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:
categories:
Small molecules
small molecules
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.
2025-07-06 | Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism
Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8-/-;acadsb-/- double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb-/- and mmut-/- survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.
gene therapies
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.
2022-09-13 | Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia.
Hereditary methylmalonic acidemia (MMA) caused by deficiency of the enzyme methylmalonyl-CoA mutase (MMUT) is a relatively common and severe organic acidemia. The recalcitrant nature of the condition to conventional dietary and medical management has led to the use of elective liver and combined liver-kidney transplantation in some patients. However, liver transplantation is intrinsically limited by organ availability, the risks of surgery, procedural and life-long management costs, transplant comorbidities, and a remaining underlying risk of complications related to MMA despite transplantation. Here, we review pre-clinical studies that present alternative approaches to solid organ transplantation as a treatment for MMUT MMA, including adeno-associated viral gene addition therapy, mRNA therapy, and genome editing, with and without nuclease enhancement.
2022-05-27 | Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin.
Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.
2019-10-01 | Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future
Methylmalonic acidemia (MMA) is a severe, and sometimes lethal, monogenic metabolic disorder in need of improved treatments. A number of new genomic therapies, which include canonical adeno-associated virus gene addition, genome editing, and systemic mRNA therapy, have shown great promise in murine models of MMA. Each approach has unique advantages and disadvantages for treating genetic disorders like MMA. This article reviews traditional viral gene therapy experiments that have provided enabling proof of concept studies in animal models, and newer approaches that may emerge as effective treatments for MMA and related disorders of organic acid metabolism.
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.
cell therapies
2022-11-01 | Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis
Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear. In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mut0-type MMAemia, one patient had a mut−-type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0–15.1 years). Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 μmol/L) was 7.8-fold higher than in LTx (176 ± 103 μmol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 ± 110 μmol/L; P < 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 m2, in LTx 99.8 ± 29.9 mL/min/1.73 m2, and in LKTx 31.5 ± 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 m2; P = 0.0403). In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.
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.
2019-04-11 | Kidney disease and organ transplantation in methylmalonic acidaemia
Abstract Objectives MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre‐, peri‐, and post‐transplant course of all children with MMA who underwent liver or combined liver‐kidney transplant in our centers. Design and methods Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. Results Five children with MMA underwent liver transplant (4/5) and combined liver‐kidney transplant (1/5). Three were Mut 0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post‐transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine‐based GFR formula. We noticed in 2 patients a big discrepancy between creatinine‐ and cystatin C‐based GFR calculations. One patient with no renal disease developed renal failure post–liver transplantation. Serum MMA levels have decreased in all to <300 μmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post‐transplant. Conclusions MMA is a complex metabolic disorder. Renal disease can continue to progress post–liver transplant and close follow‐up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post‐transplant can halt the progression of renal disease remains unclear.
2019-04-02 | Methylmalonic acidemia/propionic acidemia – the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups
Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016.During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07).MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.
2018-12-01 | Successful perioperative management of living-donor liver transplantation for a patient with severe methylmalonic acidemia: a case report
Methylmalonic acidemia (MMAemia) is a rare hereditary disease affecting organic acid metabolism. It causes recurrent metabolic acidosis and secondary mitochondrial dysfunction, resulting in a poor prognosis. Liver transplantation (LT) has been performed to facilitate the metabolism of organic acids and improve the prognosis of MMAemia. However, there have been few reports on perioperative management of LT. A 22-month-old female with severe MMAemia was scheduled to receive LT to relieve recurrent metabolic acidosis despite dietary and pharmacological treatment. General anesthesia was maintained without propofol or nitrous oxide, which can worsen MMAemia-induced metabolic acidosis during anesthesia for LT. Strict metabolic and respiratory management enabled the operation to be successfully performed without metabolic acidosis. Perioperative management of LT for MMAemia is challenging for anesthesiologists because of the possibility of serious metabolic acidosis. We succeeded in preventing metabolic decompensation by avoiding the use of propofol and nitrous oxide.
proteins
2025-07-02 | MIS-C, inherited metabolic diseases and methylmalonic acidemia: a case report and review of the literature.
Methylmalonic acidemia (MMA) secondary to mutase deficiency, mut0, is an inborn error of metabolism causing complete enzyme defect, allowing a high risk of irreversible complications, secondary to metabolic decompensation, induced by infections and the hyperinflammatory state. Multisystem Inflammatory Syndrome in Children (MIS-C) is a hyperinflammatory syndrome that manifests 14-60 days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients aged < 21 years. Only a few cases of patients with inherited metabolic diseases (IMD) and MIS-C are described. However, to our knowledge, this is the first case of MMA with MIS-C. We describe a 2-year-old child with MMA secondary to mutase deficiency, carrying the homozygous mutation c.2179 C > T of MMUT gene, associated to mut0 phenotype. One month after SARS-CoV-2 infection, he presented fever, rash, significant increase of C-reactive protein (CRP), ferritin, triglycerides, interleukin (IL)-6, N-terminal fragment of the pro brain natriuretic peptide (NT-pro-BNP), compatible with the diagnosis of MIS-C. He was treated with intravenous immunoglobulins and methylprednisolone, with rapid clinical improvement. Ten days later, he showed the worsening of clinical and hematological parameters, associated with anemia, thrombocytopenia, metabolic acidosis, hyperlactatemia, increased urinary methylmalonic acid, leading to multiorgan failure (MOF). He was treated with high caloric intake nutrition by intravenous carbohydrates infusion; sodium bicarbonate, thiamine, carnitine, coenzyme Q, vitamin C, antibiotics, methylprednisolone and anakinra. Three days after the start of anakinra, a significant improvement in clinical and biochemical parameters occurred. Twenty days later, a sepsis from Methicillin-resistant Staphylococcus Aureus and Candida Albicans required the interruption of anakinra, with the decline of the clinical conditions and the exitus. In patients with a severe form of MMA and MIS-C anakinra is a safe treatment. MOF and metabolic decompensation, secondary to the hyperinflammatory state typical of MIS-C, can be successfully treated with targeted therapy against proinflammatory cytokines. The description of these clinical cases is a precious lesson in managing IMD therapeutic emergencies. Paediatricians must provide a strict monitoring of metabolic compensation, to avoid irreversible complications.
2024-09-27 | CLYBL averts methylmalonyl-CoA mutase inhibition and loss of vitamin B12 by eliminating 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 (MCM) 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. We discovered that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side-product of promiscuous TCA 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 MCM 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.
2024-03-16 | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria
Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a novel human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we further expose an altered state of excitability, which we suggest may be connected to metabolic rewiring which is exacerbated by application of 2-dimethyloxoglutrate. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.
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.
2021-05-12 | Methylmalonyl acidemia: from mitochondrial metabolism to defective mitophagy and disease.
Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of metabolism due to the deficiency of mitochondrial MMUT (methylmalonyl-CoA mutase) - an enzyme that mediates the cellular breakdown of certain amino acids and lipids. The loss of MMUT leads to the accumulation of toxic organic acids causing severe organ dysfunctions and life-threatening complications. The mechanisms linking MMUT deficiency, mitochondrial alterations and cell toxicity remain uncharacterized. Using cell and animal-based models, we recently unveiled that MMUT deficiency impedes the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, thereby halting their delivery and subsequent degradation by macroautophagy/autophagy-lysosome systems. In turn, this defective mitophagy process instigates the accumulation of dysfunctional mitochondria that spark epithelial distress and tissue damage. Correction of PINK1-directed mitophagy defects or mitochondrial dysfunctions rescues epithelial distress in MMA cells and alleviates disease-relevant phenotypes in mmut‒deficient zebrafish. Our findings suggest a link between primary MMUT deficiency and diseased mitochondria, mitophagy dysfunction and cell distress, offering potential therapeutic perspectives for MMA and other metabolic diseases.
small molecules
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.
2025-07-06 | Metabolic rerouting of valine and isoleucine oxidation increases survival in zebrafish models of disorders of propionyl-CoA metabolism
Branched-chain amino acid (BCAA) oxidation is a multistep process leading to the formation of acetyl-CoA and propionyl-CoA. The syndromes associated with disturbed BCAA oxidation are clinically and biochemically heterogenous. While the common organic acidemias, propionic (PA) and methylmalonic acidemia (MMA), arise from deficient activity of propionyl-CoA carboxylase and methylmalonyl-CoA mutase and are life-threatening conditions with limited treatment options, isobutyryl-CoA dehydrogenase (IBD), and 2-methylbutyryl-CoA dehydrogenase (2-MBD) deficiencies manifest as biochemical traits, with no associated symptoms or consistent metabolic phenotypes. To assess whether the proximal interruption of valine and isoleucine oxidation might represent an approach to treat MMA and PA, we investigated the effects of loss of function of acad8 (encoding IBD) and acadsb (encoding 2-MBD), singly and doubly, on biochemical and morphological findings of zebrafish models of pccb-related propionic acidemia (PA) and mmut methylmalonic acidemia (MMA). Although acad8-/-;acadsb-/- double mutants showed growth failure and early mortality, the proximal interruption of valine and isoleucine oxidation in double (pccb/acad8, pccb/acadsb, mmut/acad8, mmut/acadsb) and triple (pccb/acad8/acadsb, mmut/acad8/acadsb) homozygous mutants improved pccb-/- and mmut-/- survival and reduced propionate-derived toxic metabolites, supporting the rationale for pursuing modulation of IBD and 2-MBD activity as a strategy to reduce the metabolic load and improve clinical outcomes in PA and MMA.
gene therapies
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.
2022-09-13 | Treatment of metabolic disorders using genomic technologies: Lessons from methylmalonic acidemia.
Hereditary methylmalonic acidemia (MMA) caused by deficiency of the enzyme methylmalonyl-CoA mutase (MMUT) is a relatively common and severe organic acidemia. The recalcitrant nature of the condition to conventional dietary and medical management has led to the use of elective liver and combined liver-kidney transplantation in some patients. However, liver transplantation is intrinsically limited by organ availability, the risks of surgery, procedural and life-long management costs, transplant comorbidities, and a remaining underlying risk of complications related to MMA despite transplantation. Here, we review pre-clinical studies that present alternative approaches to solid organ transplantation as a treatment for MMUT MMA, including adeno-associated viral gene addition therapy, mRNA therapy, and genome editing, with and without nuclease enhancement.
2022-05-27 | Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin.
Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.
2019-10-01 | Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future
Methylmalonic acidemia (MMA) is a severe, and sometimes lethal, monogenic metabolic disorder in need of improved treatments. A number of new genomic therapies, which include canonical adeno-associated virus gene addition, genome editing, and systemic mRNA therapy, have shown great promise in murine models of MMA. Each approach has unique advantages and disadvantages for treating genetic disorders like MMA. This article reviews traditional viral gene therapy experiments that have provided enabling proof of concept studies in animal models, and newer approaches that may emerge as effective treatments for MMA and related disorders of organic acid metabolism.
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.
cell therapies
2022-11-01 | Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis
Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear. In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mut0-type MMAemia, one patient had a mut−-type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0–15.1 years). Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 μmol/L) was 7.8-fold higher than in LTx (176 ± 103 μmol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 ± 110 μmol/L; P < 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 m2, in LTx 99.8 ± 29.9 mL/min/1.73 m2, and in LKTx 31.5 ± 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 m2; P = 0.0403). In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.
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.
2019-04-11 | Kidney disease and organ transplantation in methylmalonic acidaemia
Abstract Objectives MMA is associated with chronic tubulointerstitial nephritis and a progressive decline in GFR. Optimal management of these children is uncertain. Our objectives were to document the pre‐, peri‐, and post‐transplant course of all children with MMA who underwent liver or combined liver‐kidney transplant in our centers. Design and methods Retrospective chart review of all cases of MMA who underwent organ transplantation over the last 10 years. Results Five children with MMA underwent liver transplant (4/5) and combined liver‐kidney transplant (1/5). Three were Mut 0 and two had a cobalamin B disorder. Four of five were transplanted between ages 3 and 5 years. Renal dysfunction prior to transplant was seen in 2/5 patients. Post‐transplant (one liver transplant and one combined transplant) renal function improved slightly when using creatinine‐based GFR formula. We noticed in 2 patients a big discrepancy between creatinine‐ and cystatin C‐based GFR calculations. One patient with no renal disease developed renal failure post–liver transplantation. Serum MMA levels have decreased in all to <300 μmol/L. Four patients remain on low protein diet, carnitine, coenzyme Q, and vitamin E post‐transplant. Conclusions MMA is a complex metabolic disorder. Renal disease can continue to progress post–liver transplant and close follow‐up is warranted. More research is needed to clarify best screening GFR method in patients with MMA. Whether liver transplant alone, continued protein restriction, or the addition of antioxidants post‐transplant can halt the progression of renal disease remains unclear.
2019-04-02 | Methylmalonic acidemia/propionic acidemia – the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups
Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016.During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07).MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.
2018-12-01 | Successful perioperative management of living-donor liver transplantation for a patient with severe methylmalonic acidemia: a case report
Methylmalonic acidemia (MMAemia) is a rare hereditary disease affecting organic acid metabolism. It causes recurrent metabolic acidosis and secondary mitochondrial dysfunction, resulting in a poor prognosis. Liver transplantation (LT) has been performed to facilitate the metabolism of organic acids and improve the prognosis of MMAemia. However, there have been few reports on perioperative management of LT. A 22-month-old female with severe MMAemia was scheduled to receive LT to relieve recurrent metabolic acidosis despite dietary and pharmacological treatment. General anesthesia was maintained without propofol or nitrous oxide, which can worsen MMAemia-induced metabolic acidosis during anesthesia for LT. Strict metabolic and respiratory management enabled the operation to be successfully performed without metabolic acidosis. Perioperative management of LT for MMAemia is challenging for anesthesiologists because of the possibility of serious metabolic acidosis. We succeeded in preventing metabolic decompensation by avoiding the use of propofol and nitrous oxide.
proteins
2025-07-02 | MIS-C, inherited metabolic diseases and methylmalonic acidemia: a case report and review of the literature.
Methylmalonic acidemia (MMA) secondary to mutase deficiency, mut0, is an inborn error of metabolism causing complete enzyme defect, allowing a high risk of irreversible complications, secondary to metabolic decompensation, induced by infections and the hyperinflammatory state. Multisystem Inflammatory Syndrome in Children (MIS-C) is a hyperinflammatory syndrome that manifests 14-60 days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients aged < 21 years. Only a few cases of patients with inherited metabolic diseases (IMD) and MIS-C are described. However, to our knowledge, this is the first case of MMA with MIS-C. We describe a 2-year-old child with MMA secondary to mutase deficiency, carrying the homozygous mutation c.2179 C > T of MMUT gene, associated to mut0 phenotype. One month after SARS-CoV-2 infection, he presented fever, rash, significant increase of C-reactive protein (CRP), ferritin, triglycerides, interleukin (IL)-6, N-terminal fragment of the pro brain natriuretic peptide (NT-pro-BNP), compatible with the diagnosis of MIS-C. He was treated with intravenous immunoglobulins and methylprednisolone, with rapid clinical improvement. Ten days later, he showed the worsening of clinical and hematological parameters, associated with anemia, thrombocytopenia, metabolic acidosis, hyperlactatemia, increased urinary methylmalonic acid, leading to multiorgan failure (MOF). He was treated with high caloric intake nutrition by intravenous carbohydrates infusion; sodium bicarbonate, thiamine, carnitine, coenzyme Q, vitamin C, antibiotics, methylprednisolone and anakinra. Three days after the start of anakinra, a significant improvement in clinical and biochemical parameters occurred. Twenty days later, a sepsis from Methicillin-resistant Staphylococcus Aureus and Candida Albicans required the interruption of anakinra, with the decline of the clinical conditions and the exitus. In patients with a severe form of MMA and MIS-C anakinra is a safe treatment. MOF and metabolic decompensation, secondary to the hyperinflammatory state typical of MIS-C, can be successfully treated with targeted therapy against proinflammatory cytokines. The description of these clinical cases is a precious lesson in managing IMD therapeutic emergencies. Paediatricians must provide a strict monitoring of metabolic compensation, to avoid irreversible complications.
2024-09-27 | CLYBL averts methylmalonyl-CoA mutase inhibition and loss of vitamin B12 by eliminating 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 (MCM) 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. We discovered that CLYBL additionally functions as a metabolite repair enzyme for malyl-CoA, a side-product of promiscuous TCA 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 MCM 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.
2024-03-16 | Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria
Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a novel human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we further expose an altered state of excitability, which we suggest may be connected to metabolic rewiring which is exacerbated by application of 2-dimethyloxoglutrate. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.
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.
2021-05-12 | Methylmalonyl acidemia: from mitochondrial metabolism to defective mitophagy and disease.
Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of metabolism due to the deficiency of mitochondrial MMUT (methylmalonyl-CoA mutase) - an enzyme that mediates the cellular breakdown of certain amino acids and lipids. The loss of MMUT leads to the accumulation of toxic organic acids causing severe organ dysfunctions and life-threatening complications. The mechanisms linking MMUT deficiency, mitochondrial alterations and cell toxicity remain uncharacterized. Using cell and animal-based models, we recently unveiled that MMUT deficiency impedes the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, thereby halting their delivery and subsequent degradation by macroautophagy/autophagy-lysosome systems. In turn, this defective mitophagy process instigates the accumulation of dysfunctional mitochondria that spark epithelial distress and tissue damage. Correction of PINK1-directed mitophagy defects or mitochondrial dysfunctions rescues epithelial distress in MMA cells and alleviates disease-relevant phenotypes in mmut‒deficient zebrafish. Our findings suggest a link between primary MMUT deficiency and diseased mitochondria, mitophagy dysfunction and cell distress, offering potential therapeutic perspectives for MMA and other metabolic diseases.
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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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