Methylmalonic acidemia/propionic acidemia - the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups.
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SUBMITTER: Chu TH
PROVIDER: S-EPMC6444613 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Methylmalonic acidemia/propionic acidemia - the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups.
Chu Tzu-Hung TH Chien Yin-Hsiu YH Lin Hsiang-Yu HY Liao Hsuan-Chieh HC Ho Huey-Jane HJ Lai Chih-Jou CJ Chiang Chuan-Chi CC Lin Niang-Cheng NC Yang Chia-Feng CF Hwu Wuh-Liang WL Lee Ni-Chung NC Lin Shuan-Pei SP Liu Chin-Su CS Hu Rey-Heng RH Ho Ming-Chih MC Niu Dau-Ming DM
Orphanet journal of rare diseases 20190402 1
<h4>Background</h4>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.<h4>Results</h4>During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1 ...[more]
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Project description:BackgroundOrganic acidemias, especially propionic acidemia (PA) and methylmalonic acidemia (MMA), may manifest clinically within the first few hours to days of life. The classic presentation in the newborn period includes metabolic acidosis, hyperlactatemia, and hyperammonemia that is precipitated by unrestricted protein intake. Implementation of newborn screening to diagnose and initiate early treatment has facilitated a reduction in neonatal mortality and improved survival. Despite early diagnosis and appropriate management, these individuals are prone to have recurrent episodes of metabolic acidosis and hyperammonemia resulting in frequent hospitalizations. Liver transplantation (LT) has been proposed as a treatment modality to reduce metabolic decompensations which are not controlled by medical management. Published reports on the outcome of LT show heterogeneous results regarding clinical and biochemical features in the post transplantation period. As a result, we evaluated the outcomes of LT in our institution and compared it to the previously published data.Study design/methodsWe performed a retrospective chart review of nine individuals with PA or MMA who underwent LT and two individuals with MMA who underwent LT and kidney transplantation (KT). Data including number of hospitalizations, laboratory measures, cardiac and neurological outcomes, dietary protein intake, and growth parameters were collected.ResultsThe median age of transplantation for subjects with MMA was 7.2 years with a median follow up of 4.3 years. The median age of transplantation for subjects with PA was 1.9 years with a median follow up of 5.4 years. The survival rate at 1 year and 5 years post-LT was 100%. Most of our subjects did not have any episodes of hyperammonemia or pancreatitis post-LT. There was significant reduction in plasma glycine post-LT. One subject developed mild elevation in ammonia post-LT on an unrestricted protein diet, suggesting that protein restriction may be indicated even after LT.ConclusionIn a large single center study of LT in MMA and PA, we show that LT may reduce the incidence of metabolic decompensation. Moreover, our data suggest that LT may be associated with reduced number of hospitalizations and improved linear growth in individuals with PA and MMA.
| S-EPMC6898966 | biostudies-literature
Project description:Propionic acidemia (PA) and methylmalonic acidemia (MMA) are autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, which are caused by a deficiency in the enzyme propionyl-CoA carboxylase or the enzyme methylmalonyl-CoA (MM-CoA) mutase, respectively. The functional consequence of PA or MMA is the inability to catabolize P-CoA to MM-CoA or MM-CoA to succinyl-CoA, resulting in the accumulation of P-CoA and other metabolic intermediates, such as propionylcarnitine (C3), 3-hydroxypropionic acid, methylcitric acid (MCA), and methylmalonic acid (only in MMA). P-CoA and its metabolic intermediates, at high concentrations found in PA and MMA, inhibit enzymes in the first steps of the urea cycle as well as enzymes in the tricarboxylic acid (TCA) cycle, causing a reduction in mitochondrial energy production. We previously showed that metabolic defects of PA could be recapitulated using PA patient-derived primary hepatocytes in a novel organotypic system. Here, we sought to investigate whether treatment of normal human primary hepatocytes with propionate would recapitulate some of the biochemical features of PA and MMA in the same platform. We found that high levels of propionate resulted in high levels of intracellular P-CoA in normal hepatocytes. Analysis of TCA cycle intermediates by GC-MS/MS indicated that propionate may inhibit enzymes of the TCA cycle as shown in PA, but is also incorporated in the TCA cycle, which does not occur in PA. To better recapitulate the disease phenotype, we obtained hepatocytes derived from livers of PA and MMA patients. We characterized the PA and MMA donors by measuring key proximal biomarkers, including P-CoA, MM-CoA, as well as clinical biomarkers propionylcarnitine-to-acetylcarnitine ratios (C3/C2), MCA, and methylmalonic acid. Additionally, we used isotopically-labeled amino acids to investigate the contribution of relevant amino acids to production of P-CoA in models of metabolic stability or acute metabolic crisis. As observed clinically, we demonstrated that the isoleucine and valine catabolism pathways are the greatest sources of P-CoA in PA and MMA donor cells and that each donor showed differential sensitivity to isoleucine and valine. We also studied the effects of disodium citrate, an anaplerotic therapy, which resulted in a significant increase in the absolute concentration of TCA cycle intermediates, which is in agreement with the benefit observed clinically. Our human cell-based PA and MMA disease models can inform preclinical drug discovery and development where mouse models of these diseases are inaccurate, particularly in well-described species differences in branched-chain amino acid catabolism.
| S-EPMC7337260 | biostudies-literature
Project description:IntroductionThis pilot study assessed instruments measuring relatively discrete neuropsychological domains to inform the selection of clinical outcome assessments that may be considered for interventional trials in methylmalonic acidemia (MMA) and propionic acidemia (PA).MethodsTests and questionnaires were selected for their possible relevance to MMA and PA and potential sensitivity to modest changes in functioning and behavior.ResultsTwenty-one patients (<18 years, n = 10;>18 years, n = 11) and/or their caregivers responded to video interviews and paper tests. Language deficits and significant motor deficits in some participants impacted scoring, especially in the verbal and processing speed sections of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV). However, all participants ≥12 years of age were able to complete the Cookie Theft Picture Task. Thus, verbal discourse remains a potentially useful endpoint for participants in this age group. The Vineland Adaptive Behavior Scales (VABS-3) Adaptive Behavior Composite and Communication Scores confirmed delayed or immature functioning in day-to-day activities in these participants. Significant motor deficits prevented completion of some tests. Computerized processing speed tasks, which require pressing a button or tapping a computer screen, may be easier than writing or checking off boxes on paper in this cohort. Sleep characteristics among MMA participants were within normative ranges of the Child and Adolescent Sleep Checklist (CASC), indicating that this measurement would not provide valuable data in a clinical trial. Despite their challenges, responses to the Metabolic Quality of Life Questionnaire indicated these patients and their caregivers perceive an overall high quality of life.ConclusionOverall, test and questionnaire results were notably different between participants with MMA and participants with PA. The study demonstrates that pilot studies can detect instruments that may not be appropriate for individuals with language or motor deficits and that may not provide a broad range of scores reflecting disease severity. It also provides a rationale for focusing on discrete neuropsychological domains since some aspects of functioning were less affected than others and some were more closely related to disease severity. When global measures are used, overall scores may mask specific deficits. A pilot study like this one cannot ensure that scores will change over time in response to a specific treatment in a clinical trial. However, it can avert the selection of instruments that do not show associations with severity or biomedical parameters likely to be the target of a clinical trial. A pilot study can also identify when differences in diagnoses and baseline functioning need to be addressed prior to developing the analytical plan for the trial.
| S-EPMC9842695 | biostudies-literature
Project description:Cardiomyopathy is a frequent complication of propionic acidemia (PA). It is often fatal, and its occurrence is largely independent of classic metabolic treatment modalities. Liver transplantation (LT) is a treatment option for severe PA as the liver plays a vital role in metabolism of the precursors that accumulate in patients with PA. LT in PA is now considered to be a long-lasting and valid treatment to prevent cardiac disease. The subject of this report had severe cardiomyopathy that largely disappeared prior to undergoing a LT. Three years following the transplant, there was recurrence of cardiomyopathy following a surgery that was complicated with a postoperative aspiration pneumonia. On his last hospital admission, he was presented with pulmonary edema and heart failure. He continued with episodes of intractable hypotension, despite maximum inotropic and diuretic support. He died following redirection of care. We conclude that lethal cardiomyopathy may develop several years after successful LT in patients with PA.
| S-EPMC7358669 | biostudies-literature
Project description:BACKGROUND:Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. METHODS:The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18?years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. RESULTS:Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. CONCLUSIONS:The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.
| S-EPMC6915987 | biostudies-literature
Project description:BackgroundLiver transplantation (LT) is a therapeutic option in multiple inherited metabolic diseases (IMDs), including methylmalonic acidemia (MMA), as LT reduces the risk of acute metabolic decompensations and long-term complications associated with these diseases. In certain IMDs, such as maple syrup urine disease (MSUD), domino liver transplant (DLT) is an accepted and safe method which expands the donor pool. However, only one adult case of DLT using an MMA donor liver has been reported; outcome and safety are still unknown and questioned.Case descriptionIn this case report, we describe our experience with DLT using MMA livers. Two adult MMA patients underwent living donor liver transplant (LDLT); their MMA livers were consecutively transplanted into two patients on the liver transplant waiting list who had limited chance of receiving a liver transplant in the short term due to their low model for end-stage liver disease (MELD) scores. No severe peri- or postoperative complications occurred, however the recipients of the MMA livers biochemically now have mild MMA.ConclusionsDLT using MMA grafts is a feasible strategy to treat end-stage liver disease and expand the donor organ pool. However, the recipient of the MMA domino liver may develop mild MMA which could affect quality of life, and long-term safety remains unclear. Further long-term of outcomes for domino recipients of MMA livers, focusing on quality of life and any metabolic complications of transplantation are needed to better define the risks and benefits.
| S-EPMC10838613 | biostudies-literature
Project description:Wisconsin's newborn screening program implemented second-tier testing on specimens with elevated propionylcarnitine (C3) to aid in the identification of newborns with propionic and methylmalonic acidemias. The differential diagnosis for elevated C3 also includes acquired vitamin B12 deficiency, which is currently categorized as a false positive screen. The goal of this study was to summarize screening data and evaluate their effectiveness at establishing diagnoses and categorizing false positive cases. All Wisconsin newborns born between 2013 and 2019 with a positive first-tier screen for C3 were included in this study. For each case the first- and second-tier newborn screening data and confirmatory test results were compiled. The clinical determination for each case was reviewed and categorized into groups: inborn error of metabolism, maternal B12 deficiency, infant B12 deficiency, and false positive. A review of the screening data showed a significant overlap in the concentration of biomarkers for newborns with genetic versus acquired disease. Additionally, a review of confirmatory test results showed incomplete ascertainment of maternal vitamin B12 status. The Wisconsin newborn screening program recommended a confirmatory testing algorithm to aid in the diagnosis of inborn errors of metabolism and acquired vitamin B12 deficiency.
| S-EPMC8883915 | biostudies-literature
Project description:Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.
| S-EPMC4180313 | biostudies-literature
Project description:BACKGROUND:Methylmalonic acidemia (MMA) and propionic acidemia (PA) are related disorders of mitochondrial propionate metabolism, caused by defects in methylmalonyl-CoA mutase (MUT) and propionyl-CoA carboxylase (PCC), respectively. These biochemical defects lead to a complex cascade of downstream metabolic abnormalities, and identification of these abnormal pathways has important implications for understanding disease pathophysiology. Using a multi-omics approach in cellular models of MMA and PA, we identified serine and thiol metabolism as important areas of metabolic dysregulation. METHODS:We performed global proteomic analysis of fibroblasts and untargeted metabolomics analysis of plasma from individuals with MMA to identify novel pathways of dysfunction. We probed these novel pathways in CRISPR-edited, MUT and PCCA null HEK293 cell lines via targeted metabolomics, gene expression analysis, and flux metabolomics tracing utilization of 13C-glucose. RESULTS:Proteomic analysis of fibroblasts identified upregulation of multiple proteins involved in serine synthesis and thiol metabolism including: phosphoserine amino transferase (PSAT1), cystathionine beta synthase (CBS), and mercaptopyruvate sulfurtransferase (MPST). Metabolomics analysis of plasma revealed significantly increased levels of cystathionine and glutathione, central metabolites in thiol metabolism. CRISPR-edited MUT and PCCA HEK293 cells recapitulate primary defects of MMA and PA and have upregulation of transcripts associated with serine and thiol metabolism including PSAT1. 13C-glucose flux metabolomics in MUT and PCCA null HEK293 cells identified increases in serine de novo biosynthesis, serine transport, and abnormal downstream TCA cycle utilization. CONCLUSION:We identified abnormal serine metabolism as a novel area of cellular dysfunction in MMA and PA, thus introducing a potential new target for therapeutic investigation.
| S-EPMC6923996 | biostudies-literature
Project description:Methylmalonic acidemia (MMA) is caused by a deficiency of methyl-malonyl-CoA mutase. It is a multisystemic condition with poor clinical outcomes characterized by frequent metabolic decompensation with acidosis, hyperammonemia and encephalopathy. Restriction of intact protein and supplementation with amino acid-based formula play an important role in its management. Recently, liver transplant (LT) became a treatment option for MMA patients. However, there has been no current consensus on the post-operative nutrition management for MMA patients undergoing transplant, particularly during the initial phase of recovery period with catabolic stressors. We performed a retrospective analysis of clinical and nutritional management as well as biochemical profiles before and after LT in five patients with MMA. Through this study, we observed significant improvement of MMA-associated metabolites after LT. MMA patients were able to tolerate increased intact protein intake post-operatively. At least 1-1.5 g/kg/day of total protein during the acute phase after transplant may be tolerated without worsening of the metabolite levels. This information provides a guide in how to nutritionally manage MMA after LT.
| S-EPMC7599551 | biostudies-literature