RARE DISEASE
Methionine adenosyltransferase I/III deficiency
Methionine adenosyltransferase I/III deficiency
Methionine adenosyltransferase I/III deficiency
Synonyms: MAT I/III deficiency, Mudd's disease
Synonyms: MAT I/III deficiency, Mudd's disease
Synonyms: MAT I/III deficiency, Mudd's disease
Drug discovery
0
drugs
With orphan designations
Overview
Methionine adenosyltransferase I/III deficiency is an autosomal recessive or dominant inborn error of methionine metabolism caused by MAT1A mutations, leading to persistent hypermethioninemia. While often asymptomatic, severe cases (plasma methionine >800 µmol/L) may present with neurological abnormalities, including developmental delay, demyelination, and white matter lesions. Diagnosis typically follows newborn screening, with management involving methionine restriction and S-adenosylmethionine (SAMe) supplementation in symptomatic patients [1][6][11].
Burden
~50% of patients remain asymptomatic, but severe cases risk irreversible demyelination and cognitive deficits [6][11].
Long-term dietary adherence and SAMe therapy pose logistical and financial challenges [3][7].
Variable expressivity necessitates lifelong clinical and biochemical surveillance [1][15].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
32 drug discovery papers about Methionine adenosyltransferase I/III deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
32 drug discovery papers about Methionine adenosyltransferase I/III deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2024-11-13 | Hypermethioninemia due to methionine adenosyltransferase I/III deficiency and brain damage.
Methionine adenosyltransferase I/III deficiency used to be considered a relatively benign disease. This study aims to elucidate the clinical characteristics of methionine adenosyltransferase I/III deficiency patients with neurological manifestations. The clinical data, blood amino acids, plasma total homocysteine, gene variants, brain imaging, treatments and outcomes of 15 patients with methionine adenosyltransferase I/III deficiency were retrospectively analyzed. Of these 15 patients, 10 demonstrated neurological abnormalities, with delayed language development, learning difficulties or abnormal brain imaging findings. Eleven patients were identified by newborn screening. Patients with demyelination showed significantly higher blood methionine concentrations at baseline (1102 vs. 396 µmol/L), and their blood methionine remained markedly elevated despite a low-methionine diet. Their plasma total homocysteine was normal to moderate elevated. One patient underwent liver transplantation aged 8 years, which reduced his serum methionine concentration to normal. Compound heterozygous and homozygous MAT1A variants were identified from the patients. Among the 21 variants observed, nine have been reported previously, while 12 were novel. Methionine adenosyltransferase I/III deficiency is not just a benign disease. Severe persistent hypermethioninemia can cause brain injuries, especially in the white matter. Liver transplantation may be a potential treatment option for refractory methionine adenosyltransferase I/III deficiency.
2023-06-15 | Enhanced synthesis of S-adenosyl-L-methionine through Combinatorial metabolic engineering and Bayesian optimization in Saccharomyces cerevisiae
S-adenosyl-L-methionine (SAM) is a substrate for many enzyme-catalyzed reactions and provides methyl groups in numerous biological methylations, and thus has vast applications in the medical field. Saccharomyces cerevisiae has been engineered as a platform with significant potential for producing SAM, although the current production has room for improvement. To surpass the restriction, a series of metabolic engineering strategies were employed to enhance the synthesis of SAM in this study. These strategies included enhancing SAM synthesis by overexpression of SAM2, met6 , and str2, increasing ATP supply by integration of adkI and PYC , and down-regulating SAM metabolism by disrupting erg4 and erg6 and replacing the original promoter of CYS4 with a weaker promoter. After combinatorial metabolic engineering, Bayesian optimization was conducted on the obtained strain C262P6 to optimize the fermentation medium. A final yield of 2972.8 mg/L at 36 h with 29.7% of the L-Met conversion rate in the shake flask was achieved, which was 26.3 times higher than that of its parent strain and the highest reported production in the shake flask to date. This paper establishes a feasible foundation for the construction of SAM-produced strains using metabolic engineering strategies and demonstrates the effectiveness of Bayesian optimization in optimizing fermentation medium to enhance the generation of SAM.
2023-03-28 | S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.
Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.
2022-11-01 | Methionine restriction - Association with redox homeostasis and implications on aging and diseases
Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
2022-03-01 | Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis
Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
2024-11-13 | Hypermethioninemia due to methionine adenosyltransferase I/III deficiency and brain damage.
Methionine adenosyltransferase I/III deficiency used to be considered a relatively benign disease. This study aims to elucidate the clinical characteristics of methionine adenosyltransferase I/III deficiency patients with neurological manifestations. The clinical data, blood amino acids, plasma total homocysteine, gene variants, brain imaging, treatments and outcomes of 15 patients with methionine adenosyltransferase I/III deficiency were retrospectively analyzed. Of these 15 patients, 10 demonstrated neurological abnormalities, with delayed language development, learning difficulties or abnormal brain imaging findings. Eleven patients were identified by newborn screening. Patients with demyelination showed significantly higher blood methionine concentrations at baseline (1102 vs. 396 µmol/L), and their blood methionine remained markedly elevated despite a low-methionine diet. Their plasma total homocysteine was normal to moderate elevated. One patient underwent liver transplantation aged 8 years, which reduced his serum methionine concentration to normal. Compound heterozygous and homozygous MAT1A variants were identified from the patients. Among the 21 variants observed, nine have been reported previously, while 12 were novel. Methionine adenosyltransferase I/III deficiency is not just a benign disease. Severe persistent hypermethioninemia can cause brain injuries, especially in the white matter. Liver transplantation may be a potential treatment option for refractory methionine adenosyltransferase I/III deficiency.
2023-06-15 | Enhanced synthesis of S-adenosyl-L-methionine through Combinatorial metabolic engineering and Bayesian optimization in Saccharomyces cerevisiae
S-adenosyl-L-methionine (SAM) is a substrate for many enzyme-catalyzed reactions and provides methyl groups in numerous biological methylations, and thus has vast applications in the medical field. Saccharomyces cerevisiae has been engineered as a platform with significant potential for producing SAM, although the current production has room for improvement. To surpass the restriction, a series of metabolic engineering strategies were employed to enhance the synthesis of SAM in this study. These strategies included enhancing SAM synthesis by overexpression of SAM2, met6 , and str2, increasing ATP supply by integration of adkI and PYC , and down-regulating SAM metabolism by disrupting erg4 and erg6 and replacing the original promoter of CYS4 with a weaker promoter. After combinatorial metabolic engineering, Bayesian optimization was conducted on the obtained strain C262P6 to optimize the fermentation medium. A final yield of 2972.8 mg/L at 36 h with 29.7% of the L-Met conversion rate in the shake flask was achieved, which was 26.3 times higher than that of its parent strain and the highest reported production in the shake flask to date. This paper establishes a feasible foundation for the construction of SAM-produced strains using metabolic engineering strategies and demonstrates the effectiveness of Bayesian optimization in optimizing fermentation medium to enhance the generation of SAM.
2023-03-28 | S-adenosyl-L-methionine supplementation alleviates damaged intestinal epithelium and inflammatory infiltration caused by Mat2a deficiency.
Methionine is important for intestinal development and homeostasis in various organisms. However, the underlying mechanisms are poorly understood. Here, we demonstrate that the methionine adenosyltransferase gene Mat2a is essential for intestinal development and that the metabolite S-adenosyl-L-methionine (SAM) plays an important role in intestinal homeostasis. Intestinal epithelial cell (IEC)-specific knockout of Mat2a exhibits impaired intestinal development and neonatal lethality. Mat2a deletion in the adult intestine reduces cell proliferation and triggers IEC apoptosis, leading to severe intestinal epithelial atrophy and intestinal inflammation. Mechanistically, we reveal that SAM maintains the integrity of differentiated epithelium and protects IECs from apoptosis by suppressing the expression of caspases 3 and 8 and their activation. SAM supplementation improves the defective intestinal epithelium and reduces inflammatory infiltration sequentially. In conclusion, our study demonstrates that methionine metabolism and its intermediate metabolite SAM play essential roles in intestinal development and homeostasis in mice.
2022-11-01 | Methionine restriction - Association with redox homeostasis and implications on aging and diseases
Methionine is an essential amino acid, involved in the promotion of growth, immunity, and regulation of energy metabolism. Over the decades, research has long focused on the beneficial effects of methionine supplementation, while data on positive effects of methionine restriction (MR) were first published in 1993. MR is a low-methionine dietary intervention that has been reported to ameliorate aging and aging-related health concomitants and diseases, such as obesity, type 2 diabetes, and cognitive disorders. In addition, MR seems to be an approach to prolong lifespan which has been validated extensively in various animal models, such as Caenorhabditis elegans, Drosophila, yeast, and murine models. MR appears to be associated with a reduction in oxidative stress via so far mainly undiscovered mechanisms, and these changes in redox status appear to be one of the underlying mechanisms for lifespan extension and beneficial health effects. In the present review, the association of methionine metabolism pathways with redox homeostasis is described. In addition, the effects of MR on lifespan, age-related implications, comorbidities, and diseases are discussed.
2022-03-01 | Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis
Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
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