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:
categories:
Small molecules
small molecules
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
2025-09-09 | 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.
2025-03-20 | CLYBL averts vitamin B12 depletion by repairing malyl-CoA.
Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of CLYBL loss of function with reduced circulating vitamin B12 levels was proposed to result from inhibition of the B12-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of CLYBL across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that CLYBL knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B12 deficiency observed in individuals with CLYBL loss of function.
proteins
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.
2024-03-01 | Abstract 1766 Metabolite repair by CLYBL averts inhibition of methylmalonyl-CoA mutase
Metabolite repair is a necessary, yet understudied concept in metabolic biochemistry that strives to characterize non-canonical metabolites formed by enzymatic side activities or spontaneous reactions and the enzymes that are responsible for converting these often-toxic molecules to useful substrates. Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed, mammalian enzyme that has recently garnered attention for its role in the degradation itaconate, a highly localized metabolite that activated macrophages produce to defend against pathogens. The host cell activates itaconate to itaconyl-CoA which is then converted to citramalyl-CoA to be finally cleaved into acetyl-CoA and pyruvate by CLYBL. A loss-of-function single nucleotide polymorphism in the CLYBL gene is present in 2.7% of all human chromosomes and has been associated with low levels of circulating vitamin B12. Itaconyl-CoA is a suicide inhibitor of the B12-dependent enzyme methylmalonyl-CoA mutase (MCM); however, the highly inducible and locally confined production of itaconate makes it unlikely to be the main cause of reduced circulating B12 levels in CLYBL deficient people. We have uncovered another main physiological function of CLYBL, namely, to act as a metabolite repair enzyme to degrade a more ubiquitously formed acyl-CoA ester by promiscuity of TCA cycle enzymes that we identified using CLYBL deficient cell lines. People who harbor null CLYBL alleles cannot eliminate this damaging metabolite which we identified is a potent inhibitor of MCM, consequently depleting adenosylcobalamin. Significantly, this work establishes a molecular culprit of B12 deficiency that can form in all cell types, providing the groundwork to examine the effects of CLYBL deficiency on human health.
2018-12-05 | FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut–/–;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
2018-02-01 | New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type
Methylmalonic aciduria cblB type (MMA cblB) is caused by the impairment of ATP:cob(I)alamin adenosyltransferase (ATR), the enzyme responsible for the synthesis of adenosylcobalamin (AdoCbl) from cob(I)alamin.No definitive treatment is available for patients with this condition and novel therapeutic strategies are therefore much needed.Recently, we described a proof-of-concept regarding the use of pharmacological chaperones as a treatment.This work describes the effect of two potentialphenylacetamide) and compound VI (4-(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3yl)benzene-1,3-diol) -on six ATR mutants, including the most common, p.Arg186Trp.Comprehensive functional analysis identified destabilizing (p.Arg186Gln, p.Arg190Cys, p.Arg190His, p.Arg191Gln and p.Glu193Lys) and oligomerization (p.Arg186Trp and p.Arg191Gln) mutations.In a cellular model overexpressing the destabilizing/oligomerization mutations, compounds V and VI had a positive effect on the stability and activity of all ATR variants.When provided in combination withhydroxocobalamin a more positive effect was obtained than with the latter compounds alone, even in mutations previously described as B12 non-responsive.In addition, a normal oligomerization profile was recovered after treatment of the p.Arg186Trp mutant with both compounds.These promising results confirm MMA cblB type as a conformational disorder and hence, pharmacological chaperones as a new therapeutic option alone or in combination with hydroxocobalamin for many patients with MMA cblB.
2017-09-22 | Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation
Human mitochondrial methylmalonyl-CoA mutase (hMCM) is an isomerase that converts methylmalonyl-CoA to succinyl-CoA, a crucial step for the incorporation of some compounds derived from the diet into the central metabolism. hMCM employs highly reactive radicals from its cofactor (adenosylcobalamin, AdoCbl) to perform its reaction. Our previous work demonstrated that hMCM loses activity during catalysis and that the interaction with human MMAA (hMMAA), a GTPase protein, avoided this loss or restored hMCM activity. Even so, the mechanism by which hMMAA exerted these chaperone functions has not been described. In this work report that the formation and accumulation of OH2Cbl, the oxidized form of the AdoCbl cofactor formed during catalysis, is the cause of hMCM inactivation. Additionally, we demonstrate that the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor formation, protecting the hMCM enzyme. Moreover, an inactive model of hMCM was used to demonstrate that hMMAA is able to remove the damaged cofactor through GTP hydrolysis. Additionally, a modification in the kinetic parameters of hMCM in presence of hMMAA was observed, and for the first time, the in vivo localization of hMMAA and its colocalization with hMCM in human fibroblasts mitochondria were demonstrated.
cell therapies
2023-09-01 | Exploiting Potential Probiotic Lactic Acid Bacteria Isolated from Chlorella vulgaris Photobioreactors as Promising Vitamin B12 Producers
Lactic acid bacteria (LAB) have been documented as potential vitamin B12 producers and may constitute an exogenous source of cobalamin for the microalga Chlorella vulgaris, which has been described as being able to perform vitamin uptake. Hence, there is an interest in discovering novel B12-producing probiotic LAB. Therefore, the purpose of the current work was to perform a phenotype-genotype analysis of the vitamin B12 biosynthesis capacity of LAB isolated from C. vulgaris bioreactors, and investigate their probiotic potential. Among the selected strains, Lactococcus lactis E32, Levilactobacillus brevis G31, and Pediococcus pentosaceus L51 demonstrated vitamin B12 biosynthesis capacity, with the latter producing the highest (28.19 ± 2.27 pg mL-1). The genomic analysis confirmed the presence of pivotal genes involved in different steps of the biosynthetic pathway (hemL, cbiT, cobC, and cobD). Notably, P. pentosaceus L51 was the only strain harboring cobA, pduU, and pduV genes, which may provide evidence for the presence of the cobalamin operon. All strains demonstrated the capability to withstand harsh gastrointestinal conditions, although P. pentosaceus L51 was more resilient. The potential for de novo cobalamin biosynthesis and remarkable probiotic features highlighted that P. pentosaceus L51 may be considered the most promising candidate strain for developing high-content vitamin B12 formulations.
2019-10-01 | Perioperative characteristics and management of liver transplantation for isolated methylmalonic acidemia—the largest experience in China
There are few detailed consensus and guidelines on perioperative clinical characteristics of liver transplantation (LT) in patients with methylmalonic acidemia (MMA). This retrospective study investigated details of the clinical course and individualized treatment plan of the center with largest experience in China.A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 to December 2017 were enrolled in the study, whose clinical data (clinical characteristics, laboratory findings, chronological changes in urine MMA levels, treatment, etc.) during perioperative period were analyzed retrospectively. All the patients received strict postoperative management.All the 7 cases were confirmed to have isolated MMA, among which, 3 cases received living donor liver transplantation (LDLT), 4 cases received deceased donor liver transplantation (DDLT). A wild fluctuate of metabolic condition was observed within the first few days after surgery and two weeks after LT, the mean base excess of blood value (BE-B) restored to normal whereas plasma bicarbonate (HCO3-) was still below normal value even with intermittent sodium bicarbonate correction. It also showed marked reduction in propionylcarnitine (C3) and C3/C2 level and the mean urine MMA by gas chromatography-mass spectrometry (GC-MS) was reduced by 81.7% (P<0.01) but remained >72× higher than upper limit of normal. The metabolism-correcting medications were administered as before. The renal function of one case with renal insufficiency before LT (serum creatinine rising) maintained stable by adjusting the immunosuppressive regimen during the observation period. All patients survive to date.LT is an effective treatment to prevent metabolic crisis, but patients with MMA tend to be metabolically fragile even after surgery. During perioperative period, close monitoring should be given for acidosis episodes so as to implement sodium bicarbonate correction. Metabolism-correcting medications are still needed. Special immunosuppressive regimen is an effective way of maintaining renal function for those with kidney dysfunction.
2019-03-21 | The Value of Liver Transplantation for Methylmalonic Acidemia
Introduction: MMA is a rare autosomal recessive disorder with the manifestation of recurrent and severe episodes of acute metabolic decompensation or a variety of long-term complications that require timely treatment. While conventional long-term medical and dietary management cannot prevent rapid progression of conditions in patients with severe complications, LT or CKLT has become an option. Methods: We reviewed the literature for MMA patients undergoing LT/CKLT published since 2006, and data on metabolic decompensation status, protein dietary, neurological damage, renal insufficiency and developmental delay before and after transplantations were compared to evaluate the clinical value of the procedure in the treatment of MMA. Results: To date, some successful LTs/CKLT procedures have prolonged survival and resulted in better quality of life in patients (lowered urine/plasma MMA levels but still much higher than normal, reduced onset of metabolic stroke, occasional improved developmental delay and relaxed protein diet), although these procedures cannot reverse neurological damage or thoroughly stop the progress of complications, such as renal dysfunction. Conclusion: LT is the only effective treatment for MMA patients with recurrent metabolic decompensation. However, it is still possible that neurological and renal damage remains irreversible. Metabolism-correcting medications should be administered even after surgery.
2016-12-01 | Methylmalonic and propionic acidemias: clinical management update
Purpose of review Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. Recent findings Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. Summary Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.
2016-09-26 | Improvement in the prognosis and development of patients with methylmalonic acidemia after living donor liver transplant
Abstract Liver transplant is a treatment option for patients with MMA ‐emia. While this therapy does not bring about a complete cure, it is expected to prolong survival and improve the QOL of patients. The aim of this study was to evaluate the significance of LDLT for patients with MMA ‐emia in Japan. Clinical information on 13 patients with MMA ‐emia who underwent LDLT was acquired using a self‐developed questionnaire sent to the doctors who provided medical care to patients with MMA ‐emia after LDLT . Almost all of the patients continued on a protein‐restricted diet, and the number of acidosis attacks had significantly decreased. Physical growth had recovered to within the normal range by 2.5 years after LDLT , especially in patients who underwent LDLT before the age of 1 year. The average propionyl carnitine (C3) level had significantly decreased after LDLT , and the DQs had not worsened. Liver transplant should be performed for MMA ‐emia in early life. This can be expected to maintain neurological development and improve the growth and QOL of patients. However, LDLT is not a curative treatment for MMA ‐emia. A protein‐restricted diet should be continued, and renal function should be monitored closely, with consideration of a renal transplant.
gene therapies
2021-03-10 | Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type.
Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Here, we report the generation and characterization of two new mouse models to study the role of MMACHC in vivo. CRISPR/Cas9 genome editing was used to develop a Mmachc floxed allele (Mmachcflox/flox), which we validated as a conditional null. For a gain-of-function approach, we generated a transgenic mouse line that over-expresses functional Mmachc (Mmachc-OE+/tg) capable of rescuing Mmachc homozygous mutant lethality. Surprisingly, our data also suggest that these mice may exhibit a partially penetrant maternal-effect rescue, which might have implications for in utero therapeutic interventions to treat cblC. Both the Mmachcflox/flox and Mmachc-OE+/tg mouse models will be valuable resources for understanding the biological roles of MMACHC in a variety of tissue contexts and allow for deeper understanding of the pathophysiology of cblC.
small molecules
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
2025-09-09 | 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.
2025-03-20 | CLYBL averts vitamin B12 depletion by repairing malyl-CoA.
Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed mammalian enzyme known for its role in the degradation of itaconate, a bactericidal immunometabolite produced in activated macrophages. The association of CLYBL loss of function with reduced circulating vitamin B12 levels was proposed to result from inhibition of the B12-dependent enzyme methylmalonyl-CoA mutase by itaconyl-CoA. The discrepancy between the highly inducible and locally confined production of itaconate and the broad expression profile of CLYBL across tissues suggested a role for this enzyme beyond itaconate catabolism. Here we discover that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side product of promiscuous citric acid cycle enzymes. We found that CLYBL knockout cells, accumulating malyl-CoA but not itaconyl-CoA, show decreased levels of adenosylcobalamin and that malyl-CoA is a more potent inhibitor of methylmalonyl-CoA mutase than itaconyl-CoA. Our work thus suggests that malyl-CoA plays a role in the B12 deficiency observed in individuals with CLYBL loss of function.
proteins
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.
2024-03-01 | Abstract 1766 Metabolite repair by CLYBL averts inhibition of methylmalonyl-CoA mutase
Metabolite repair is a necessary, yet understudied concept in metabolic biochemistry that strives to characterize non-canonical metabolites formed by enzymatic side activities or spontaneous reactions and the enzymes that are responsible for converting these often-toxic molecules to useful substrates. Citrate lyase beta-like protein (CLYBL) is a ubiquitously expressed, mammalian enzyme that has recently garnered attention for its role in the degradation itaconate, a highly localized metabolite that activated macrophages produce to defend against pathogens. The host cell activates itaconate to itaconyl-CoA which is then converted to citramalyl-CoA to be finally cleaved into acetyl-CoA and pyruvate by CLYBL. A loss-of-function single nucleotide polymorphism in the CLYBL gene is present in 2.7% of all human chromosomes and has been associated with low levels of circulating vitamin B12. Itaconyl-CoA is a suicide inhibitor of the B12-dependent enzyme methylmalonyl-CoA mutase (MCM); however, the highly inducible and locally confined production of itaconate makes it unlikely to be the main cause of reduced circulating B12 levels in CLYBL deficient people. We have uncovered another main physiological function of CLYBL, namely, to act as a metabolite repair enzyme to degrade a more ubiquitously formed acyl-CoA ester by promiscuity of TCA cycle enzymes that we identified using CLYBL deficient cell lines. People who harbor null CLYBL alleles cannot eliminate this damaging metabolite which we identified is a potent inhibitor of MCM, consequently depleting adenosylcobalamin. Significantly, this work establishes a molecular culprit of B12 deficiency that can form in all cell types, providing the groundwork to examine the effects of CLYBL deficiency on human health.
2018-12-05 | FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia
Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut–/–;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
2018-02-01 | New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type
Methylmalonic aciduria cblB type (MMA cblB) is caused by the impairment of ATP:cob(I)alamin adenosyltransferase (ATR), the enzyme responsible for the synthesis of adenosylcobalamin (AdoCbl) from cob(I)alamin.No definitive treatment is available for patients with this condition and novel therapeutic strategies are therefore much needed.Recently, we described a proof-of-concept regarding the use of pharmacological chaperones as a treatment.This work describes the effect of two potentialphenylacetamide) and compound VI (4-(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3yl)benzene-1,3-diol) -on six ATR mutants, including the most common, p.Arg186Trp.Comprehensive functional analysis identified destabilizing (p.Arg186Gln, p.Arg190Cys, p.Arg190His, p.Arg191Gln and p.Glu193Lys) and oligomerization (p.Arg186Trp and p.Arg191Gln) mutations.In a cellular model overexpressing the destabilizing/oligomerization mutations, compounds V and VI had a positive effect on the stability and activity of all ATR variants.When provided in combination withhydroxocobalamin a more positive effect was obtained than with the latter compounds alone, even in mutations previously described as B12 non-responsive.In addition, a normal oligomerization profile was recovered after treatment of the p.Arg186Trp mutant with both compounds.These promising results confirm MMA cblB type as a conformational disorder and hence, pharmacological chaperones as a new therapeutic option alone or in combination with hydroxocobalamin for many patients with MMA cblB.
2017-09-22 | Human MMAA induces the release of inactive cofactor and restores methylmalonyl-CoA mutase activity through their complex formation
Human mitochondrial methylmalonyl-CoA mutase (hMCM) is an isomerase that converts methylmalonyl-CoA to succinyl-CoA, a crucial step for the incorporation of some compounds derived from the diet into the central metabolism. hMCM employs highly reactive radicals from its cofactor (adenosylcobalamin, AdoCbl) to perform its reaction. Our previous work demonstrated that hMCM loses activity during catalysis and that the interaction with human MMAA (hMMAA), a GTPase protein, avoided this loss or restored hMCM activity. Even so, the mechanism by which hMMAA exerted these chaperone functions has not been described. In this work report that the formation and accumulation of OH2Cbl, the oxidized form of the AdoCbl cofactor formed during catalysis, is the cause of hMCM inactivation. Additionally, we demonstrate that the complex formation of hMCM/hMMAA decreases the rate of oxidized cofactor formation, protecting the hMCM enzyme. Moreover, an inactive model of hMCM was used to demonstrate that hMMAA is able to remove the damaged cofactor through GTP hydrolysis. Additionally, a modification in the kinetic parameters of hMCM in presence of hMMAA was observed, and for the first time, the in vivo localization of hMMAA and its colocalization with hMCM in human fibroblasts mitochondria were demonstrated.
cell therapies
2023-09-01 | Exploiting Potential Probiotic Lactic Acid Bacteria Isolated from Chlorella vulgaris Photobioreactors as Promising Vitamin B12 Producers
Lactic acid bacteria (LAB) have been documented as potential vitamin B12 producers and may constitute an exogenous source of cobalamin for the microalga Chlorella vulgaris, which has been described as being able to perform vitamin uptake. Hence, there is an interest in discovering novel B12-producing probiotic LAB. Therefore, the purpose of the current work was to perform a phenotype-genotype analysis of the vitamin B12 biosynthesis capacity of LAB isolated from C. vulgaris bioreactors, and investigate their probiotic potential. Among the selected strains, Lactococcus lactis E32, Levilactobacillus brevis G31, and Pediococcus pentosaceus L51 demonstrated vitamin B12 biosynthesis capacity, with the latter producing the highest (28.19 ± 2.27 pg mL-1). The genomic analysis confirmed the presence of pivotal genes involved in different steps of the biosynthetic pathway (hemL, cbiT, cobC, and cobD). Notably, P. pentosaceus L51 was the only strain harboring cobA, pduU, and pduV genes, which may provide evidence for the presence of the cobalamin operon. All strains demonstrated the capability to withstand harsh gastrointestinal conditions, although P. pentosaceus L51 was more resilient. The potential for de novo cobalamin biosynthesis and remarkable probiotic features highlighted that P. pentosaceus L51 may be considered the most promising candidate strain for developing high-content vitamin B12 formulations.
2019-10-01 | Perioperative characteristics and management of liver transplantation for isolated methylmalonic acidemia—the largest experience in China
There are few detailed consensus and guidelines on perioperative clinical characteristics of liver transplantation (LT) in patients with methylmalonic acidemia (MMA). This retrospective study investigated details of the clinical course and individualized treatment plan of the center with largest experience in China.A total of 7 MMA patients undergoing LT in Beijing Friendship Hospital from June 2013 to December 2017 were enrolled in the study, whose clinical data (clinical characteristics, laboratory findings, chronological changes in urine MMA levels, treatment, etc.) during perioperative period were analyzed retrospectively. All the patients received strict postoperative management.All the 7 cases were confirmed to have isolated MMA, among which, 3 cases received living donor liver transplantation (LDLT), 4 cases received deceased donor liver transplantation (DDLT). A wild fluctuate of metabolic condition was observed within the first few days after surgery and two weeks after LT, the mean base excess of blood value (BE-B) restored to normal whereas plasma bicarbonate (HCO3-) was still below normal value even with intermittent sodium bicarbonate correction. It also showed marked reduction in propionylcarnitine (C3) and C3/C2 level and the mean urine MMA by gas chromatography-mass spectrometry (GC-MS) was reduced by 81.7% (P<0.01) but remained >72× higher than upper limit of normal. The metabolism-correcting medications were administered as before. The renal function of one case with renal insufficiency before LT (serum creatinine rising) maintained stable by adjusting the immunosuppressive regimen during the observation period. All patients survive to date.LT is an effective treatment to prevent metabolic crisis, but patients with MMA tend to be metabolically fragile even after surgery. During perioperative period, close monitoring should be given for acidosis episodes so as to implement sodium bicarbonate correction. Metabolism-correcting medications are still needed. Special immunosuppressive regimen is an effective way of maintaining renal function for those with kidney dysfunction.
2019-03-21 | The Value of Liver Transplantation for Methylmalonic Acidemia
Introduction: MMA is a rare autosomal recessive disorder with the manifestation of recurrent and severe episodes of acute metabolic decompensation or a variety of long-term complications that require timely treatment. While conventional long-term medical and dietary management cannot prevent rapid progression of conditions in patients with severe complications, LT or CKLT has become an option. Methods: We reviewed the literature for MMA patients undergoing LT/CKLT published since 2006, and data on metabolic decompensation status, protein dietary, neurological damage, renal insufficiency and developmental delay before and after transplantations were compared to evaluate the clinical value of the procedure in the treatment of MMA. Results: To date, some successful LTs/CKLT procedures have prolonged survival and resulted in better quality of life in patients (lowered urine/plasma MMA levels but still much higher than normal, reduced onset of metabolic stroke, occasional improved developmental delay and relaxed protein diet), although these procedures cannot reverse neurological damage or thoroughly stop the progress of complications, such as renal dysfunction. Conclusion: LT is the only effective treatment for MMA patients with recurrent metabolic decompensation. However, it is still possible that neurological and renal damage remains irreversible. Metabolism-correcting medications should be administered even after surgery.
2016-12-01 | Methylmalonic and propionic acidemias: clinical management update
Purpose of review Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. Recent findings Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. Summary Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.
2016-09-26 | Improvement in the prognosis and development of patients with methylmalonic acidemia after living donor liver transplant
Abstract Liver transplant is a treatment option for patients with MMA ‐emia. While this therapy does not bring about a complete cure, it is expected to prolong survival and improve the QOL of patients. The aim of this study was to evaluate the significance of LDLT for patients with MMA ‐emia in Japan. Clinical information on 13 patients with MMA ‐emia who underwent LDLT was acquired using a self‐developed questionnaire sent to the doctors who provided medical care to patients with MMA ‐emia after LDLT . Almost all of the patients continued on a protein‐restricted diet, and the number of acidosis attacks had significantly decreased. Physical growth had recovered to within the normal range by 2.5 years after LDLT , especially in patients who underwent LDLT before the age of 1 year. The average propionyl carnitine (C3) level had significantly decreased after LDLT , and the DQs had not worsened. Liver transplant should be performed for MMA ‐emia in early life. This can be expected to maintain neurological development and improve the growth and QOL of patients. However, LDLT is not a curative treatment for MMA ‐emia. A protein‐restricted diet should be continued, and renal function should be monitored closely, with consideration of a renal transplant.
gene therapies
2021-03-10 | Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type.
Combined methylmalonic acidemia and homocystinuria, cblC type, is the most common inherited disorder of cobalamin metabolism and is characterized by severe fetal developmental defects primarily impacting the central nervous system, hematopoietic system, and heart. CblC was previously shown to be due to mutations in the MMACHC gene, which encodes a protein thought to function in intracellular cobalamin trafficking and biosynthesis of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl). These coenzymes are required for the production of succinyl-CoA and methionine, respectively. However, it is currently unclear whether additional roles for MMACHC exist outside of cobalamin metabolism. Furthermore, due to a lack of sufficient animal models, the exact pathophysiology of cblC remains unknown. Here, we report the generation and characterization of two new mouse models to study the role of MMACHC in vivo. CRISPR/Cas9 genome editing was used to develop a Mmachc floxed allele (Mmachcflox/flox), which we validated as a conditional null. For a gain-of-function approach, we generated a transgenic mouse line that over-expresses functional Mmachc (Mmachc-OE+/tg) capable of rescuing Mmachc homozygous mutant lethality. Surprisingly, our data also suggest that these mice may exhibit a partially penetrant maternal-effect rescue, which might have implications for in utero therapeutic interventions to treat cblC. Both the Mmachcflox/flox and Mmachc-OE+/tg mouse models will be valuable resources for understanding the biological roles of MMACHC in a variety of tissue contexts and allow for deeper understanding of the pathophysiology of cblC.
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
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. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.