK gene, which encodes the enzyme adenosine kinase (ADK; E.C.2.7.1.20). This enzyme converts adenosine to adenosine monophosphate (AMP) during the conversion of S-adenosyl methionine to S-adenosylhomocysteine in the transmethylation pathway (10). Adenosine kinase is not a direct part of the transmethylation process but affects the methylation processes. ADK deficiency leads to the accumulation of adenosine and hypoxanthine and to moderately to markedly elevated blood S-adenosylhomocysteine, homocysteine, and methionine concentrations. There are limited clinical studies on this rare disorder of the methionine pathway. In a cohort of 19 patients, ADK deficiency manifested with macrocephaly, frontal bossing, hypertelorism, cardiac anomalies, neurologic complications (severe developmental delay, hypotonia, and epilepsy), failure to thrive, and liver disease (neonatal jaundice, elevated aminotransferases, and impaired coagulation) (75; 76; 06). A low-methionine diet ameliorates the liver phenotype, but the neurologic impairment may persist (01). Recurrent hypoglycemia due to hyperinsulinism of unclear origin has also been noted with ADK deficiency and is treated with diazoxide (06).

SAHH deficiency. The clinical features of SAHH deficiency in the neonatal period, such as hypotonia, psychomotor retardation, and strabismus, as well as the systemic manifestations, such as severe coagulopathy, hepatopathy, and myopathy, resemble a congenital disorder of glycosylation due to PMM2 deficiency. The differential diagnosis may be particularly difficult in early infancy, when the typical changes of fat pads and inverted nipples and the elevated levels of homocysteine and methionine may be absent in PMM2 deficiency and SAHH deficiency, respectively (16). Thus, normal homocysteine and methionine levels in the neonatal period or in early infancy do not exclude SAHH deficiency.

Diagnostic workup

The majority of cases of genetic hypermethioninemia are symptomatic and picked up on biochemical or genetic testing for prominent neurologic or hepatic abnormalities. In regions where newborn screening is mandatory, these babies are picked up at birth. The genetic confirmation can be sought by sequencing of a limited panel of genes or exome sequencing, which clinches the diagnosis. The following text gives the typical biochemical profiles of the three causes of primary hypermethioninemia.

MAT I/III deficiency. Isolated hypermethioninemia is the key feature of MAT I/III deficiency. The severity of hypermethioninemia depends on the type of genetic mutation: patients with homozygous truncating mutations and no residual MAT I/III activity may have plasma methionine up to 2500 mM (28; 15; 36; 56). Patients with the heterozygous variant and dominant inheritance have lesser elevations up to 400 to 500 mM due to residual enzyme activity (13; 61). A small subset of patients may have slightly low or normal plasma S-adenosyl methionine due to its formation by MAT II isoform of the enzyme (36). Additionally, patients with severe MAT I/III may also have mild elevations of plasma total homocysteine (up to 59 mM) (74), probably due to the suboptimal stimulation of CBS enzyme activity due to low S-adenosyl methionine levels. This feature is important to recognize as this combined elevation may lead to an erroneous diagnosis of CBS deficiency. This can be settled by assays of plasma S-adenosyl methionine and cystathionine; however, these are not routinely indicated or available.

GNMT deficiency. The biochemical features include hypermethioninemia with elevated S-adenosyl methionine levels and normal sarcosine. Plasma S-adenosylhomocysteine and homocysteine are usually normal. Non-elevation of sarcosine (N-methylglycine) distinguishes this condition from conditions with further block in the metabolic pathway. The major cause of hypermethioninemia is postulated to be inhibition of MAT I and MAT II by S-adenosyl methionine (44; 59).

AHCY deficiency. The biochemical feature of AHCY deficiency is elevations of S-adenosylhomocysteine and S-adenosyl methionine, with elevated sarcosine levels. Methionine levels are elevated in only 50% of the cases and, thus, have low sensitivity in the neonatal period (39). The methionine level appears to increase in the weeks to months following birth. The exact reason for this is not clear. Hence, the disorder needs a high suspicion in infants with unexplained liver dysfunction and hypotonia with persistently elevated CK. The levels of S-adenosyl methionine, S-adenosylhomocysteine, or molecular testing are needed to rule out AHCY deficiency in suspected cases (39). Besides these instances, homocysteine has been reported to be mildly elevated in some patients (07; 37).

Newborn screening. In regions where newborn screening is available, measurement of methionine levels in dried blood spots has led to the identification of asymptomatic hypermethioninemia at birth. However, as both the etiology and natural history of isolated hypermethioninemia have not yet been clearly resolved, the impact of this condition on screening programs where homocystinuria is rare should be carefully evaluated. In a study from Taiwan, 1,701,591 newborns were screened at the National Taiwan University Hospital neonatal screening center between January 1991 and June 2003 (18). Of these, 17 cases of hypermethioninemia were detected, but among them only one had homocystinuria. More than half of the 16 cases of isolated hypermethioninemia had mutations in the MAT1A gene and were put on a medical diet. However, there was no correlation found between IQ scores at 4 years of age and methionine levels at baseline or follow-up (18).

A systematic review and proposed guidelines by Huemer and colleagues concluded that amongst the primary hypermethioninemia, individuals homozygous or compound heterozygous for MAT1A mutations may benefit from detection by newborn screening using methionine, which, on the other hand, also detects asymptomatic heterozygotes (40). Clinical and laboratory data were considered insufficient to develop any recommendation on newborn screening for the GNMT and AHCY deficiencies.

Management

MAT I/III deficiency. Treatment is recommended only in symptomatic patients with the recessive form or in asymptomatic individuals with plasma methionine within 500 to 800 µmol/L. Dietary methionine restriction, avoidance of betaine, and possibly S-adenosylmethionine supplementation are the recommended therapeutic measures (06). Mice with MAT1A knocked out are predisposed to liver injury (50) and may develop hepatocellular carcinoma by the age of 18 months (54). However, liver carcinoma has not been found in MAT I/III–deficient patients to date.

MAT II deficiency. No clinical cases have been described; hence, no treatment recommendations are given.

GNMT deficiency. There is no evidence that therapy using a low-methionine diet is beneficial; however, it may be considered in patients with plasma methionine greater than 500 to 600 μmol/L (06). Development of fatty liver and hepatic fibrosis in GNMT knock-out mice was shown to be prevented by the administration of nicotinamide, a substrate for an alternative S-adenosyl methionine–dependent methyltransferase. This treatment intervention led to normal hepatic S-adenosyl methionine levels, prevented DNA hypermethylation, and normalized expression of several genes involved in fatty acid metabolism, oxidative stress, inflammation, cell proliferation, and apoptosis (84). It is not known whether the risk of hepatocellular carcinoma seen in mouse models was mitigated by this intervention.

AHCY deficiency. Dietary management by methionine restriction and pharmacological treatment with phosphatidylcholine and N-acetyl cysteine has been recommended, but the efficacy is not clear (06). Liver transplantation may be beneficial. Liver segment transplantation from a healthy, unrelated living donor has been tried in a child with severe AHCY deficiency at 40 months of age, which resulted in the reduction of the mean S-adenosylhomocysteine to 96%; normalization of blood methionine and S-adenosyl methionine levels during next 6 months on an unrestricted diet; and gains in gross motor, language, and social skills (78). However, the long-term data are not available.

In animal models, several compounds have been shown to mitigate the harmful levels of hypermethioninemia, such as the protective effect of pioglitazone as an antioxidant through lowering oxidative stress and subsequent memory loss in the hippocampus (03). Similarly, pretreatment with tannic acid prevented both oxidative and nitrosative damage induced by methionine (21). However, none of these treatments is currently evidence-based.

Outcomes

Chien and colleagues found that half of their samples of patients with MAT deficiency developed neurologic symptoms later in life (17). In a study of the long-term prognosis of 35 patients with methionine adenosyl transferase deficiency based on newborn screening of 4,065,644 neonates screened between November 2010 and December 2021 in China, the authors reported on a follow-up of 11 years (80). Of these 35 patients, 15 unrelated autosomal dominant patients harbored a common dominant variant, c.791 G>A or c.776 C>T, and were clinically unaffected, with a mean plasma methionine value of less than 300 μmol/L. The other 20 autosomal recessive cases presented with a wide range of genetic and clinical abnormalities from asymptomatic to white matter lesions. Of these, 10 cases were severely affected with verbal difficulty, motor delay, development delay, and white matter lesions, with a mean methionine of greater than 500 μmol/L. They were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Two additional patients stabilized with liver transplantation. Overall, it was difficult to predict phenotype-genotype correlations in the autosomal recessive cases.

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Arushi Gahlot Saini MD DM MNAMS

Dr. Saini of Postgraduate Institute of Medical Education and Research, Chandigarh, India, has no relevant financial relationships to disclose.
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Deepa S Rajan MD

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Hypermethioninemia

Associated Disorders

Adenosine kinase (ADK) deficiency
SAHH deficiency

Differential Diagnosis

Transient hypermethioninemia
Liver disease
CBS deficiency
Tyrosinemia type I or fumaryl acetoacetate hydrolase deficiency (FAH)
Citrin deficiency

Hypermethionemias …

Hypermethioninemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Biological basis

Etiology and pathogenesis

Table 1. Methionine Function in The Body

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

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to access the full version.

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Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Nonketotic hyperglycinemia

Hypermethioninemia

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Biological basis

Etiology and pathogenesis

Table 1. Methionine Function in The Body

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Vanishing white matter disease

Wilson disease

White matter abnormalities in the brain

POLG-related mitochondrial disorders

Multiple acyl-CoA dehydrogenase deficiency

Medium-chain acyl-CoA dehydrogenase deficiency

Long-chain fatty acid oxidation defects

Nonketotic hyperglycinemia

This is an article preview.
Start a Free Account
to access the full version.