The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

Cerebral White Matter Alterations Associated With Oligodendrocyte Vulnerability in Organic Acidurias: Insights in Glutaric Aciduria Type I.

The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.

A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency.

Carbonic anhydrase VA (CA-VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA-VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition.

The utility of methylmalonic acid, methylcitrate acid, and homocysteine in dried blood spots for therapeutic monitoring of three inherited metabolic diseases.

Backgroud: Routine metabolic assessments for methylmalonic acidemia (MMA), propionic acidemia (PA), and homocysteinemia involve detecting metabolites in dried blood spots (DBS) and analyzing specific biomarkers in serum and urine. This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of three specific biomarkers (methylmalonic acid, methylcitric acid, and homocysteine) in DBS, as well as to appraise the applicability of these three DBS metabolites in monitoring patients with MMA, PA, and homocysteinemia during follow-up. Methods: A total of 140 healthy controls and 228 participants were enrolled, including 205 patients with MMA, 17 patients with PA, and 6 patients with homocysteinemia. Clinical data and DBS samples were collected during follow-up visits. Results: The reference ranges (25th-95th percentile) for DBS methylmalonic acid, methylcitric acid, and homocysteine were estimated as 0.04-1.02 µmol/L, 0.02-0.27 µmol/L and 1.05-8.22 µmol/L, respectively. Following treatment, some patients achieved normal metabolite concentrations, but the majority still exhibited characteristic biochemical patterns. The concentrations of methylmalonic acid, methylcitric acid, and homocysteine in DBS showed positive correlations with urine methylmalonic acid (r = 0.849, p < 0.001), urine methylcitric acid (r = 0.693, p < 0.001), and serum homocysteine (r = 0.721, p < 0.001) concentrations, respectively. Additionally, higher levels of DBS methylmalonic acid and methylcitric acid may be associated with increased cumulative complication scores. Conclusion: The LC-MS/MS method established in this study reliably detects methylmalonic acid, methylcitric acid, and homocysteine in DBS. These three DBS metabolites can be valuable for monitoring patients with MMA, PA, and homocysteinemia during follow-up. Further investigation is required to determine the significance of these DBS biomarkers in assessing disease burden over time.

Hypogammaglobulinemia Class G Is Present in Compensated and Decompensated Patients with Propionate Defects, Independent of Their Nutritional Status.

Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated stages, the latter of which are characterized by life-threatening acidemia and hyperammonemia crises. PD patients can suffer immunocompromise, especially during the decompensation stage. There is a significant gap in the research regarding the humoral immune response in PD patients. Here, we analyzed serum immunoglobulin concentrations and hemograms across compensated and decompensated stages in PD patients. Nutritional status and crisis triggers of decompensation were also explored. Twenty patients were studied, and 25 decompensation events (DE) and 8 compensation events (CE) were recorded. Compared with those in the CE group, the IgG levels in the DE group (513.4 ± 244.5 mg/dL) were significantly lower than those in the CE group (860.8 ± 456.5 mg/dL) (p < 0.0087). The mean hemoglobin concentration was significantly lower in the DE group (11.8 g/dL) than in the CE group (13.4 g/dL) (p < 0.05). The most frequent (48%) possible decompensation trigger factor was infection. Most of the events were registered in eutrophic patients (87.9%), despite which 65.2% and 50% of patients who experienced decompensated and compensated events, respectively, presented with hypogammaglobulinemia G. These findings provide evidence of the immunodeficiency of PD patients, independent of their nutritional status. We suggest that PD patients be managed as immunocompromised independently of their nutritional status or metabolic state (compensated or decompensated).

Survival of propionic acidemia patients with liver transplant.

Propionic acidemia (PA) is a rare metabolic disorder affecting amino acid metabolism. Liver transplantation improves some outcomes, but the impact on long-term survival remains unclear. A systematic literature review and survival analysis, identifying 94 PA patients who underwent transplantation, revealed a survival probability of 62% at age 33; while median survival was estimated at 40 years. These findings highlight a substantial survival deficit of PA patients compared to the general population despite liver transplantation.

The iPREFACE score is useful for predicting fetal acidemia: A retrospective cohort study of 113 patients who underwent emergency cesarean section for non-reassuring fetal status during labor.

BACKGROUND: The iPREFACE score may aid in predicting fetal acidemia and neonatal asphyxia in emergency cesarean and vaginal deliveries, which may improve labor management precision in the future. OBJECTIVE: This study aimed to assess the score use of the iPREFACE as an objective indicator of the need for rapid delivery in cases of repeated abnormal waveforms without concurrent indications for immediate medical intervention during labor. STUDY DESIGN: This retrospective cohort study was conducted among term (37+ 0 days to 41+6 days) singleton pregnant women who underwent emergency cesarean delivery owing to a nonreassuring fetal status. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery score, calculated from a 30-minute cardiotocography waveform before the decision to perform emergency cesarean delivery, and the integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer score, calculated from a 30-minute cardiotocography waveform before cardiotocography transducer removal, were employed. The primary outcome was the assessment of the predictive ability of these scores for fetal acidemia, whereas the secondary outcomes were differences in umbilical artery blood gas findings and postnatal outcomes between the 2 groups, divided by the cutoff values of the integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography score. RESULTS: The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery and integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer scores demonstrated the capability to predict an umbilical artery blood pH of <7.2. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-decision of emergency cesarean delivery and -removal of cardiotocography transducer score, with cutoff values of 37 and 46 points, respectively, exhibited an area under the receiver operating characteristic curve of 0.82 and 0.87, respectively. The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring-removal of cardiotocography transducer group with ≥46 points had higher incidence rates of an umbilical cord artery blood pH of <7.2, <7.1, and <7.0 and neonatal intensive care unit admissions for neonatal asphyxia. CONCLUSION: The integrated score index to predict fetal acidemia by intrapartum fetal heart rate monitoring, derived from cardiotocography during an emergency cesarean delivery, may enable clinicians to predict fetal acidemia in cases of nonreassuring fetal status. Improved prediction of fetal acidemia and facilitation of timely intervention hold promise for enhancing the outcomes of mothers and newborns during childbirth. Prospective studies are warranted to establish precise cutoff values and to validate the clinical application of these scores.

Aminotransferase trends in propionic acidemia.

Propionic acidemia is a metabolic condition with multiple serious acute and chronic presentations that require strict monitoring. Literature on liver function abnormalities in propionic acidemia is scarce, and the mechanism of liver impairment in this condition remains unclear. Currently, there is no indication for liver-function tests during follow-up and their clinical or prognostic utility is unknown. This study aimed to determine aminotransferase trends in individuals with propionic acidemia at a single institution. We retrospectively evaluated and classified the aminotransferases of 12 patients with propionic acidemia during hospital admissions and routine office visits. The present findings suggest that aminotransferase elevations are very common in this population and can persist beyond acute illness. During hospitalization events, aminotransferases were not a predictor of severity, duration of stay, and readmission within 1 month. Understanding aminotransferase trends in these patients will help clinicians make decisions in the acute setting and potentially in the follow-up of new therapies.

A multiomics approach reveals evidence for phenylbutyrate as a potential treatment for combined D,L-2- hydroxyglutaric aciduria.

PURPOSE: To identify therapies for combined D, L-2-hydroxyglutaric aciduria (C-2HGA), a rare genetic disorder caused by recessive variants in the SLC25A1 gene. METHODS: Patients C-2HGA were identified and diagnosed by whole exome sequencing and biochemical genetic testing. Patient derived fibroblasts were then treated with phenylbutyrate and the functional effects assessed by metabolomics and RNA-sequencing. RESULTS: In this study, we demonstrated that C-2HGA patient derived fibroblasts exhibited impaired cellular bioenergetics. Moreover, Fibroblasts form one patient exhibited worsened cellular bioenergetics when supplemented with citrate. We hypothesized that treating patient cells with phenylbutyrate (PB), an FDA approved pharmaceutical drug that conjugates glutamine for renal excretion, would reduce mitochondrial 2-ketoglutarate, thereby leading to improved cellular bioenergetics. Metabolomic and RNA-seq analyses of PB-treated fibroblasts demonstrated a significant decrease in intracellular 2-ketoglutarate, 2-hydroxyglutarate, and in levels of mRNA coding for citrate synthase and isocitrate dehydrogenase. Consistent with the known action of PB, an increased level of phenylacetylglutamine in patient cells was consistent with the drug acting as 2-ketoglutarate sink. CONCLUSION: Our pre-clinical studies suggest that citrate supplementation has the possibility exacerbating energy metabolism in this condition. However, improvement in cellular bioenergetics suggests phenylbutyrate might have interventional utility for this rare disease.

NMR Spectroscopy in Diagnosis and Monitoring of Methylmalonic and Propionic Acidemias.

Although both localized nuclear magnetic resonance spectroscopy (MRS) and non-localized nuclear magnetic resonance spectroscopy (NMR) generate the same information, i.e., spectra generated by various groups from the structure of metabolites, they are rarely employed in the same study or by the same research group. As our review reveals, these techniques have never been applied in the same study of methylmalonic acidemia (MMA), propionic acidemia (PA) or vitamin B12 deficiency patients. On the other hand, MRS and NMR provide complementary information which is very valuable in the assessment of the severity of disease and efficiency of its treatment. Thus, MRS provides intracellular metabolic information from localized regions of the brain, while NMR provides extracellular metabolic information from biological fluids like urine, blood or cerebrospinal fluid. This paper presents an up-to-date review of the NMR and MRS studies reported to date for methylmalonic and propionic acidemias. Vitamin B12 deficiency, although in most of its cases not inherited, shares similarities in its metabolic effects with MMA and it is also covered in this review.

Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions.

BACKGROUND: Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT deficiency through the combination of multi-proteomics and bioinformatics approaches. RESULTS: Our data show that MUT deficiency is connected with profound proteome dysregulations, revealing molecular actors involved in lysosome and autophagy functioning. To elucidate the effects of defective MUT on lysosomal and autophagy regulation, we analyzed the morphology and functionality of MMA-lysosomes that showed deep alterations, thus corroborating omics data. Lysosomes of MMA cells present as enlarged vacuoles with low degradative capabilities. Notwithstanding, treatment with an anti-propionigenic drug is capable of totally rescuing lysosomal morphology and functional activity in MUT-deficient cells. These results indicate a strict connection between MUT deficiency and lysosomal-autophagy dysfunction, providing promising therapeutic perspectives for MMA. CONCLUSIONS: Defective homeostatic mechanisms in the regulation of autophagy and lysosome functions have been demonstrated in MUT-deficient cells. Our data prove that MMA triggers such dysfunctions impacting on autophagosome-lysosome fusion and lysosomal activity.

Diagnostic utility of capnography in emergency department triage for screening acidemia: a pilot study.

BACKGROUND: Capnography is a quantitative and reliable method of determining the ventilatory status of patients. We describe the test characteristics of capnography obtained during Emergency Department triage for screening acidemia. RESULTS: We performed an observational, pilot study of adult patients presenting to Emergency Department (ED) triage. The primary outcome was acidemia, as determined by the basic metabolic panel and/or blood gas during the ED visit. Secondary outcomes include comparison of estimated and measured respiratory rates (RR), relationships between end-tidal CO2 (EtCO2) and venous partial pressure of CO2, admission disposition, in-hospital mortality during admission, and capnogram waveform analysis. A total of 100 adult ED encounters were included in the study and acidemia ([Formula: see text] or [Formula: see text]) was identified in 28 patients. The measured respiratory rate (20.3 ± 6.4 breaths/min) was significantly different from the estimated rate (18.4 ± 1.6 breaths/min), and its area under the receiver operating curve (c-statistic) to predict acidemia was only 0.60 (95% CI 0.51-0.75, p = 0.03). A low end-tidal CO2 (EtCO2 < 32 mmHg) had positive (LR+) and negative (LR-) likelihood ratios of 4.68 (95% CI 2.59-8.45) and 0.34 (95% CI 0.19-0.61) for acidemia, respectively-corresponding to sensitivity 71.4% (95% CI 51.3-86.8) and specificity 84.7% (95% CI 74.3-92.1). The c-statistic for EtCO2 was 0.849 (95% CI 0.76-0.94, p = 0.00). Waveform analysis further revealed characteristically abnormal capnograms that were associated with underlying pathophysiology. CONCLUSIONS: Capnography is a quantitative method of screening acidemia in patients and can be implemented feasibly in Emergency Department triage as an adjunct to vital signs. While it was shown to have only modest ability to predict acidemia, triage capnography has wide generalizability to screen other life-threatening disease processes such as sepsis or can serve as an early indicator of clinical deterioration.

Incidence of encephalopathy and comorbidity in infants with perinatal asphyxia: a comparative prospective cohort study.

Background: Programs that aim to improve the detection hypoxic-ischemic encephalopathy (HIE) should establish which neonates suffering from perinatal asphyxia need to be monitored within the first 6 h of life. Method: An observational prospective cohort study of infants with gestational age ≥35 weeks, and above 1,800g, were included according to their arterial cord pH value (ApH): ≤7.00 vs. 7.01-7.10. Data was collected including obstetrical history, as well as neonatal comorbidities, including the presence of HIE, that happened within 6 h of life. A standardized neurological exam was performed at discharge. Results: There were 9,537 births; 176 infants with ApH 7.01-7.10 and 117 infants with ApH ≤7.00. All 9 cases with moderate-to-severe HIE occurred among infants with ApH ≤7.00. The incidence of global and moderate-severe HIE was 3/1,000 and 1/1,000 births, respectively. Outcome at discharge (abnormal exam or death) showed an OR 12.03 (95% CI 1.53, 94.96) in infants with ApH ≤7.00 compared to ApH 7.01-7.10 cohort. Ventilation support was 5.1 times (95% CI 2.87, 9.03) more likely to be needed by those with cord ApH ≤7.00 compared to those with ApH 7.01-7.10, as well as hypoglycemia (37% vs. 25%; p = 0.026). In 55%, hypoglycemia occurred despite oral and/or intravenous glucose administration had been already initiated. Conclusions: Cord pH 7.00 might be a safe pH cut-off point when developing protocols to monitor infants born with acidemia in order to identify infants with moderate or severe HIE early on. There is non-negligible comorbidity in the ApH ≤7.00 cohort, but also in the 7.01-7.10 cohort.

Point-of-Care Ultrasound for the Diagnosis of Congestive Kidney Due to Severe Acidemia: A Case Report.

A 51-year-old woman with mitochondrial myopathy and congestive heart failure with reduced left ventricular ejection fraction was admitted due to loss of appetite and progressive frailty. She presented with acute kidney injury (AKI) and severe acidemia. Given her medical history and physical examination (jugular vein distention was not obvious), prerenal causes (hypovolemia/hypotension) of AKI were considered most likely. However, with a significantly elevated N-terminal pro-b-type natriuretic peptide level of 14,700 pg/mL, a congestive kidney was also considered. Bedside echocardiography showed no evidence of low output syndrome, whereas venous excess ultrasound (VExUS) score was assessed as Grade 2 (moderate congestion). In addition to administering fluids for the suspected prerenal causes (hypovolemia/hypotension), sodium bicarbonate was administered suspecting a negative impact of severe acidemia on cardiac function. With the improvement of acidemia and only a small volume of fluid therapy, there was a rapid improvement in AKI with the normalization of the VExUS score. This suggested that the main cause of AKI was congestive kidney. In this case, VExUS helped us make a correct diagnosis of acidemia-induced congestive kidney rather than hypovolemia as a cause of AKI, leading to the appropriate treatment.

Computer Vision for Identification of Increased Fetal Heart Variability in Cardiotocogram.

INTRODUCTION: Increased fetal heart rate variability (IFHRV), defined as fetal heart rate (FHR) baseline amplitude changes of >25 beats per minute with a duration of ≥1 min, is an early sign of intrapartum fetal hypoxia. This study evaluated the level of agreement of machine learning (ML) algorithms-based recognition of IFHRV patterns with expert analysis. METHODS: Cardiotocographic recordings and cardiotocograms from 4,988 singleton term childbirths were evaluated independently by two expert obstetricians blinded to the outcomes. Continuous FHR monitoring with computer vision analysis was compared with visual analysis by the expert obstetricians. FHR signals were graphically processed and measured by the computer vision model labeled SALKA. RESULTS: In visual analysis, IFHRV pattern occurred in 582 cardiotocograms (11.7%). Compared with visual analysis, SALKA recognized IFHRV patterns with an average Cohen's kappa coefficient of 0.981 (95% CI: 0.972-0.993). The sensitivity of SALKA was 0.981, the positive predictive rate was 0.822 (95% CI: 0.774-0.903), and the false-negative rate was 0.01 (95% CI: 0.00-0.02). The agreement between visual analysis and SALKA in identification of IFHRV was almost perfect (0.993) in cases (N = 146) with neonatal acidemia (i.e., umbilical artery pH <7.10). CONCLUSIONS: Computer vision analysis by SALKA is a novel ML technique that, with high sensitivity and specificity, identifies IFHRV features in intrapartum cardiotocograms. SALKA recognizes potential early signs of fetal distress close to those of expert obstetricians, particularly in cases of neonatal acidemia.

Intrapartum electronic fetal heart rate monitoring to predict acidemia at birth with the use of deep learning.

BACKGROUND: Electronic fetal monitoring is used in most US hospital births but has significant limitations in achieving its intended goal of preventing intrapartum hypoxic-ischemic injury. Novel deep learning techniques can improve complex data processing and pattern recognition in medicine. OBJECTIVE: This study aimed to apply deep learning approaches to develop and validate a model to predict fetal acidemia from electronic fetal monitoring data. STUDY DESIGN: The database was created using intrapartum electronic fetal monitoring data from 2006 to 2020 from a large, multisite academic health system. Data were divided into training and testing sets with equal distribution of acidemic cases. Several different deep learning architectures were explored. The primary outcome was umbilical artery acidemia, which was investigated at 4 clinically meaningful thresholds: 7.20, 7.15, 7.10, and 7.05, along with base excess. The receiver operating characteristic curves were generated with the area under the receiver operating characteristic assessed to determine the performance of the models. External validation was performed using a publicly available Czech database of electronic fetal monitoring data. RESULTS: A total of 124,777 electronic fetal monitoring files were available, of which 77,132 had <30% missingness in the last 60 minutes of the electronic fetal monitoring tracing. Of these, 21,041 were matched to a corresponding umbilical cord gas result, of which 10,182 were time-stamped within 30 minutes of the last electronic fetal monitoring reading and composed the final dataset. The prevalence rates of the outcomes in the data were 20.9% with a pH of <7.2, 9.1% with a pH of <7.15, 3.3% with a pH of <7.10, and 1.3% with a pH of <7.05. The best performing model achieved an area under the receiver operating characteristic of 0.85 at a pH threshold of <7.05. When predicting the joint outcome of both pH of <7.05 and base excess of less than -10 meq/L, an area under the receiver operating characteristic of 0.89 was achieved. When predicting both pH of <7.20 and base excess of less than -10 meq/L, an area under the receiver operating characteristic of 0.87 was achieved. At a pH of <7.15 and a positive predictive value of 30%, the model achieved a sensitivity of 90% and a specificity of 48%. CONCLUSION: The application of deep learning methods to intrapartum electronic fetal monitoring analysis achieves promising performance in predicting fetal acidemia. This technology could help improve the accuracy and consistency of electronic fetal monitoring interpretation.

The utility of fetal heart rate deceleration's descending slope in searching for a non-National Institute of Child Health and Human Development parameter for the detection of fetal acidosis.

OBJECTIVE: To identify new parameters predicting fetal acidemia. METHODS: A retrospective case-control study in a cohort of deliveries from a tertiary referral hospital-based cohort deliveries in Zaragoza, Spain between 2018 and 2021 was performed. To predict fetal acidemia, the NICHD categorizations and non-NICHD parameters were analyzed in the electronic fetal monitoring (EFM). Those included total reperfusion time, total deceleration area and the slope of the descending limb of the fetal heart rate of the last deceleration curve. The accuracy of the parameters was evaluated using the specificity for (80%, 85%, 90%, 95%) sensitivity and the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 10 362 deliveries were reviewed, with 224 cases and 278 controls included in the study. The NICHD categorizations showed reasonable discriminatory ability (AUC = 0.727). The non-NICHD parameters measured during the 30-min fetal monitoring, total deceleration area (AUC = 0.807, 95% CI: 0.770, 0.845) and total reperfusion time (AUC = 0.750, 95% CI: 0.707, 0.792), exhibited higher discriminatory ability. The slope of the descending limb of the fetal heart rate of the last deceleration curve had the best AUC value (0.853, 95% CI: 0.816, 0.889). The combination of total deceleration area or total reperfusion time with the slope demonstrated high discriminatory ability (AUC = 0.908, 95% CI: 0.882, 0.933; specificities of 71.6% and 72.7% for a sensitivity of 90%). CONCLUSIONS: The slope of the descending limb of the fetal heart rate of the last deceleration curve is the strongest predictor of fetal acidosis, but its combination with the total reperfusion time shows better clinical utility.

A novel MMUT splicing variant causing mild methylmalonic acidemia phenotype.

Objectives: Methylmalonic acidemia (MMA) is a rare inborn genetic disorder that is characterized by increased levels of methylmalonic acid in blood plasma and urine. Isolated methylmalonic acidemia is one of the most common types of MMA and is caused by mutations in the gene encoding methyl-malonyl coenzyme A mutase (MMUT). In this study, we investigated the possible mechanisms underlying the symptoms of isolated MMA in a patient by molecular analysis. Methods: PCR amplification and Sanger sequencing analysis was performed to identify variants in the MMUT gene in the proband and his family. Furthermore, minigene constructs were generated to validate the splicing defects in the MMUT gene variant identified in the proband. Results: The 3-year-old patient was admitted to the hospital with symptoms of MMA, including fever, convulsions, and vomiting. He showed metabolic acidosis, high levels of methylmalonic acid in blood and urine, and normal blood homocysteine levels. Genetic analysis demonstrated that the patient was a compound heterozygous carrier of two variants in the MMUT gene: a missense c.278G > A variant that has already been reported in a patient with the severe mut° phenotype; and a novel splice site variant c.2125-2A > G. RT-PCR analysis showed that, while the novel variant clearly alters splicing, a minor amount of a full-length transcript is generated, suggesting that a wild-type protein may be produced although at a lower quantitative level. The patient's condition improved after treatment with vitamin B12. Serious complications were not reported during follow-up at age 5. Conclusions: We identified a novel splice site variant that partially disrupts normal splicing of the MMUT pre-mRNA. Production of a reduced amount of full-length transcript is responsible for the mild clinical phenotype observed in this patient. Functional studies have proven useful in exploring the genotype-phenotype association and in providing guidance for the genetic diagnosis of MMA.

Non-Hodgkin lymphoma in a kidney transplanted patient with methylmalonic acidemia: Metabolic susceptibility and the role of immunosuppression.

Methylmalonic acidemia cblB type (MMA cblB) is an autosomal recessive inborn error of amino acid metabolism that results in impaired synthesis of adenosylcobalamin, a cofactor of methylmalonyl-CoA mutase. It presents with episodes of coma, vomiting, hypotonia, metabolic acidosis, and hyperammonemia. End-stage kidney disease is a long-term complication. Treatments include vitamin B12 supplementation, L-carnitine, and a low-protein diet. Liver, kidney, or combined liver-kidney transplantations are promising options, but they are not without complications. We report a patient suffering from MMA cblB who developed end-stage kidney disease at 18 years of age. Kidney transplantation allowed him to recover normal kidney function and good metabolic control. Unfortunately, after two decades, he developed non-Hodgkin lymphoma and severe chemotherapy toxicity which led to his death. The risk of lymphoproliferative diseases is known to increase after solid organ transplantation. However, in MMA, factors including mitochondrial dysfunction and oncometabolites, may further increase the risk of malignancy and drug toxicity. Our report highlights the importance of considering the increased risk of cancer in long-term follow-up of MMA cblB patients, especially after solid organ transplantation. Moreover, when chemotherapy is needed, the increased risk of toxicity and metabolic decompensation should be considered and monitored.

Is it time to end the use of base deficit for fetal well-being assessment?

Authors have expressed reservations regarding the use of base deficit measured in umbilical artery blood samples to assess fetal well-being during the course of labor and to predict neonatal neurologic morbidity. Despite its integration into clinical practice for more than 50 years, obstetricians and maternal-fetal medicine specialists may not realize that this marker has significant limitations in accurately identifying neonatal metabolic acidosis as a proxy for fetal well-being. In brief, there are 2 large families of base deficit, namely whole blood and extracellular fluid. Both rely on equations that use normal adult acid-base characteristics (pH 7.40 and partial CO2 pressure of 40 mm Hg) that overlook the specificity of the normal in utero acid-base status of pH 7.27 and partial CO2 pressure of 54 mm Hg. In addition, it ignores the unique characteristic of the in utero fetal response to acute hypoxia. The dependence on placental circulation for CO2 elimination may lead to extremely high values (up to 130 to 150 mm Hg) during hypoxic events, a phenomenon that is absent in adults with acute metabolic acidosis who can hyperventilate. The dispute over if to include a correction for high partial CO2 pressure in the bicarbonate estimation, as presented in the Great Trans-Atlantic Debates, remains unresolved. The key constants computed for adult acid-base physiology in the current base deficit algorithms, without accounting for the impact of high partial CO2 pressure or other fetal characteristics of buffering capacity (eg, differences in body water content composition, plasma protein, and hemoglobin attributes), may lead to an overestimation of metabolic acidosis, especially in newborns who are experiencing hypercarbia during the early stages of the hypoxic response. These unrecognized limitations impact the base deficit results and may mislead clinicians on fetal well-being assessments when discussing the management of fetal heart rate monitoring and neonatal outcomes. Based on our arguments, we believe that it is prudent to consider an alternative to base deficit for drawing conclusions regarding fetal well-being during the course of birth management. We propose a marker specifically related to the newborn acid-base physiology--the neonatal eucapnic pH correction. This marker can be added to arterial cord blood gas analysis, and we have described how to interpret it as a marker of neonatal metabolic acidosis.