Search Results (106)

Organic acidemias (OADs) are a group of inherited metabolic disorders with a high false-positive rate in newborn screening. In this study, we aimed to evaluate the clinical performance of next-generation sequencing (NGS) as a combined genetic test for OADs. From September 2022 to August 2025, 154,634 newborns underwent primary screening using tandem mass spectrometry (MS/MS). Among them, 151 neonates with suspected OADs underwent combined genetic screening using a pre-designed NGS panel. Of these, 55 cases tested positive on genetic screening, and 17 were ultimately diagnosed with OADs, yielding a prevalence of 1 in 9096. The positive predictive value of NGS was 30.91% (17/55). The genotypes of nine patients (9/17, 52.9%) were identified through NGS screening. Notably, one case of methylmalonic acidemia that would have been missed by MS/MS screening was successfully identified using the combined genetic screening. Additionally, 37 neonates with positive biochemical screening results were confirmed to be either carriers or unaffected individuals. Two cases of Wilson’s disease were also identified through combined genetic screening. Therefore, integrating NGS into conventional MS/MS-based screening can significantly reduce the false-positive rate and shorten the time from screening to definitive diagnosis. This approach provides a valuable model for improving the efficiency and accuracy of newborn genetic screening. Full article

Background/Objectives: Conventional diagnosis of inborn errors of metabolism (IEMs) requires multiple specimen types—urine organic acids, plasma amino acids, and serum acylcarnitines—analyzed on distinct analytical platforms. This multi-assay approach is labor-intensive and limits timely clinical decision making. We aimed to develop a fully automated serum-based LC–MS/MS platform for integrated quantitative metabolite profiling and to establish pediatric reference intervals (RIs) to support diagnostic interpretation. Methods: A fully automated LC–MS/MS system integrated with the CLAM-2030 automated pretreatment module was developed to enable simultaneous quantification of 25 organic acids, 8 amino acids, and 21 acylcarnitines. Analytical performance was assessed for linearity, limits of detection and quantification, precision and accuracy. Serum samples from 296 non-IEM children aged 0–6 years were analyzed to establish pediatric RIs using Box–Cox transformation and Gaussian modeling. Clinical utility was evaluated in sera from 89 patients diagnosed with IEM using z-score-based logistic regression models. Results: The method demonstrated excellent performance, with linearity (r² > 0.99) across calibration ranges, limits of detection and quantification defined by signal-to-noise ratios > 3 and >10, and intra- and inter-assay precision < 15% CV for all 54 analytes. Twenty-one analytes met the acceptance criterion of ±20% accuracy at all quality-control levels. Pediatric RIs provided a quantitative framework for interpreting the metabolic abnormalities. In IEM patients, disease-specific metabolites were consistently outside the established ranges, and z-score-based logistic regression models successfully distinguished major IEM categories, including organic acidemias and long-chain fatty acid oxidation disorders. Conclusions: This fully automated, serum-based LC–MS/MS platform provides a clinically practical and quantitative framework for integrated metabolic profiling using pediatric RIs, supporting diagnosis and monitoring of IEMs in pediatric settings. Full article

Background/Objectives: Isolated methylmalonic acidemia (iMMA) is a rare autosomal recessive metabolic disorder caused by defects in methylmalonyl-CoA mutase (MCM) activity or in the biosynthesis of its cofactor, adenosylcobalamin. Mutations in five genes—MMUT, MMAA, MMAB, MMADHC, and MCEE—are known to underlie this condition. This study aimed to characterize the clinical features and molecular spectrum of iMMA in Malaysian patients of diverse ethnic backgrounds. Material and Methods: Patients with biochemical evidence suggestive of iMMA, including elevated propionylcarnitine (C3), increased C3/C2 ratio, and raised urine methylmalonic acid levels in the absence of hyperhomocysteinemia, were selected for genetic testing. Sanger sequencing was performed to identify pathogenic variants in the MMUT, MMAA, MMAB, MMADHC, or MCEE genes. Results: The cohort consisted predominantly of Iban patients (n = 5), with the remaining cases comprising one Malay and one Thai–Malay individual. Age at diagnosis ranged from Day 1 of life to 6 years. All 7 patients were confirmed to have iMMA through molecular analysis. A total of seven pathogenic or likely pathogenic variants were identified, including two novel MMUT variants (c.246_250delinsGA and c.1358G>C), four known MMUT variants (c.560C>G, c.693C>G, c.982C>T, c.1106G>A), and one known MMAB variant (c.644+1G>A). Clinical presentation and disease severity varied across cases, reflecting underlying genotypic heterogeneity. Conclusions: This study highlights the molecular diversity and clinical variability of iMMA in Malaysia. Our findings reinforce the importance of integrating metabolic screening with molecular diagnostics to identify disease-causing variants and guide patient management strategies effectively. Full article

Introduction: Cardiac complications are well-documented in propionic acidemia (PA), and there are a few reported cases of cardiomyopathies in methylmalonic acidemia (MMA). Left-ventricular global longitudinal strain (LV GLS) measurement is known to be able to detect early ventricular dysfunction, leading potentially to cardiomyopathy. The aim of our study was to evaluate left-ventricular global longitudinal strain (LV GLS) in MMA and PA patients and compare it with the pediatric general population. Methods: In this monocentric retrospective study, 26 patients with organic aciduria (OA) were included. Demographic, clinical, electrocardiographic and echocardiographic data were collected. The mean LV GLS in MMA and PA patients was compared with the GLS in the pediatric general population. Results: The left-ventricular ejection fraction (LVEF) was similar between MMA and PA patients and in the normal range (66.27 ± 6.24% vs. 61.41 ± 11.02%; p = 0.182). LV GLS was significantly lower in PA patients than in MMA patients (−15.8 ± 5.67% vs. −20.6 ± 3.19%; p = 0.011). LV GLS was significantly lower in PA patients when compared with the general pediatric population (p = 0.029). Conclusions: Patients with propionic acidemia may have impaired global longitudinal strain even in the presence of normal LVEF. LV GLS might be a useful tool for cardiac follow-up in pediatric patients with OA. Full article

Fetal acidemia, caused by impaired gas exchange between the fetus and the mother, is a leading cause of stillbirth and neurologic complications. Early prediction is therefore essential to guide timely clinical intervention. Several strategies rely on cardiotocography (CTG), which combines fetal heart rate (fHR) with uterine contractions and has led to development of clinical guidelines for CTG interpretation and the introduction of different fHR features. Additionally, ST event analysis, investigating changes in the ST segments of the fetal electrocardiogram (fECG), has been proposed as a complementary tool. This narrative review adopts a systematic approach, with comprehensive searches in Embase and PubMed to ensure full coverage of the available literature, and summarizes findings from 30 studies. Clinical guidelines for CTG interpretation frequently lead to intermediate risk level annotations, leaving the final decision regarding fetal management to clinical experience. In contrast, various fHR features can successfully discriminate between fetuses developing acidemia and healthy controls. Evidence regarding the added value of ST events derived from the scalp electrode remains conflicting, due to concerns about invasiveness. Recent studies on machine learning models highlight their ability to integrate multiple fHR features and improve predictive performance, suggesting a promising direction for enhancing acidemia prediction during labor. Full article

In the Netherlands, the newborn screening (NBS) program includes screening for propionic aciduria (PA) and methylmalonic aciduria (MMA). When initial screening reveals elevated C3 concentrations or abnormal ratios (C3/C2, C3/C16), a second-tier test measuring methylcitric acid (MCA) for PA and methylmalonic acid (MMA^mb) for MMA is performed. While this two-tier approach reduces false positives effectively, it can delay referral from the NBS program and diagnosis of propionic aciduria. We describe four early-onset PA cases in which the current Dutch screening algorithm negatively impacted clinical outcomes, highlighting the need for expedited referral. We investigated different alternative screening strategies to identify the most effective approach for improving timeliness, while maintaining the high specificity of Dutch PA NBS. This revised approach prioritizes the evaluation of the C3/C2 ratio in first-tier screening. Specifically, samples with a C3/C2 ratio ≥ 0.75 should be referred directly for medical consultation and confirmatory testing. For all other samples with less pronounced biochemical abnormalities, the existing two-tier screening algorithm remains an appropriate NBS protocol. To position our approach internationally, a survey of European NBS programs was conducted to compare screening and referral protocols for PA across the region. Full article

Background/Objectives: Propionic acidemia (PA) and methylmalonic acidemia (MMA) affect methionine, threonine, valine (Val), and isoleucine (Ile) (MTVI) metabolism, leading to the production of highly neurotoxic organic acids. Treatment involves a diet restricted in natural proteins and supplemented with a protein substitute (PS) with traces of MTVI. The aim was to analyze natural protein and PS intake in relation to linear growth impairment in individuals with PA and MMA. Methods: We followed the PRISMA protocol. We considered articles published between 1970 and 2025. We determined the eligibility criteria for selecting articles and evaluated the quality. Results: Thirteen studies were selected: two case reports, eight longitudinal, three cohorts, and one cross-sectional. Articles demonstrated that natural protein intake decreases with age, consistent with previous reports, underscoring the need for PS supplementation to meet protein requirements. Subjects with PA and non-responsive MMA had greater restriction of natural proteins, and the majority required PS; a higher PS intake was negatively correlated with a higher height-for-age (H/A) z-score. When analyzing the ratio of protein to energy (P:E), a negative correlation was found between the intake of natural proteins and energy, and a positive correlation with H/A z-score (p-value < 0.05). Supplementation with PS increased leucine levels, causing an imbalance with MTVI amino acids. This imbalance led to the paradoxical need to supplement L-Val and L-Ile, both propiogenic amino acids. As a result, a decrease in the H/A z-score was observed, particularly in PA and non-responsive MMA. Responsive MMA tolerated more natural proteins, received a lower intake of PS, and had a better H/A z-score. Conclusions: Restriction of natural proteins and PS is associated with a lower H/A z-score, primarily in subjects with PA and non-responsive MMA. Full article

Neurological and neurodegenerative diseases encompass a wide range of conditions affecting the central nervous system, leading to progressive dysfunction and damage. These diseases, such as Alzheimer’s, Parkinson’s, and some cerebral organic acidurias, often result in debilitating symptoms impacting motor control, cognitive function, and sensory processing. Research into their complex etiologies, including the role of energy and redox homeostasis, is crucial for developing effective diagnostics and therapeutic interventions. Despite the current lack of effective treatments for many neurological and neurodegenerative disorders, nutraceuticals are garnering significant interest. These food-derived compounds offer benefits beyond basic nutrition, primarily due to their ability to modulate intracellular processes that are known to be disrupted in these diseases. This study reviews the neuroprotective potential of several nutraceuticals, specifically creatine, acetyl-L-carnitine, melatonin, and resveratrol, as promising adjuvants to therapeutic interventions in neurological and neurodegenerative diseases. Full article

Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70–118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China. Full article

This study evaluates the incidence of metabolic disorders detected from January 2005 to December 2024 and their clinical outcomes. Data were retrospectively collected from the Louisiana Newborn Screening database. Clinical outcomes were obtained through review of corresponding medical records. In addition, an electronic questionnaire assessing educational attainment and neurodevelopmental disorders was sent to the patients’ families. Of 1,230,356 infants screened, 478 were diagnosed with metabolic disorders, corresponding to an incidence of 1 in 2574 live births. The three most commonly identified conditions were biotinidase deficiency, phenylketonuria (PKU), and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). During the study period, at least 11 patients died. The program demonstrated a false-positive rate of 0.93%. Twelve patients (7%) were symptomatic before or at the time of NBS result notification. Recurrent metabolic decompensations occurred in 3 of 4 maple syrup urine disease (MSUD) cases, 7 of 7 methylmalonic acidemia (MMA) cases, 1 of 4 propionic acidemia (PA) cases and 1 of 7 urea cycle defect cases. Regarding long-term outcomes, 45.7% of survey respondents reported adverse neurodevelopmental outcomes of varying severity. Early detection and timely intervention have contributed to normal or near-normal outcomes in many cases. However, the morbidity and mortality observed in some patients despite early diagnosis highlights the severity and complexity of certain metabolic conditions. Additionally, the relatively high false positive rate underscores the need for ongoing efforts to improve the specificity of screening protocols to reduce unnecessary follow-ups and mitigate potential stress for families. Full article

Beta ketothiolase deficiency is a hereditary metabolic disorder caused by the pathogenic variants of the ACAT gene, which encodes for the mitochondrial enzyme acetoacetyl-CoA thiolase. Patients with a deficiency of the enzyme experience recurrent episodes of metabolic ketoacidosis. Knowledge of the clinical course of this entity, together with the available diagnostic tests, allows for its early diagnosis and prompt intervention to avoid complications or death of the infant. In this study, we present a case of a 9-month-old girl that attended the emergency room and diagnosis was made at the first episode of metabolic ketoacidosis. Full article

Isovaleric acidemia (IVA, OMIM 243500) is an inherited disorder of leucine metabolism caused by a deficiency of isovaleryl-CoA dehydrogenase (IVD), leading to an accumulation of isovaleric acid and its derivates 3-hydroxyisovaleric acid, isovaleryl (C5)-carnitine and isovalerylglycine in body fluids. The clinical presentation is highly variable, ranging from life-threatening metabolic crises with metabolic acidosis and hyperammonemia to a clinically asymptomatic only biochemical phenotype. Newborn screening for IVA has been established in many countries. Treatment consists of a protein-restricted diet combined with supplementation of carnitine and/or glycine and emergency treatment in catabolic episodes. Still, evidence-based recommendations for the diagnosis and management of IVA patients with various phenotypes are lacking. Therefore, a systematic search and review of the literature was conducted to make suggestions for the care of patients with IVA based on both the available scientific evidence and consensus-derived expert conclusions. Based on a comprehensive set of literature data published between 1966 and 2024, 15 statements were phrased on the presentation, diagnosis, management, and outcome of IVA involving clinical, biochemical, and nutrition expertise. These statements can serve as a basis for more standardized care for IVA. Full article

Background: The primary treatment for inborn errors of metabolism (IEM) involves restricted intake of natural protein. Inadequate diets can lead to an increased risk of inflammation and susceptibility to infections. The Dietary Inflammatory Index (DII) is used to estimate whether a diet has anti-inflammatory or pro-inflammatory properties. This study aimed to investigate the relationship between the inflammatory index score of natural protein-restricted diets used in medical nutrition therapy for IEM intoxication, the anthropometric measurements and nutritional status of affected children. Method: The study included 20 patients (5 organic acidemia, 5 urea cycle disorders, 10 phenylketonuria) and 20 healthy children. Patients followed a natural protein-restricted diet, while the healthy control group maintained their usual dietary habits. Dietary records were collected for both groups, and the DII and macro-micronutrient intakes were calculated. Result: DII scores were similar between the patient and control groups. Anthropometric measurements did not differ significantly between the groups. However, carbohydrate and fat intakes were higher in the patient group compared to the control group (p < 0.05). Additionally, comparative analyses revealed that vitamin B1, C and E, iron, and magnesium intakes were higher in the patient group than in the control group. Conclusions: Children on a natural protein-restricted diet showed growth patterns comparable to their healthy peers. This study demonstrated that nutritional deficiencies can be prevented in amino acid metabolism disorders treated with a natural protein-restricted diet by carefully controlling nutrition with vitamin and mineral-fortified formulas. Full article

Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS. Full article

Background/Objectives: Sodium–glucose co-transporter 2 inhibitors (SGLT2i) are associated with increased rates of diabetic ketoacidosis (DKA). The difference in the management and outcomes of SGLT2i-associated DKA (SGLT2i DKA) from non-SGLT2i-associated DKA (non-SGLT2i DKA) remains unclear due to a lack of specific reporting on dextrose and insulin. This study aims to compare the management and outcome of SGLT2i and non-SGLT2i diabetic ketoacidosis. Methods: In this retrospective cohort study, patients admitted to the Intensive Care Unit (ICU) for diabetic ketosis between 1 January 2020 to 31 December 2021 at a tertiary hospital were identified. For each SGLT2i diabetic ketosis, two non-SGLT2i diabetic ketosis admissions closest to the SGLT2i admission date were evaluated for comparison. Clinical data including biochemistry, ICU length of stay (LOS), time to normalize acidemia and ketonemia, dextrose and insulin requirements, were evaluated. Results: In the SGLT2i group (n = 30), there were 22 DKA and 8 diabetic ketosis cases; in the non-SGLT2i group (n = 60), there were 54 DKA and 6 diabetic ketosis cases. SGLT2i DKA (n = 22) required 62% greater total insulin (154 [117–249] vs. 95 [59–150] units; p = 0.004), which remained statistically significant after weight adjustment (p = 0.02), and longer ICU LOS (52 [42–97] vs. 39 [23–68] hours; p = 0.01) compared to non-SGLT2i DKA (n = 54), despite a comparable time to DKA resolution (22 [15–35] vs. 20 [15–35] hours; p = 0.91). In the intercurrent illness subgroup analysis, neither total insulin dose nor ICU LOS remained statistically significantly different between SGLT2i (n = 16) and non-SGLT2i DKA (n = 21). The majority of cases received 10% dextrose and variable rate intravenous insulin infusion (VRIII). Conclusions: The greater insulin requirement in SGLT2i DKA compared to non-SGLT2i DKA may be explained by the greater proportion of precipitating intercurrent illnesses and demographic differences in SGLT2i DKA, highlighting that SGLT2i DKA (predominantly comprising T2D) and non-SGLT2i DKA (predominantly comprising T1D) represent distinct clinical entities. Our findings in comparison to the literature imply that in SGLT2i DKA, the need for prolonged IV insulin infusion may be reduced through intensive management using intravenous 10% dextrose and VRIII. Prospective studies are warranted to evaluate the efficacy of different management strategies for SGLT2i DKA. Full article