RARE DISEASE
Vitamin B12-unresponsive methylmalonic acidemia type mut0
Vitamin B12-unresponsive methylmalonic acidemia type mut0
Vitamin B12-unresponsive methylmalonic acidemia type mut0
Synonyms: Complete deficiency of methylmalonyl-CoA mutase, Vitamin B12-unresponsive methylmalonic aciduria type mut0
Synonyms: Complete deficiency of methylmalonyl-CoA mutase, Vitamin B12-unresponsive methylmalonic aciduria type mut0
Synonyms: Complete deficiency of methylmalonyl-CoA mutase, Vitamin B12-unresponsive methylmalonic aciduria type mut0
Drug discovery
1
drug
With orphan designation
Overview
Vitamin B12-unresponsive methylmalonic acidemia type mut0 is a severe autosomal recessive disorder caused by complete deficiency of methylmalonyl-CoA mutase due to biallelic MUT gene mutations [1][2][9]. This inborn error of metabolism disrupts branched-chain amino acid and fatty acid catabolism, leading to toxic methylmalonic acid accumulation [7][9]. Neonatal onset (<4 weeks) is typical, with lethargy, vomiting, respiratory distress, metabolic acidosis, hyperammonemia, and hypotonia [1][5][11]. Despite aggressive management, complications include intellectual disability, metabolic strokes, cardiomyopathy, and progressive renal failure [1][4][5].
Burden
High mortality (60-88% historically), with 25% dying during initial decompensation [4][11]
80% of survivors develop chronic kidney disease; 30% experience metabolic strokes [5][13]
Median survival of 6.3 years post-transplant, with frequent hospitalizations and neurodevelopmental delays in 70% of cases [3][13]
Therapies
Protein-restricted diet with medical formulas limiting methionine, threonine, valine, and isoleucine [2][7][11]
Carnitine supplementation, antibiotics to reduce gut propionate, and emergency protocols for metabolic crises [4][13]
Liver transplantation as disease-modifying intervention despite persistent metabolite elevation [3][13]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare renal diseases, rare transplant-related disorders
Research Papers
74 drug discovery papers about Vitamin B12-unresponsive methylmalonic acidemia type mut0, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
74 drug discovery papers about Vitamin B12-unresponsive methylmalonic acidemia type mut0, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-01-27 | Kinetics of Cellular Cobalamin Uptake and Conversion: Comparison of Aquo/Hydroxocobalamin to Cyanocobalamin
Cyanocobalamin (CNCbl) and aquo/hydroxocobalamin (HOCbl) are the forms of vitamin B12 that are most commonly used for supplementation. They are both converted to methylcobalamin (MeCbl) and 5′-deoxyadenosylcobalamin (AdoCbl), which metabolize homocysteine and methylmalonic acid, respectively. Here, we compare the kinetics of uptake and the intracellular transformations of radiolabeled CNCbl vs. HOCbl in HeLa cells. More HOCbl was accumulated over 4–48 h, but further extrapolation indicated similar uptake (>90%) for both vitamin forms. The initially synthesized coenzyme was MeCbl, which noticeably exceeded AdoCbl during 48 h. Yet, the synthesis of AdoCbl accelerated, and the predicted final levels of Cbls were MeCbl ≈ AdoCbl ≈ 40% and HOCbl ≈ 20%. The designed kinetic model revealed the same patterns of the uptake and turnover for CNCbl and HOCbl, apart from two steps. First, the “activating” intracellular processing of the internalized HOCbl was six-fold faster. Second, the detachment rates from the cell surface (when the “excessive” Cbl-molecules were refluxed into the external medium) related as 4:1 for CNCbl vs. HOCbl. This gave a two-fold faster cellular accumulation and processing of HOCbl vs. CNCbl. In medical terms, our data suggest (i) an earlier response to the treatment of Cbl-deficiency with HOCbl, and (ii) the manifestation of a successful treatment initially as a decrease in homocysteine.
2024-01-10 | Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA. Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up. Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14–77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97–2569) before treatment to 103 µmol/L (range 97–171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of – 41% (range − 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated. In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients. ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
2023-03-23 | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B 12 delivery and repair.
G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. MMAA, a G-protein motor, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B 12 -dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the motor assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nanomotor assembly, which reveals a dramatic 180° rotation of the B 12 domain, exposing it to solvent. The nanomotor complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the newly identified MMAA-MMUT interfaces.
2022-11-04 | Management of methylmalonic acidemia (MMA) with N-carbamylglutamate: A case report from Italy.
Methylmalonic acidemia (MMA) is an inborn error of metabolism whose optimal management, especially in the long-term remains to be established.We describe the case of a child with MMA mut0 who was in a cycle of episodes of decompensation and hospitalization when we started to use carglumic acid (CA), a well-known adjunctive therapy to standard care for the treatment of acute hyperammonemia due to MMA.Using the lowest effective therapeutic dose of CA and adjusting the patient's diet with caloric and protein intake adequate for her age and pathology, we managed to keep ammonium levels within the normal range, and to ensure a normal growth pattern.The present case adds further confirmation of the long-term management of MMA using CA, focusing on the long duration of follow up and on the use of a lower dose of CA in real life settings.
2022-01-29 | Integrated multi-omics reveals anaplerotic insufficiency in methylmalonyl-CoA mutase deficiency
Abstract Multi-layered omics approaches can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of inherited diseases beyond identifying their monogenic cause 1 . We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria (MMA). We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (177/210) of affected individuals, the majority (148) of whom had pathogenic variants in methylmalonyl-CoA mutase ( MMUT ). Untargeted analysis of all three omics layers revealed dysregulation of the TCA cycle and surrounding metabolic pathways, a finding that was further corroborated by multi-organ metabolomics of a hemizygous Mmut mouse model. Integration of phenotypic disease severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase, two proteins involved in glutamine anaplerosis of the TCA cycle. The relevance of disturbances in this pathway was supported by metabolomics and isotope tracing studies which showed decreased glutamine-derived anaplerosis in MMA. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase complex components and glutamate dehydrogenase providing evidence for a multi-protein metabolon that orchestrates TCA cycle anaplerosis. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA. Take home message Combination of integrative multi-omics technologies with clinical and biochemical features leads to an increased diagnostic rate compared to genome sequencing alone and identifies anaplerotic rewiring as a targetable feature of the rare inborn error of metabolism methylmalonic aciduria. Graphical abstract
cell therapies
2022-10-03 | 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.
2020-01-22 | Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature
New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke-like-events. Since calcineurin inhibitors (CNIs) are a well-known cause of new neurological symptoms in non-MMA transplanted patients, we investigated the incidence of CNI-induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post-transplanted MMA patients.We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post-transplanted MMA patients and determined if CNI-induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI-induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI-induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)-scan post-transplantation.Our two MMA patients both developed CNI-induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow-up was reported in 54 of them, of which 24 were excluded from analysis since no anti-rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post-transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post-transplanted MMA patients on CNI.In MMA post-transplanted patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered. Early recognition of CNI-induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome.In all post-transplanted MMA patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.
2019-12-02 | Intrahepatic Administration of Human Liver Stem Cells in Infants with Inherited Neonatal-Onset Hyperammonemia: A Phase I Study
Abstract Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01–11, EudraCT-No. 2012–002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.
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.
2019-04-02 | 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.
oligonucleotides
2019-02-22 | Messenger RNA therapy for rare genetic metabolic diseases
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
small molecules
2024-01-27 | Kinetics of Cellular Cobalamin Uptake and Conversion: Comparison of Aquo/Hydroxocobalamin to Cyanocobalamin
Cyanocobalamin (CNCbl) and aquo/hydroxocobalamin (HOCbl) are the forms of vitamin B12 that are most commonly used for supplementation. They are both converted to methylcobalamin (MeCbl) and 5′-deoxyadenosylcobalamin (AdoCbl), which metabolize homocysteine and methylmalonic acid, respectively. Here, we compare the kinetics of uptake and the intracellular transformations of radiolabeled CNCbl vs. HOCbl in HeLa cells. More HOCbl was accumulated over 4–48 h, but further extrapolation indicated similar uptake (>90%) for both vitamin forms. The initially synthesized coenzyme was MeCbl, which noticeably exceeded AdoCbl during 48 h. Yet, the synthesis of AdoCbl accelerated, and the predicted final levels of Cbls were MeCbl ≈ AdoCbl ≈ 40% and HOCbl ≈ 20%. The designed kinetic model revealed the same patterns of the uptake and turnover for CNCbl and HOCbl, apart from two steps. First, the “activating” intracellular processing of the internalized HOCbl was six-fold faster. Second, the detachment rates from the cell surface (when the “excessive” Cbl-molecules were refluxed into the external medium) related as 4:1 for CNCbl vs. HOCbl. This gave a two-fold faster cellular accumulation and processing of HOCbl vs. CNCbl. In medical terms, our data suggest (i) an earlier response to the treatment of Cbl-deficiency with HOCbl, and (ii) the manifestation of a successful treatment initially as a decrease in homocysteine.
2024-01-10 | Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA. Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up. Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14–77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97–2569) before treatment to 103 µmol/L (range 97–171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of – 41% (range − 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated. In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients. ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
2023-03-23 | Architecture of the human G-protein-methylmalonyl-CoA mutase nanoassembly for B 12 delivery and repair.
G-proteins function as molecular switches to power cofactor translocation and confer fidelity in metal trafficking. MMAA, a G-protein motor, together with MMAB, an adenosyltransferase, orchestrate cofactor delivery and repair of B 12 -dependent human methylmalonyl-CoA mutase (MMUT). The mechanism by which the motor assembles and moves a >1300 Da cargo, or fails in disease, are poorly understood. Herein, we report the crystal structure of the human MMUT-MMAA nanomotor assembly, which reveals a dramatic 180° rotation of the B 12 domain, exposing it to solvent. The nanomotor complex, stabilized by MMAA wedging between two MMUT domains, leads to ordering of the switch I and III loops, revealing the molecular basis of mutase-dependent GTPase activation. The structure explains the biochemical penalties incurred by methylmalonic aciduria-causing mutations that reside at the newly identified MMAA-MMUT interfaces.
2022-11-04 | Management of methylmalonic acidemia (MMA) with N-carbamylglutamate: A case report from Italy.
Methylmalonic acidemia (MMA) is an inborn error of metabolism whose optimal management, especially in the long-term remains to be established.We describe the case of a child with MMA mut0 who was in a cycle of episodes of decompensation and hospitalization when we started to use carglumic acid (CA), a well-known adjunctive therapy to standard care for the treatment of acute hyperammonemia due to MMA.Using the lowest effective therapeutic dose of CA and adjusting the patient's diet with caloric and protein intake adequate for her age and pathology, we managed to keep ammonium levels within the normal range, and to ensure a normal growth pattern.The present case adds further confirmation of the long-term management of MMA using CA, focusing on the long duration of follow up and on the use of a lower dose of CA in real life settings.
2022-01-29 | Integrated multi-omics reveals anaplerotic insufficiency in methylmalonyl-CoA mutase deficiency
Abstract Multi-layered omics approaches can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of inherited diseases beyond identifying their monogenic cause 1 . We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria (MMA). We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (177/210) of affected individuals, the majority (148) of whom had pathogenic variants in methylmalonyl-CoA mutase ( MMUT ). Untargeted analysis of all three omics layers revealed dysregulation of the TCA cycle and surrounding metabolic pathways, a finding that was further corroborated by multi-organ metabolomics of a hemizygous Mmut mouse model. Integration of phenotypic disease severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase, two proteins involved in glutamine anaplerosis of the TCA cycle. The relevance of disturbances in this pathway was supported by metabolomics and isotope tracing studies which showed decreased glutamine-derived anaplerosis in MMA. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase complex components and glutamate dehydrogenase providing evidence for a multi-protein metabolon that orchestrates TCA cycle anaplerosis. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA. Take home message Combination of integrative multi-omics technologies with clinical and biochemical features leads to an increased diagnostic rate compared to genome sequencing alone and identifies anaplerotic rewiring as a targetable feature of the rare inborn error of metabolism methylmalonic aciduria. Graphical abstract
cell therapies
2022-10-03 | 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.
2020-01-22 | Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature
New neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke-like-events. Since calcineurin inhibitors (CNIs) are a well-known cause of new neurological symptoms in non-MMA transplanted patients, we investigated the incidence of CNI-induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post-transplanted MMA patients.We report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post-transplanted MMA patients and determined if CNI-induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI-induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI-induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)-scan post-transplantation.Our two MMA patients both developed CNI-induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow-up was reported in 54 of them, of which 24 were excluded from analysis since no anti-rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post-transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post-transplanted MMA patients on CNI.In MMA post-transplanted patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered. Early recognition of CNI-induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome.In all post-transplanted MMA patients with new neurological symptoms CNI-induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.
2019-12-02 | Intrahepatic Administration of Human Liver Stem Cells in Infants with Inherited Neonatal-Onset Hyperammonemia: A Phase I Study
Abstract Previous studies have shown that human liver stem-like cells (HLSCs) may undergo differentiation in vitro into urea producing hepatocytes and in vivo may sustain liver function in models of experimentally induced acute liver injury. The aim of this study was to assess the safety of HLSCs intrahepatic administration in inherited neonatal-onset hyperammonemia. The study was approved by the Agenzia Italiana del Farmaco on favorable opinion of the Italian Institute of Health as an open-label, prospective, uncontrolled, monocentric Phase I study (HLSC 01–11, EudraCT-No. 2012–002120-33). Three patients affected by argininosuccinic aciduria (patient 1) and methylmalonic acidemia (patients 2 and 3) and included in the liver transplantation list were enrolled. In all patients, HLSCs were administered by percutaneous intrahepatic injections (once a week for two consecutive weeks) within the first months of life. The first patient received 125,000 HLSCs x gram of liver/dose while the other two patients received twice this dose. No immunosuppression was administered since HLSCs possess immunomodulatory activities. None of the patients experienced infections, hyperammonemia decompensation, or other adverse events during the whole observation period. No donor specific antibodies (DSA) against HLSCs were detected. Patients were metabolic stable despite an increase (~30%) in protein intake. Two patients underwent liver transplantation after 19 and 11 months respectively, and after explantation, the native livers showed no histological alterations. In conclusion, percutaneous intrahepatic administration of HLSCs was safe in newborn with inherited neonatal-onset hyperammonemia. These data pave the way for Phase II studies in selected inherited and acquired liver disorders.
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.
2019-04-02 | 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.
oligonucleotides
2019-02-22 | Messenger RNA therapy for rare genetic metabolic diseases
Decades of intense research in molecular biology and biochemistry are fructifying in the emergence of therapeutic messenger RNAs (mRNA) as a new class of drugs. Synthetic mRNAs can be sequence optimised to improve translatability into proteins, as well as chemically modified to reduce immunogenicity and increase chemical stability using naturally occurring uridine modifications. These structural improvements, together with the development of safe and efficient vehicles that preserve mRNA integrity in circulation and allow targeted intracellular delivery, have paved the way for mRNA-based therapeutics. Indeed, mRNAs formulated into biodegradable lipid nanoparticles are currently being tested in preclinical and clinical studies for multiple diseases including cancer immunotherapy and vaccination for infectious diseases. An emerging application of mRNAs is the supplementation of proteins that are not expressed or are not functional in a regulated and tissue-specific manner. This so-called ‘protein replacement therapy’ could represent a solution for genetic metabolic diseases currently lacking effective treatments. Here we summarise this new class of drugs and discuss the preclinical evidence supporting the potential of liver-mediated mRNA therapy for three rare genetic conditions: methylmalonic acidaemia, acute intermittent porphyria and ornithine transcarbamylase deficiency.
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Drug Discovery Landscape
1 orphan drug designation for Vitamin B12-unresponsive methylmalonic acidemia type mut0.
1 orphan drug designation for Vitamin B12-unresponsive methylmalonic acidemia type mut0.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
messanger ribonucleic acid (mRNA)-based therapeutic agent encoding human methylmalonyl-coenzyme A mutase | RNAs | FDA | Moderna Therapeutics, Inc. |
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