RARE DISEASE
Vitamin B12-responsive methylmalonic acidemia
Vitamin B12-responsive methylmalonic acidemia
Vitamin B12-responsive methylmalonic acidemia
Synonyms: Adenosylcobalamin deficiency, Vitamin B12-responsive methylmalonic aciduria
Synonyms: Adenosylcobalamin deficiency, Vitamin B12-responsive methylmalonic aciduria
Synonyms: Adenosylcobalamin deficiency, Vitamin B12-responsive methylmalonic aciduria
Drug discovery
1
drug
With orphan designation
Overview
Vitamin B12-responsive methylmalonic acidemia (MMA) is an inborn error of cobalamin metabolism caused by impaired adenosylcobalamin synthesis, leading to toxic methylmalonic acid accumulation. It presents with ketoacidosis, dehydration, hypotonia, developmental delay, and metabolic strokes. Three subtypes exist (cblA, cblB, and cblDv2), distinguished by genetic mutations (MMAA, MMAB, and MMADHC genes). Diagnosis relies on elevated MMA levels and genetic testing. Early vitamin B12 therapy improves outcomes, particularly in cblA and some cblB cases [1][2][4][10].
Burden
Neurological sequelae (intellectual disability, metabolic strokes) in 30–60% [2][9].
Mortality: 25–50% in untreated cases, with lifelong management required [5][6].
Vitamin B12 responsiveness correlates with prognosis, with cblA patients often achieving near-normal development under therapy [1][7]. Regular monitoring for renal and neurological complications is critical [4][6].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
164 drug discovery papers about Vitamin B12-responsive methylmalonic acidemia, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
164 drug discovery papers about Vitamin B12-responsive methylmalonic acidemia, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-01 | Neuropsychiatric Manifestations in Methylmalonic Acidemia and Homocystinuria of Adult Presentation. A Case Report
Introduction Each neurometabolic disorder is individually rare, but their cumulative incidence is relatively high, around 1/1,500 to 1/5,000 live births. In neurometabolic diseases, there is a deficit in the transformation of a substrate that prevents the production of one or more enzymes. Common neuropsychiatric manifestations associated with vitamin B12 deficiency include motor, sensory, and autonomic symptoms, cognitive impairment, mood disorders, and psychotic symptoms. Psychiatric manifestations are considered a particular form of presentation which, precisely because of their isolated nature, make diagnostic identification difficult, given that behavioral changes in these NME generally have an insidious onset. Objectives Objective: To report the neuropsychiatric alterations associated with inborn errors of vitamin B12 metabolism in adults Methods Case report. Results 30-year-old woman who starts with anxiety, difficulty in daily organization, suspected to be reactive to active mourning and initiation of Duncan’s hyperproteic diet; 7 months later she debuts with acute encephalopathy (confusion, bradypsychia, parkinsonism), admitted to ICU for focal status epilepticus coinciding with the initiation of parenteral feeding. Brain MRI showed pericerebellar and basal ganglia hyperintensity, although LP showed no alterations, Hashimoto’s encephalopathy was initially diagnosed with minimal response to corticosteroids. The evolution in the following 4 months was torpid, persisting frontal-subcortical dysfunction, with bradypsychia, loss of skills, memory, language, gait and behavioral alterations (irritability, agitation), as well as psychotic symptoms with polymorphous delusional ideation: of harm, control and pregnancy with auditory hallucinations. She was admitted to Neurology to study the picture and was referred to Psychiatry. Due to hyperhomocysteinemia and hyperammonemia and aciduria in urine, genetic screening was performed to rule out alteration of Vitb12 metabolism, diagnosing methylmalonic aciduria with homocystinuria due to deficiency in MMACHC (cbIC) (anomaly in the synthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are coenzymes derived from Vitb12). She was treated with Vit B12 and B9 supplements, L-carnitine, betaine, and paliperidone, with significant early improvements in biochemical parameters, and later in clinical manifestations. After discharge he did not present psychosis again. Conclusions alterations in cobalamin metabolism may present psychiatric alterations. The manifestations are usually very polimorfic. Disclosure of Interest None Declared
2025-12-18 | Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.
2025-09-09 | Immunostimulatory and Immunomodulatory Effects of Vitamin B12 Derivatives on Macrophages Through the Modulation of JNK Pathway.
Vitamin B12 is a vital water-soluble vitamin containing a central cobalt atom within its corrin ring structure. It exists in several derivatives, among which methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl) are the biologically active forms that serve as cofactors in essential enzymatic reactions. Although the neurological and hematological consequences of vitamin B12 deficiency have been extensively studied, its role in immune regulation remains less well understood. Considering that macrophages are key effector cells of innate immunity, this study aimed to investigate the immunostimulatory and immunomodulatory properties of MeCbl and AdCbl on murine macrophages (J774.2 cell line) with a particular focus on cytokine responses and the JNK signaling pathway. Macrophages were cultured under controlled conditions and treated with non-cytotoxic concentrations of MeCbl and AdCbl (1, 5, and 10 µg/mL), either alone or in combination with lipopolysaccharide (LPS, 1 µg/mL) as a pro-inflammatory stimulus. Cell viability was first confirmed using Trypan Blue exclusion to ensure that the tested concentrations did not impair cellular survival. Supernatants were then analyzed for cytokine production (TNF-α, IL-6, IL-12p40, GM-CSF) using ELISA, and intracellular signaling was investigated through flow cytometric analysis of phosphorylated JNK (p-JNK) levels. The results revealed that under non-inflammatory conditions, neither MeCbl nor AdCbl significantly altered cytokine production, suggesting a lack of direct immunostimulatory activity in resting macrophages. However, in the presence of LPS, both derivatives markedly increased TNF-α levels, consistent with enhanced pro-inflammatory activation. At the same time, both compounds significantly suppressed IL-6 and IL-12p40 production, pointing to their capacity to counterbalance excessive Th1-driven responses. Importantly, AdCbl demonstrated a unique, concentration-dependent reduction in GM-CSF levels, whereas MeCbl induced only minimal and inconsistent changes, indicating that AdCbl exerts a more selective regulatory profile while MeCbl has broader but less concentration-dependent effects. Flow cytometry further confirmed that both derivatives strongly enhanced JNK phosphorylation, implicating this signaling pathway as a mechanistic link between vitamin B12 derivatives and cytokine modulation. Taken together, these findings demonstrate that MeCbl and AdCbl exert distinct yet overlapping immunomodulatory effects in macrophages. By simultaneously promoting TNF-α while limiting IL-6, IL-12p40, and GM-CSF (for AdCbl), these compounds display a complex balance of pro- and anti-inflammatory activities mediated, at least in part, through the JNK pathway. This dual role highlights their potential relevance in fine-tuning immune responses, preventing excessive inflammation, and supporting host defense. The study provides new insights into the immunological functions of vitamin B12 derivatives and suggests that future research should explore their therapeutic applications in immune-related disorders and inflammatory diseases.
2025-06-18 | A case report of combined methylmalonic acidemia and homocysteinemia presented with cerebral sinus thrombosis and fluctuating cognitive impairment.
MMACHC deficiency leads to combined methylmalonic acidemia and homocysteinemia. The disease is characterized by the presence of methylmalonic acidemia and hyperhomocysteinemia, leading to widespread clinical manifestations affecting multiple organs. Due to the low incidence of cblC deficiency and the diversity of its clinical phenotypes, diagnosis was challenging and often results in delays or missed diagnoses. We now report a case of a male patient who experienced fluctuating cognitive impairment and headaches for 3 times. He was initially diagnosed with encephalitis and venous sinus thrombosis, but his symptoms recurred. Later, significantly elevated levels of homocysteine and methylmalonic acid were detected. Genetic analysis confirmed the presence of a heterozygous mutation in the MMACHC gene, establishing the definitive diagnosis. This case is reported due to its rarity and diverse clinical presentations, highlighting the need for increased awareness of this condition. A male patient exhibited recurrent episodes of fluctuating cognitive impairment and headaches. The patient underwent magnetic resonance imaging, lumbar puncture, and cerebrospinal fluid analysis. To confirm the diagnosis, genetic sequencing analysis was also conducted. In terms of intervention, the patient received supplementation with cobamamide, vitamin B1, and folic acid, leading to gradual relief and improvement of symptoms. The patient's headaches and cognitive impairment symptoms have alleviated, and there have been no recurrences during follow-up. To our knowledge, there are few clinical cases of methylmalonic acidemia presenting primarily with episodic cognitive impairment and venous sinus thrombosis. Therefore, it is essential to enhance the recognition and differential diagnosis of such symptoms to improve the accuracy and speed of the disease diagnosis.
2025-05-29 | Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation.
MMACHC protein plays a crucial role in the metabolism of vitamin B12 (cobalamin, Cbl) by catalyzing its conversion into the active forms adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which serve as essential cofactors in key cellular reactions. Mutations in the gene encoding MMACHC lead to the rare metabolic disorder known as methylmalonic aciduria and homocystinuria, cblC type. This condition predominantly affects children and is characterized by cardiovascular dysfunction, intellectual disability, and a severe form of maculopathy. The most common missense mutation, R161Q, impairs enzymatic activity despite not being directly involved in cobalamin binding. Here, using a comprehensive set of biophysical techniques, we demonstrate that this pathogenic variant compromises MMACHC structural stability, alters the thermal unfolding cooperativity and pathway, as well as the populations of conformational intermediates. Moreover, we show that the R161Q mutation decreases AdoCbl binding affinity and impairs the protein's ability to form homodimers, which are supposed to have a functional role. A partial recovery in protein activity upon treatment with betaine, an osmolyte known for its stabilizing effect on proteins, was observed. This suggests a direct correlation between the energetics of MMACHC thermal unfolding and its functional activity. These findings contribute to a deeper understanding of the molecular mechanisms underlying MMACHC function and open avenues for potential therapeutic interventions.
2026-06-01 | Neuropsychiatric Manifestations in Methylmalonic Acidemia and Homocystinuria of Adult Presentation. A Case Report
Introduction Each neurometabolic disorder is individually rare, but their cumulative incidence is relatively high, around 1/1,500 to 1/5,000 live births. In neurometabolic diseases, there is a deficit in the transformation of a substrate that prevents the production of one or more enzymes. Common neuropsychiatric manifestations associated with vitamin B12 deficiency include motor, sensory, and autonomic symptoms, cognitive impairment, mood disorders, and psychotic symptoms. Psychiatric manifestations are considered a particular form of presentation which, precisely because of their isolated nature, make diagnostic identification difficult, given that behavioral changes in these NME generally have an insidious onset. Objectives Objective: To report the neuropsychiatric alterations associated with inborn errors of vitamin B12 metabolism in adults Methods Case report. Results 30-year-old woman who starts with anxiety, difficulty in daily organization, suspected to be reactive to active mourning and initiation of Duncan’s hyperproteic diet; 7 months later she debuts with acute encephalopathy (confusion, bradypsychia, parkinsonism), admitted to ICU for focal status epilepticus coinciding with the initiation of parenteral feeding. Brain MRI showed pericerebellar and basal ganglia hyperintensity, although LP showed no alterations, Hashimoto’s encephalopathy was initially diagnosed with minimal response to corticosteroids. The evolution in the following 4 months was torpid, persisting frontal-subcortical dysfunction, with bradypsychia, loss of skills, memory, language, gait and behavioral alterations (irritability, agitation), as well as psychotic symptoms with polymorphous delusional ideation: of harm, control and pregnancy with auditory hallucinations. She was admitted to Neurology to study the picture and was referred to Psychiatry. Due to hyperhomocysteinemia and hyperammonemia and aciduria in urine, genetic screening was performed to rule out alteration of Vitb12 metabolism, diagnosing methylmalonic aciduria with homocystinuria due to deficiency in MMACHC (cbIC) (anomaly in the synthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are coenzymes derived from Vitb12). She was treated with Vit B12 and B9 supplements, L-carnitine, betaine, and paliperidone, with significant early improvements in biochemical parameters, and later in clinical manifestations. After discharge he did not present psychosis again. Conclusions alterations in cobalamin metabolism may present psychiatric alterations. The manifestations are usually very polimorfic. Disclosure of Interest None Declared
2025-12-18 | Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.
2025-09-09 | Immunostimulatory and Immunomodulatory Effects of Vitamin B12 Derivatives on Macrophages Through the Modulation of JNK Pathway.
Vitamin B12 is a vital water-soluble vitamin containing a central cobalt atom within its corrin ring structure. It exists in several derivatives, among which methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl) are the biologically active forms that serve as cofactors in essential enzymatic reactions. Although the neurological and hematological consequences of vitamin B12 deficiency have been extensively studied, its role in immune regulation remains less well understood. Considering that macrophages are key effector cells of innate immunity, this study aimed to investigate the immunostimulatory and immunomodulatory properties of MeCbl and AdCbl on murine macrophages (J774.2 cell line) with a particular focus on cytokine responses and the JNK signaling pathway. Macrophages were cultured under controlled conditions and treated with non-cytotoxic concentrations of MeCbl and AdCbl (1, 5, and 10 µg/mL), either alone or in combination with lipopolysaccharide (LPS, 1 µg/mL) as a pro-inflammatory stimulus. Cell viability was first confirmed using Trypan Blue exclusion to ensure that the tested concentrations did not impair cellular survival. Supernatants were then analyzed for cytokine production (TNF-α, IL-6, IL-12p40, GM-CSF) using ELISA, and intracellular signaling was investigated through flow cytometric analysis of phosphorylated JNK (p-JNK) levels. The results revealed that under non-inflammatory conditions, neither MeCbl nor AdCbl significantly altered cytokine production, suggesting a lack of direct immunostimulatory activity in resting macrophages. However, in the presence of LPS, both derivatives markedly increased TNF-α levels, consistent with enhanced pro-inflammatory activation. At the same time, both compounds significantly suppressed IL-6 and IL-12p40 production, pointing to their capacity to counterbalance excessive Th1-driven responses. Importantly, AdCbl demonstrated a unique, concentration-dependent reduction in GM-CSF levels, whereas MeCbl induced only minimal and inconsistent changes, indicating that AdCbl exerts a more selective regulatory profile while MeCbl has broader but less concentration-dependent effects. Flow cytometry further confirmed that both derivatives strongly enhanced JNK phosphorylation, implicating this signaling pathway as a mechanistic link between vitamin B12 derivatives and cytokine modulation. Taken together, these findings demonstrate that MeCbl and AdCbl exert distinct yet overlapping immunomodulatory effects in macrophages. By simultaneously promoting TNF-α while limiting IL-6, IL-12p40, and GM-CSF (for AdCbl), these compounds display a complex balance of pro- and anti-inflammatory activities mediated, at least in part, through the JNK pathway. This dual role highlights their potential relevance in fine-tuning immune responses, preventing excessive inflammation, and supporting host defense. The study provides new insights into the immunological functions of vitamin B12 derivatives and suggests that future research should explore their therapeutic applications in immune-related disorders and inflammatory diseases.
2025-06-18 | A case report of combined methylmalonic acidemia and homocysteinemia presented with cerebral sinus thrombosis and fluctuating cognitive impairment.
MMACHC deficiency leads to combined methylmalonic acidemia and homocysteinemia. The disease is characterized by the presence of methylmalonic acidemia and hyperhomocysteinemia, leading to widespread clinical manifestations affecting multiple organs. Due to the low incidence of cblC deficiency and the diversity of its clinical phenotypes, diagnosis was challenging and often results in delays or missed diagnoses. We now report a case of a male patient who experienced fluctuating cognitive impairment and headaches for 3 times. He was initially diagnosed with encephalitis and venous sinus thrombosis, but his symptoms recurred. Later, significantly elevated levels of homocysteine and methylmalonic acid were detected. Genetic analysis confirmed the presence of a heterozygous mutation in the MMACHC gene, establishing the definitive diagnosis. This case is reported due to its rarity and diverse clinical presentations, highlighting the need for increased awareness of this condition. A male patient exhibited recurrent episodes of fluctuating cognitive impairment and headaches. The patient underwent magnetic resonance imaging, lumbar puncture, and cerebrospinal fluid analysis. To confirm the diagnosis, genetic sequencing analysis was also conducted. In terms of intervention, the patient received supplementation with cobamamide, vitamin B1, and folic acid, leading to gradual relief and improvement of symptoms. The patient's headaches and cognitive impairment symptoms have alleviated, and there have been no recurrences during follow-up. To our knowledge, there are few clinical cases of methylmalonic acidemia presenting primarily with episodic cognitive impairment and venous sinus thrombosis. Therefore, it is essential to enhance the recognition and differential diagnosis of such symptoms to improve the accuracy and speed of the disease diagnosis.
2025-05-29 | Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation.
MMACHC protein plays a crucial role in the metabolism of vitamin B12 (cobalamin, Cbl) by catalyzing its conversion into the active forms adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which serve as essential cofactors in key cellular reactions. Mutations in the gene encoding MMACHC lead to the rare metabolic disorder known as methylmalonic aciduria and homocystinuria, cblC type. This condition predominantly affects children and is characterized by cardiovascular dysfunction, intellectual disability, and a severe form of maculopathy. The most common missense mutation, R161Q, impairs enzymatic activity despite not being directly involved in cobalamin binding. Here, using a comprehensive set of biophysical techniques, we demonstrate that this pathogenic variant compromises MMACHC structural stability, alters the thermal unfolding cooperativity and pathway, as well as the populations of conformational intermediates. Moreover, we show that the R161Q mutation decreases AdoCbl binding affinity and impairs the protein's ability to form homodimers, which are supposed to have a functional role. A partial recovery in protein activity upon treatment with betaine, an osmolyte known for its stabilizing effect on proteins, was observed. This suggests a direct correlation between the energetics of MMACHC thermal unfolding and its functional activity. These findings contribute to a deeper understanding of the molecular mechanisms underlying MMACHC function and open avenues for potential therapeutic interventions.
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Drug Discovery Landscape
1 orphan drug designation for Vitamin B12-responsive methylmalonic acidemia.
1 orphan drug designation for Vitamin B12-responsive methylmalonic acidemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant adeno-associated viral vector with human methylmalonyl-COA mutase (MUT) gene | gene therapies | FDA | 2019-04-22 | — | LogicBio Therapeutics, Inc. |
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