Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.
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ABSTRACT:
SUBMITTER: Forny P
PROVIDER: S-EPMC8252715 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:Methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are very rare autosomal recessive inherited metabolic diseases from the group of organoacidopathies. Katabolism due to minor infections can lead to metabolic decompensation including hyperammonemia and ketoacidosis, especially in small children. We present data from a small cohort to clarify whether placement of a percutaneous endoscopic gastrostomy with jejunal tube (J-PEG) reduce metabolic imbalances and hospital stays. The aim is to prevent emergencies from occurring by preventing metabolic derailments at an early stage. 4 patients with MMA (N = 3) or PA (N = 1) were included. Data were collected at every investigation, in particular pH value, pCO2, bicarbonate, base excess, ammonia and lactate. Due to repeated metabolic derailments, a percutaneous endoscopic gastrostomy was placed for postpyloric nutrition. In conclusion, placement of a percutaneous endoscopic gastrostomy with postpyloric tube appears to reduce the rate of metabolic decompensations. In addition, hospital stays and especially the number of treatment days can be reduced. This method, especially the placement of a postpyloric tube could enable parents to prevent catabolism when vomiting begins by continuously feeding through the jejunal part, as a step to prevent a metabolic emergency from occurring.
| S-EPMC9939511 | biostudies-literature
Project description:Propionic acidaemia (PA) is an autosomal recessive disease that results from deficiency of propionyl-CoA carboxylase (PCC). In the majority of reported cases, the phenotype includes metabolic acidosis and/or neurological deficits. We report on a 14-year-old Asian-American male with PA who presented with isolated cardiomyopathy without any documented episodes of metabolic acidosis or evidence of any neurocognitive deficits. On routine metabolic screening, the patient was found to have urine organic acids suggestive of PA. Biochemical and genetic characterization confirmed a PCC deficiency with two novel mutations in PCCB: IVS7 + 2 T > G (c.763 + 2 T > G) and p.R410Q (c.1229 G > A). Residual enzyme activity likely explains our patient's mild phenotype. Splicing mutations tend to result in a milder phenotype as these mutations may still produce small amounts of normal enzyme. In addition, the similar p.R410W mutation has been shown to have partial residual activity. Moreover, this case illustrates that a thorough metabolic evaluation should be performed in both paediatric and adult patients with cardiomyopathy. Such an evaluation has important implications for clinical management and genetic counselling.
| S-EPMC3777722 | biostudies-literature
Project description:We present the nutritional and pharmacological management of a 2-year-old girl with a severe form of propionic acidaemia and a genitourinary embryonal rhabdomyosarcoma. This association has not been described before, nor the utilization of chemotherapy in patients with propionic acidaemia.The patient is a girl with neonatal onset of propionic acidaemia, homozygous for the c.2041-2924del3889 mutation in PCCA gene. At 23 months of age she was diagnosed with genitourinary embryonal rhabdomyosarcoma. Conservative surgery, brachytherapy and nine cycles of chemotherapy with iphosphamide, vincristine and actinomycin were recommended by oncologists. Due to the possibility that the child could present decompensations, we elaborated three different courses of treatment: when the patient was stable (treatment 1), intermittent bolus feeding through gastrostomy, containing 70 kcal/kg/day and 1.4 g/kg/day of total protein (0.6 g/kg/day of natural protein and 0.8 g/kg/day of amino acid-based formula) was prescribed; on the chemotherapy-days (treatment 2), diet consisted on continuous feeding, with the same energy and amino acid-based formula but half of natural protein intake; in case of decompensation (treatment 3), we increased by 10% the energy intake, and completely stopped natural protein in the diet but maintaining the amino acid-based formula. On chemotherapy- days carnitine was increased from 100 mg/kg/day to 150 mg/kg/day, and N-carbamylglutamate was added.Through the 7 months with chemotherapy the patient did not suffer decompensations, while she maintained good nutritional status.Enteral continuous feeding by gastrostomy, amino acid-based formula, and preventive use of N-carbamylglutamate during chemotherapy-days are the principal measures we propose in these situations.
| S-EPMC3565659 | biostudies-literature
Project description:Methylmalonic acidaemia (MMA) has been reported to be associated with cardiovascular involvement, especially for the combined type with homocystinuria. We have screened 80 control subjects and 99 MMA patients (23 isolated type and 76 combined type) using electrocardiograph and echocardiography. 32 cases (34%) of ECG changes were found including sinus tachycardia (n = 11), prolonged QTc interval (n = 1), I-degree atrioventricular block (n = 1), left axis deviation (n = 5) and T wave change (n = 14). By echocardiography, 8 cases of congenital heart disease were found in 4 combined MMA patients (5.3%) including ventricular septal defect (n = 2), atrial septal defect (n = 3), patent ductus arteriosus (n = 1) and coronary artery-pulmonary artery fistula (n =2). Pulmonary hypertension (n = 2) and hypertrophic cardiomyopathy (n = 1) in combined subtype were also noted. Moreover, echocardiographic parameters were analyzed by multiple regression to clarify the influence of different subtypes on cardiac function. It was found that the left ventricular mass index (LVMI) was significantly reduced only in combined subtype [R = -3.0, 95%CI (-5.4, -0.5), P = 0.017]. For left ventricle, the mitral E' velocity was significantly reduced [isolated type: R = -1.8, 95%CI (-3.3, -0.4), P = 0.016; combined type: R = -2.5, 95%CI (-3.5, -1.5), P < 0.001], the global longitudinal strain (GLS) was the same [isolated type: R = -1.4, 95%CI (-2.3, -0.4), P = 0.007; Combined type: R = -1.1, 95%CI (-1.8, -0.4), P = 0.001], suggesting weakened left ventricular diastolic and systolic functions in both subtypes. For right ventricle, only in combined subtype, the tricuspid E' velocity was significantly reduced [R = -1.4, 95%CI (-2.6, -0.2), P = 0.021], and the tricuspid annular plane systolic excursion (TAPSE) was the same [R = -1.3, 95%CI (-2.3, -0.3), P=0.013], suggesting impaired right ventricular systolic and diastolic function. In conclusion, isolated and combined types showed different pattern of cardiac dysfunction, specifically the former only affected the left ventricle while the latter affected both ventricles. And it is necessary to perform echocardiographic screening and follow up in both MMA subtypes.
| S-EPMC8904414 | biostudies-literature
Project description:There is an unmet need for the development and validation of biomarkers and surrogate endpoints for clinical trials in propionic acidemia (PA) and methylmalonic acidemia (MMA). This review examines the pathophysiology and clinical consequences of PA and MMA that could form the basis for potential biomarkers and surrogate endpoints. Changes in primary metabolites such as methylcitric acid (MCA), MCA:citric acid ratio, oxidation of 13 C-propionate (exhaled 13 CO2 ), and propionylcarnitine (C3) have demonstrated clinical relevance in patients with PA or MMA. Methylmalonic acid, another primary metabolite, is a potential biomarker, but only in patients with MMA. Other potential biomarkers in patients with either PA and MMA include secondary metabolites, such as ammonium, or the mitochondrial disease marker, fibroblast growth factor 21. Additional research is needed to validate these biomarkers as surrogate endpoints, and to determine whether other metabolites or markers of organ damage could also be useful biomarkers for clinical trials of investigational drug treatments in patients with PA or MMA. This review examines the evidence supporting a variety of possible biomarkers for drug development in propionic and methylmalonic acidemias.
| S-EPMC9303879 | biostudies-literature
Project description:Propionic acidaemia (PA) is an innate error of metabolism involving a deficiency in the enzyme propionyl-CoA carboxylase. Better control of acute decompensation episodes together with better treatment and monitoring have improved the prognosis of patients with this problem. However, long-term complications can arise in those in whom good metabolic control is achieved, the result of mitochondrial dysfunction caused by deficient anaplerosis, increased oxidative stress, and reduced antioxidative capacity. Coenzyme Q10 (CoQ10) is a nutritional supplement that has a notable antioxidative effect and has been shown to improve mitochondrial function. The present prospective, interventional study examines the plasma concentration of CoQ10 in patients with PA, their tolerance of such supplementation with ubiquinol, and its benefits. Seven patients with PA (aged 2.5 to 20 years, 4 males) received supplements of CoQ10 in the form of ubiquinol (10 mg/kg/day for 6 months). A total of 6/7 patients showed reduced plasma CoQ10 concentrations that normalized after supplementation with ubiquinol (p-value < 0.001), which was well tolerated. Urinary citrate levels markedly increased during the study (p-value: 0.001), together with elevation of citrate/methlycitrate ratio (p-value: 0.03). No other significant changes were seen in plasma or urine biomarkers of PA. PA patients showed a deficiency of plasma CoQ10, which supplementation with ubiquinol corrected. The urinary excretion of Krebs cycle intermediate citrate and the citrate/methylcitrate ratio significantly increased compared to the baseline, suggesting improvement in anaplerosis. This treatment was well tolerated and should be further investigated as a means of preventing the chronic complications associated with likely multifactorial mitochondrial dysfunction in PA.
| S-EPMC9405378 | 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: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:Combined methylmalonic acidemia and homocystinuria, cblC type, is an inborn error of intracellular cobalamin metabolism with a wide spectrum of clinical manifestations that is stated to be the most common inherited disorder of cobalamin metabolism. This metabolic disease is caused by mutations in the MMACHC gene and results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, cofactors for the methylmalonyl-CoA mutase and methionine synthase enzymes. Elevated methylmalonic acid and homocysteine with decreased methionine production are the biochemical hallmarks of this disorder. Awareness of the diverse clinical presentations associated with cblC disease is necessary to provide a timely diagnosis, to guide management of affected individuals and to establish a framework for the future treatment of individuals detected through expanded newborn screening. This article reviews the biochemistry, clinical presentations, genotype-phenotype correlations, diagnosis and management of cblC disease.
| S-EPMC4219318 | biostudies-literature