RARE DISEASE
Vitamin B12-unresponsive methylmalonic acidemia
Vitamin B12-unresponsive methylmalonic acidemia
Vitamin B12-unresponsive methylmalonic acidemia
Synonyms: Methylmalonyl-CoA mutase deficiency, Methylmalonyl-Coenzyme A mutase deficiency, Vitamin B12-unresponsive methylmalonic aciduria
Synonyms: Methylmalonyl-CoA mutase deficiency, Methylmalonyl-Coenzyme A mutase deficiency, Vitamin B12-unresponsive methylmalonic aciduria
Synonyms: Methylmalonyl-CoA mutase deficiency, Methylmalonyl-Coenzyme A mutase deficiency, Vitamin B12-unresponsive methylmalonic aciduria
Drug discovery
3
drugs
With orphan designations
Overview
Vitamin B12-unresponsive methylmalonic acidemia is an autosomal recessive disorder caused by MUT gene mutations, resulting in partial (mut–) or complete (mut0) methylmalonyl-CoA mutase deficiency. This leads to toxic methylmalonic acid accumulation, causing life-threatening metabolic crises (ketoacidosis, hyperammonemia), neurological impairment, renal failure, and cardiomyopathy. Unlike B12-responsive forms, it shows no meaningful improvement with cobalamin therapy. Prognosis varies by subtype, with mut0 carrying higher morbidity/mortality risks [1][4][6].
Therapies
Dietary: Protein restriction (1.0–1.2 g/kg/day), precursor-free formulas [8][11].
Pharmacologic: Carnitine supplementation, antibiotics (neomycin/metronidazole) to reduce gut propionate [4][18].
Surgical: Liver transplantation (partial mitigation of metabolic crises, no renal/neurological protection) [4][11].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
252 drug discovery papers about Vitamin B12-unresponsive methylmalonic acidemia, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
252 drug discovery papers about Vitamin B12-unresponsive methylmalonic acidemia, with 3 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-01 | Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice
BACKGROUND & AIMS: Isolated methylmalonic acidemia (MMA) is a severe inherited metabolic disorder caused by a deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase, encoded by the MMUT gene. Lentiviral vector (LV)-based liver gene therapy may offer sustained therapeutic benefits even in paediatric patients, whose livers are still growing, due to the stable genomic integration of the therapeutic transgene. METHODS: We evaluated the efficacy of liver-directed LV gene therapy in a mouse model of MMA and in patient-derived human fibroblasts. RESULTS: Systemic administration of an MMUT-expressing LV to 2-week-old MMA mice yielded a rapid, strong, and long-lasting (>1 year) therapeutic effect, with normalization of liver histology and mitochondrial ultrastructure. LV-mediated supraphysiological hepatic expression of MMUT promoted detoxification of the kidney and brain from methylmalonic acid and achieved broad correction of metabolomic, lipidomic, and proteomic profiles. Subsequently, we developed a codon-optimized MMUT transgene to increase expression and lower the minimal therapeutic dose. In 2-week-old MMA mice, this LV variant showed a dose-dependent improvement in metabolic biomarkers, clinical phenotype, and hepatocyte transduction efficiency (exceeding 80%). At the lower LV doses, corrected hepatocytes showed a selective proliferative advantage. Throughout all treated animals, LV integration site analysis revealed a high number of integrations without dominant clones, supporting a polyclonal profile. LV gene therapy provided metabolic improvement even in adult MMA mice, which had a more advanced disease stage than 2-week-old MMA mice. In vitro, LV delivery restored MMUT expression in patient-derived fibroblasts and partially corrected their metabolic abnormalities. CONCLUSION: These data provide preclinical proof-of-concept for the efficacy, safety, and extrahepatic therapeutic benefit of liver-directed LV gene therapy for MMA. IMPACT AND IMPLICATIONS: Methylmalonic acidemia (MMA) is a severe metabolic disorder with few treatment options. A liver-targeted gene therapy using integrating lentiviral vectors (LV) could allow for treatment of pediatric patients with a single dose, due to the stable integration of the therapeutic transgene into the DNA of target cells. In this study, we showed that in a relevant MMA mouse model, systemic LV administration led to long-lasting expression of the therapeutic enzyme in hepatocytes, which corrected metabolic abnormalities and significantly improved the disease phenotype. Supranormal enzyme levels in the liver enabled systemic detoxification and widespread metabolic normalization without detectable LV-related toxicity. We provide a detailed LV dose-response study evaluating the efficiency of gene transfer to hepatocytes and its therapeutic outcomes. Overall, these findings offer strong preclinical evidence to support progressing to clinical trials for patients with MMA and may help guide the use of liver-directed LV gene therapy for other inherited metabolic diseases.
2026-04-28 | Oxidative Stress and Inflammation in Methylmalonic and Propionic Acidemias: A Review.
Methylmalonic acidemia and propionic acidemia are inherited organic acidemias resulting from deficiencies in the enzymes methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Impaired activity of these enzymes leads to the accumulation of propionyl-CoA and methylmalonyl-CoA metabolites in tissues and biological fluids. The two disorders share similar clinical features, most notably severe neurological involvement. In the absence of early diagnosis and appropriate treatment, affected individuals may develop irreversible neurological injury, progress to coma, and, in severe cases, death. In this scenario, this review presents some findings from studies in patients, cells and animal models, evidencing that oxidative stress and inflammation plays a crucial role in the pathophysiology of methylmalonic acidemia and propionic acidemia. Furthermore, it allows us to understand the profile of oxidative stress and new perspectives for the treatment of these diseases. Decreased antioxidant defenses, as well as increased levels of markers of inflammation, oxidative damage to lipids, proteins and DNA were observed in animal models, cells and patients, possibly due to the increase in the production of reactive species caused by the accumulated metabolites. The literature also indicates that the use of specific antioxidants may provide benefits by improving the oxidative profile. Based on this evidence, it is widely accepted that oxidative stress and inflammation contribute to severe neurological damage in patients with methylmalonic acidemia and propionic acidemia.
2026-03-24 | MMA-F6: A First-in-Class Pharmacological Chaperone Candidate for Methylmalonic Acidemia Targeting the MUT--MMAA Interface
Methylmalonic acidemia (MMA) is a rare autosomal recessive organic aciduria caused by deficiency of the mitochondrial enzyme methylmalonyl-coenzyme A mutase (MUT). No approved pharmacological therapy exists; current management is limited to dietary protein restriction and, in severe cases, organ transplantation. A first-in-class small-molecule pharmacological chaperone candidate, MMA-F6 (SMILES: Cc1cc(C2(O)CC2)c(C2CCNCC2)cn1; MW 232.3 Da) is reported. MMA-F6 targets the MUT surface pocket at the interface with its accessory protein, methylmalonyl-CoA mutase chaperone A (MMAA), as defined by Protein Data Bank (PDB) structure 3BIC. Multistage computational validation comprising solvation free energy analysis, a 100-target Virtual Phase I safety simulation, a 72-slot gut transit model, and an external absorption, distribution, metabolism, excretion, and toxicity (ADMET) panel (PAINS/Brenk/NIH filters all clean; Ames negative; acute oral toxicity class V) support progression to synthesis and experimental validation. An aqueous binding free energy of −7.93 kcal mol^−1 corresponds to a predicted dissociation constant (Kd) of approximately 2.6 μM. The hydroxycyclopropanol motif, identified through iterative optimization, provides a rigid, directional hydrogen bond to the polar rim of the target pocket with a lower desolvation penalty than prior-generation carboxamide-containing analogues. MMA-F6 is released into the public domain without restriction
2025-12-05 | Nutritional Management in Severe Methylmalonic and Propionic Acidemias: How Much Medical Food Is Too Much?
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic disorders affecting valine and isoleucine catabolism. Long-term therapy mainly involves dietary protein restriction. An amino acid mixture (AAM, medical food) free of the precursor amino acids is frequently used, especially when protein intake does not reach World Health Organization (WHO) recommendations. However, its clinical impact on disease control and patient outcomes remains unclear. Our study aimed to retrospectively review the dietary prescriptions in a cohort of vitamin B12-unresponsive MMA and PA patients and to analyze their impact on clinical and laboratory parameters. Clinical data, anthropometric measurements and dietary prescriptions were collected from the patients' medical and dietary files. We included 71 patients (38 MMA and 33 PA). Fifty-nine percent of the patients' dietary prescriptions did not reach the safe WHO-recommended daily total protein intake. Among these, 28% included AAM supplementation versus 62% in the group of patients that met the WHO recommendations (p < 0.001). AAM was associated with a decrease in mean plasma concentrations of isoleucine and valine. These plasma amino acid concentrations were corrected by isoleucine and valine supplementation; however, leucine/isoleucine and leucine/valine ratios remained elevated in comparison to patients without AAM. Nutritional and clinical scores were worsened by AAM supplementation. We found that MMA/PA patients receiving AAM tend to have altered plasma amino acid concentrations, raising concerns about potential long-term deleterious consequences of AAM. We recommend prioritizing natural protein intake over AAM when possible, and if not, to carefully monitor and moderately supplement valine and isoleucine to prevent deficiencies.
2025-09-26 | Effects of anserine on oxidative stress and on cell barrier integrity in methylmalonic aciduria.
Kidney damage in individuals with methylmalonyl-CoA mutase deficiency (mut0) results from metabolic and oxidative stress, and disrupted mitochondrial homeostasis. Anserine, known for its antioxidant properties and protective effect on cell barrier integrity of endothelial and epithelial kidney and vascular cells, may offer therapeutic potential for chronic disorders. This study explored anserine's effects on immortalized kidney tubular epithelial cells (iKTEC) from mut0 patients. Compared to healthy controls, iKTEC from mut0 patients showed reduced cell viability, antioxidant capacity, oxygen consumption, and ATP production. Expression of the tight junction scaffolding protein zonula occludens-1 (ZO-1) was increased in mut0 cells compared to control while transepithelial resistance (TER), and dextran transport (10 kDa) remained unchanged. Anserine treatment restored antioxidant capacity and normalized ZO-1 expression but had no effect on TER or dextran transport. Additionally, cell viability, mitochondrial respiration, and ATP production were unaffected by anserine. Metabolic stress induced by high protein load or disease-associated branched-chain amino acids did not worsen mitochondrial dysfunction or epithelial integrity, and anserine exposure showed no further effects. In conclusion, anserine showed promise in restoring antioxidant capacity in iKTEC from mut0 patients, highlighting its potential as a therapeutic agent to mitigate ROS, although its effects on mitochondrial function and epithelial integrity warrant further investigation.
2026-05-01 | Liver-directed lentiviral gene therapy confers durable hepatic and systemic amelioration of methylmalonic acidemia in mice
BACKGROUND & AIMS: Isolated methylmalonic acidemia (MMA) is a severe inherited metabolic disorder caused by a deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase, encoded by the MMUT gene. Lentiviral vector (LV)-based liver gene therapy may offer sustained therapeutic benefits even in paediatric patients, whose livers are still growing, due to the stable genomic integration of the therapeutic transgene. METHODS: We evaluated the efficacy of liver-directed LV gene therapy in a mouse model of MMA and in patient-derived human fibroblasts. RESULTS: Systemic administration of an MMUT-expressing LV to 2-week-old MMA mice yielded a rapid, strong, and long-lasting (>1 year) therapeutic effect, with normalization of liver histology and mitochondrial ultrastructure. LV-mediated supraphysiological hepatic expression of MMUT promoted detoxification of the kidney and brain from methylmalonic acid and achieved broad correction of metabolomic, lipidomic, and proteomic profiles. Subsequently, we developed a codon-optimized MMUT transgene to increase expression and lower the minimal therapeutic dose. In 2-week-old MMA mice, this LV variant showed a dose-dependent improvement in metabolic biomarkers, clinical phenotype, and hepatocyte transduction efficiency (exceeding 80%). At the lower LV doses, corrected hepatocytes showed a selective proliferative advantage. Throughout all treated animals, LV integration site analysis revealed a high number of integrations without dominant clones, supporting a polyclonal profile. LV gene therapy provided metabolic improvement even in adult MMA mice, which had a more advanced disease stage than 2-week-old MMA mice. In vitro, LV delivery restored MMUT expression in patient-derived fibroblasts and partially corrected their metabolic abnormalities. CONCLUSION: These data provide preclinical proof-of-concept for the efficacy, safety, and extrahepatic therapeutic benefit of liver-directed LV gene therapy for MMA. IMPACT AND IMPLICATIONS: Methylmalonic acidemia (MMA) is a severe metabolic disorder with few treatment options. A liver-targeted gene therapy using integrating lentiviral vectors (LV) could allow for treatment of pediatric patients with a single dose, due to the stable integration of the therapeutic transgene into the DNA of target cells. In this study, we showed that in a relevant MMA mouse model, systemic LV administration led to long-lasting expression of the therapeutic enzyme in hepatocytes, which corrected metabolic abnormalities and significantly improved the disease phenotype. Supranormal enzyme levels in the liver enabled systemic detoxification and widespread metabolic normalization without detectable LV-related toxicity. We provide a detailed LV dose-response study evaluating the efficiency of gene transfer to hepatocytes and its therapeutic outcomes. Overall, these findings offer strong preclinical evidence to support progressing to clinical trials for patients with MMA and may help guide the use of liver-directed LV gene therapy for other inherited metabolic diseases.
2026-04-28 | Oxidative Stress and Inflammation in Methylmalonic and Propionic Acidemias: A Review.
Methylmalonic acidemia and propionic acidemia are inherited organic acidemias resulting from deficiencies in the enzymes methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Impaired activity of these enzymes leads to the accumulation of propionyl-CoA and methylmalonyl-CoA metabolites in tissues and biological fluids. The two disorders share similar clinical features, most notably severe neurological involvement. In the absence of early diagnosis and appropriate treatment, affected individuals may develop irreversible neurological injury, progress to coma, and, in severe cases, death. In this scenario, this review presents some findings from studies in patients, cells and animal models, evidencing that oxidative stress and inflammation plays a crucial role in the pathophysiology of methylmalonic acidemia and propionic acidemia. Furthermore, it allows us to understand the profile of oxidative stress and new perspectives for the treatment of these diseases. Decreased antioxidant defenses, as well as increased levels of markers of inflammation, oxidative damage to lipids, proteins and DNA were observed in animal models, cells and patients, possibly due to the increase in the production of reactive species caused by the accumulated metabolites. The literature also indicates that the use of specific antioxidants may provide benefits by improving the oxidative profile. Based on this evidence, it is widely accepted that oxidative stress and inflammation contribute to severe neurological damage in patients with methylmalonic acidemia and propionic acidemia.
2026-03-24 | MMA-F6: A First-in-Class Pharmacological Chaperone Candidate for Methylmalonic Acidemia Targeting the MUT--MMAA Interface
Methylmalonic acidemia (MMA) is a rare autosomal recessive organic aciduria caused by deficiency of the mitochondrial enzyme methylmalonyl-coenzyme A mutase (MUT). No approved pharmacological therapy exists; current management is limited to dietary protein restriction and, in severe cases, organ transplantation. A first-in-class small-molecule pharmacological chaperone candidate, MMA-F6 (SMILES: Cc1cc(C2(O)CC2)c(C2CCNCC2)cn1; MW 232.3 Da) is reported. MMA-F6 targets the MUT surface pocket at the interface with its accessory protein, methylmalonyl-CoA mutase chaperone A (MMAA), as defined by Protein Data Bank (PDB) structure 3BIC. Multistage computational validation comprising solvation free energy analysis, a 100-target Virtual Phase I safety simulation, a 72-slot gut transit model, and an external absorption, distribution, metabolism, excretion, and toxicity (ADMET) panel (PAINS/Brenk/NIH filters all clean; Ames negative; acute oral toxicity class V) support progression to synthesis and experimental validation. An aqueous binding free energy of −7.93 kcal mol^−1 corresponds to a predicted dissociation constant (Kd) of approximately 2.6 μM. The hydroxycyclopropanol motif, identified through iterative optimization, provides a rigid, directional hydrogen bond to the polar rim of the target pocket with a lower desolvation penalty than prior-generation carboxamide-containing analogues. MMA-F6 is released into the public domain without restriction
2025-12-05 | Nutritional Management in Severe Methylmalonic and Propionic Acidemias: How Much Medical Food Is Too Much?
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic disorders affecting valine and isoleucine catabolism. Long-term therapy mainly involves dietary protein restriction. An amino acid mixture (AAM, medical food) free of the precursor amino acids is frequently used, especially when protein intake does not reach World Health Organization (WHO) recommendations. However, its clinical impact on disease control and patient outcomes remains unclear. Our study aimed to retrospectively review the dietary prescriptions in a cohort of vitamin B12-unresponsive MMA and PA patients and to analyze their impact on clinical and laboratory parameters. Clinical data, anthropometric measurements and dietary prescriptions were collected from the patients' medical and dietary files. We included 71 patients (38 MMA and 33 PA). Fifty-nine percent of the patients' dietary prescriptions did not reach the safe WHO-recommended daily total protein intake. Among these, 28% included AAM supplementation versus 62% in the group of patients that met the WHO recommendations (p < 0.001). AAM was associated with a decrease in mean plasma concentrations of isoleucine and valine. These plasma amino acid concentrations were corrected by isoleucine and valine supplementation; however, leucine/isoleucine and leucine/valine ratios remained elevated in comparison to patients without AAM. Nutritional and clinical scores were worsened by AAM supplementation. We found that MMA/PA patients receiving AAM tend to have altered plasma amino acid concentrations, raising concerns about potential long-term deleterious consequences of AAM. We recommend prioritizing natural protein intake over AAM when possible, and if not, to carefully monitor and moderately supplement valine and isoleucine to prevent deficiencies.
2025-09-26 | Effects of anserine on oxidative stress and on cell barrier integrity in methylmalonic aciduria.
Kidney damage in individuals with methylmalonyl-CoA mutase deficiency (mut0) results from metabolic and oxidative stress, and disrupted mitochondrial homeostasis. Anserine, known for its antioxidant properties and protective effect on cell barrier integrity of endothelial and epithelial kidney and vascular cells, may offer therapeutic potential for chronic disorders. This study explored anserine's effects on immortalized kidney tubular epithelial cells (iKTEC) from mut0 patients. Compared to healthy controls, iKTEC from mut0 patients showed reduced cell viability, antioxidant capacity, oxygen consumption, and ATP production. Expression of the tight junction scaffolding protein zonula occludens-1 (ZO-1) was increased in mut0 cells compared to control while transepithelial resistance (TER), and dextran transport (10 kDa) remained unchanged. Anserine treatment restored antioxidant capacity and normalized ZO-1 expression but had no effect on TER or dextran transport. Additionally, cell viability, mitochondrial respiration, and ATP production were unaffected by anserine. Metabolic stress induced by high protein load or disease-associated branched-chain amino acids did not worsen mitochondrial dysfunction or epithelial integrity, and anserine exposure showed no further effects. In conclusion, anserine showed promise in restoring antioxidant capacity in iKTEC from mut0 patients, highlighting its potential as a therapeutic agent to mitigate ROS, although its effects on mitochondrial function and epithelial integrity warrant further investigation.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Vitamin B12-unresponsive methylmalonic acidemia.
3 orphan drug designations for Vitamin B12-unresponsive methylmalonic acidemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
hydroxocobalamin | other | FDA | 2025-09-26 | — | Meta Healthcare Ltd, |
Modified mRNA encoding human methylmalonyl-coenzyme A mutase containing a polymorphism at position 671 | RNAs | EMA | 2022-06-21 | — | Moderna Biotech Spain S.L. |
Adeno-associated viral vector LK03 encoding human methylmalonyl-CoA mutase | gene therapies | EMA | 2021-06-21 | — | Parexel International (IRL) Limited |
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