Search Results (255)

Background: Inborn errors of metabolism (IEMs) represent a diverse group of genetic disorders affecting biochemical pathways. Despite advances in diagnostic technologies, comprehensive understanding of their historical evolution, classification systems, and diagnostic approaches remains fragmented. Objectives: This systematic review and meta-analysis aimed to synthesize evidence on the historical development, classification frameworks, and diagnostic modalities for IEMs, diagnostic accuracy, and prevalence estimates, providing a comprehensive resource for clinicians and researchers. Methods: Following PRISMA 2020 guidelines, we conducted a systematic search of seven electronic databases (PubMed/MEDLINE, Embase, Scopus, Web of Science, Google Scholar, SciSpace and ArXiv) from January 2000 to March 2026. Studies addressing historical perspectives, classification systems, or diagnostic approaches for IEMs were included. Two independent reviewers performed screening, data extraction, and quality assessment. Meta-analyses were conducted using random-effects models for diagnostic accuracy and prevalence estimates. Results: From 1342 identified records, 54 studies met the inclusion criteria, encompassing 8,234,567 individuals across 35 countries. Historical analysis revealed 16 major milestones from Garrod’s 1902 “chemical individuality” concept to the current AI-powered diagnostics. Four major classification systems were identified: pathophysiological (intoxication, energy deficiency, complex molecule disorders), biochemical pathway (amino acid, organic acid, urea cycle, carbohydrate, fatty acid oxidation, mitochondrial, peroxisomal, lysosomal disorders), organelle-based, and the integrated Society for the Study of Inborn Errors of Metabolism (SSIEM) nosology. Meta-analysis demonstrated high diagnostic performance of tandem mass spectrometry (MS/MS) with a pooled sensitivity of 99.1% (95% CI: 98.6–99.5) and specificity of 99.8% (95% CI: 99.7–99.9%). The pooled global prevalence of IEMs was 50.9 per 100,000 live births (95% CI 45.2–56.8). Next-generation sequencing achieved a diagnostic yield of 42.8% (95% CI: 38.2–47.5%) in suspected cases. Emerging AI-powered diagnostic tools demonstrated high discrimination performance with area under the curve (AUC) values exceeding 0.95 for specific IEM, though external validation remains limited. Newborn screening expanded from single-disease to comprehensive panels detecting over 50 disorders. Conclusions: This comprehensive review demonstrates that IEMs have evolved from rare curiosities to systematically diagnosable conditions through technological advances. Integration of metabolomics, genomics, proteomics and artificial intelligence promises further diagnostic improvements. Standardized classification systems and evidence-based diagnostic algorithms are essential for optimal patient care. Future directions include artificial intelligence-enhanced diagnostics, expanded screening, and personalized medicine approaches. Full article

Urea cycle disorders (UCDs) are rare inherited metabolic diseases associated with toxic hyperammonemia, leading to severe neurological damage and early mortality. Early diagnosis of distal UCDs through newborn screening (NBS) enables presymptomatic intervention; however, comparative real-world outcome data remain limited. We conducted a retrospective, multicenter study using data from the Spanish UCD Registry to describe the clinical characteristics and compare health outcomes between patients diagnosed through NBS (n = 40) and those diagnosed after clinical presentation (n = 53). Patients identified by NBS showed a markedly more favorable clinical prognosis, with a mortality rate of 2.5% compared with 15.1% in the unscreened cohort, as well as significantly lower rates of neurological involvement, fewer hospital admissions due to metabolic decompensation, and a reduced need for liver transplantation. Screening also identified a high prevalence of argininosuccinate synthetase deficiency (ASS1D) cases with attenuated biochemical profiles, highlighting the relevance of sensitive screening cutoffs. These findings provide real-world evidence that presymptomatic diagnosis through NBS is associated with improved survival and long-term neurological outcomes in patients with distal UCDs. Full article

Umbilical cord mesenchymal stromal cells (UC-MSCs) are a key element of regenerative medicine due to their ability to secrete growth factors that stimulate proliferation and angiogenesis, and modulate the inflammatory response. Despite their widespread use, the influence of the perinatal microenvironment on their biological properties remains poorly understood. The aim of this study was to assess the influence of pH and blood gas parameters in umbilical cord blood on the global transcriptomic profile of UC-MSCs and to analyze the correlation between the metabolic status of the newborn and the expression of key trophic factors: EGF, FGF2, FGFR1, FGFR3, GDNF, HGF, IGF1, NES, NGF, and PGF. Methods: The study was conducted in two stages. In the first phase, transcriptomic screening was performed using Affymetrix HuGene 2.0 ST microarray on cells isolated from three environmental groups defined by cord blood pH: acidic (pH < 7.35), physiological (7.35–7.39), and alkaline (pH ≥ 7.4). In the second phase, the results were validated using qPCR on an expanded study group (N = 50). Gene expression levels (RQ) were related to blood gas parameters (pH, pCO₂, pO₂, cHCO₃) and the presence of clinical features of threatened neonatal asphyxia. Results: Microarray analysis revealed that environmental pH acts as a molecular phenotypic switch. Under low pH conditions (<7.35), a shift in cell profile from proliferative to structural–migratory was observed. Significant overexpression of genes responsible for extracellular matrix (ECM) organization and adhesion (e.g., COMP, DCN, LUM, FMOD) was observed, while pathways related to cell cycle and cell division (↓CDK1, AURKA, TOP2A) were downregulated. qPCR validation confirmed these observations, demonstrating a strong positive correlation between blood pH and the expression of regenerative mediators: FGFR1 (r = 0.28), EGF (r = 0.30), NGF (r = 0.39), and IGF1 (r = 0.30). A negative correlation was also found between carbon dioxide pressure (pCO₂) and the expression of NGF, FGFR1, and EGF. A significant clinical finding was that in newborns diagnosed with threatened asphyxia, EGF, FGFR1, and NGF gene expression was significantly reduced, indicating impaired trophic potential of the cells in response to metabolic stress. Conclusions: These results indicate that cord blood gas parameters are critical regulators of the genetic activity of UC-MSCs. Metabolic and respiratory acidosis not only inhibit the cells’ proliferative potential but also force them into a matrix remodeling mode, permanently modifying their transcriptomic profile. This suggests that the neonatal acid–base status may serve as an objective indicator of the “biological quality” of isolated stromal cells, which has significant implications for their future applications in cell therapies. Full article

Newborn screening in England is a national program with laboratories adhering to common screening algorithms. Until recently, screening for inherited metabolic disorders was provided by ten laboratories using laboratory-developed tests (LDTs) and three using commercial assays: harmonization of results proved challenging. Introduction of hereditary tyrosinemia type 1 screening meant LDTs required modification to include the measurement of succinylacetone, and subsequent re-validation. This provided an opportunity to implement a single commercial reagent kit in all laboratories. It was anticipated that this would improve analytical performance and harmonization. This study aimed to determine whether these goals were achieved. Verification across the 13 laboratories revealed that the commercial kit reduced inter-laboratory variation for all analytes demonstrating improved harmonization. However, this was achieved by applying instrument-specific correction factors to all analytes, the magnitude of which were significant, indicating a lack of standardization. Performance of succinylacetone was limited by instrument-dependent background interference from the methionine stable isotope label, underscoring the need to establish evidence-based screening cut-off values (COV) rather than adopting published thresholds. This study emphasizes the need for traceable reference materials to improve laboratory quality and the value of screening outcome data. Full article

Background: Phenylketonuria (PKU) is a rare genetic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in a deficiency of the enzyme responsible for metabolizing phenylalanine (Phe) and its accumulation. PKU can be identified through newborn screening (NBS) or genetic sequencing; however, both approaches have limitations, including high false-discovery rates and variants of uncertain significance (VUS). This study aims to identify a PKU metabolomic profile using unique biomarkers to enhance early diagnosis and improve treatment outcomes. Methods: Dried blood spot (DBS) samples from 65 patients diagnosed with PKU and matched healthy controls were collected through the NBS program. An untargeted metabolomics analysis was conducted using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to profile metabolites and investigate altered metabolic pathways in patients with PKU. Results: A total of 418 significantly dysregulated metabolites were identified in PKU patients. Among them, 90 metabolites were identified as endogenous human metabolites. The most significantly affected pathways were those related to the metabolism of aromatic amino acids and polysaccharides. Moreover, lipid metabolic pathways were dysregulated, including those involved in fatty acid and phospholipid biosynthesis. In addition to phenylalanine (AUC = 0.994), 1,11-Undecanedicarboxylic acid (UDCA) (AUC = 0.969) was significantly elevated in patients with PKU, suggesting it is a promising potential biomarker for PKU. Conclusions: Untargeted metabolomics revealed distinct metabolic alterations in patients with PKU, providing insights into disease pathophysiology. The identification of UDCA as a consistently elevated metabolite supports its potential utility as a supplementary biomarker for PKU diagnosis and monitoring. Further validation in larger cohorts, using a targeted metabolomics approach, is warranted. Full article

Proximal urea-cycle disorders (PUCDs), including N-acetylglutamate synthase deficiency (NAGSD), ornithine transcarbamylase deficiency (OTCD), and carbamoyl phosphate synthase 1 deficiency (CPS1D), cause hyperammonemia and impair neurological outcomes. Early detection of late-onset forms allows presymptomatic intervention to prevent hyperammonemia; however, reliable newborn screening (NBS) markers are lacking. This prospective pilot study in Hyogo Prefecture, Japan, evaluated hypocitrullinemia as a screening marker for late-onset PUCDs. Newborns with citrulline levels below the 0.05th percentile on NBS between June 2020 and May 2024 were enrolled in the study. Confirmatory diagnosis of PUCDs was performed using plasma amino acids, urinary organic acids, and genetic testing. During the first period (101,172 newborns), 11 newborns exhibited hypocitrullinemia; 10 underwent further evaluation. One newborn was diagnosed with CPS1D (compound heterozygous CPS1 variants); another was later diagnosed with Leigh syndrome. The remaining eight cases were false positives, often associated with prematurity, poor feeding, or gastrointestinal disorders. A second dried blood spot (DBS) card protocol was introduced in the second period (34,694 newborns), reducing false positives. One neonatal-onset OTCD case was detected, and citrulline levels were normalized in six of the seven other cases. In summary, hypocitrullinemia can identify presymptomatic PUCDs, and requesting a second DBS card reduces false positives, supporting its feasibility for incorporation into NBS programs. Full article

Inborn errors of metabolism (IEMs) are a group of inherited genetic conditions that, in general, result from a specific enzyme defect. Clinical consequences caused by abnormal enzyme levels often disrupt affected metabolic pathways and their intermediary metabolites. Because diagnostic outcomes depend on early intervention, a timely and accurate diagnosis is essential. Quantitative targeted metabolomics (QTM) is an analytical approach that quantifies predefined metabolites and generates interpretable biochemical phenotypes. Instead of focusing solely on screening, expanded QTM methods enable higher coverage with multi-analyte profiling that can provide more comprehensive characterization of disease-associated metabolic perturbations, particularly in IEMs with overlapping biochemical profiles. This review summarizes diagnostic techniques for IEMs, outlines the principles and advantages of QTM, and evaluates its established role and emerging opportunities and limitations in advancing method development and deep metabolic phenotyping to support precision medicine. Full article

Next-generation sequencing (NGS) has transformed the diagnostic landscape for inherited metabolic diseases by enabling high-resolution detection of pathogenic variants across genetically heterogeneous lysosomal pathways. This is particularly impactful for lysosomal diseases (LDs), including the mucolipidoses (ML I–IV), and for disorders involving lysosomal membranes, transporters, and lysosome-related organelles (LROs). These conditions often present with overlapping biochemical and clinical features that historically complicated accurate diagnosis. This review synthesizes current knowledge on the application of next-generation sequencing (NGS) technologies in the detection and interpretation of variants underlying mucolipidoses types I-IV and selected LRO and lysosomal membrane transport disorders. We summarize expanded variant catalogues, genotype–phenotype correlations, and functional evidence informing pathogenicity classification. In addition, we discuss the integration of NGS into newborn screening and population-level genomics. Collectively, these advances have refined disease definitions, resolved diagnostically challenging cases, and reshaped clinical workflows across the LD and LRO disease spectra. Full article

Background: Providing optimal parenteral nutrition to extremely preterm babies in the first week after birth is challenging, and different strategies may be associated with both short- and long-term outcomes. Methods: In a secondary cohort analysis of the ProVIDe trial, a multicentre, randomised, controlled trial in extremely-low-birthweight babies of increased amino acid intake in the first five days after birth, we explored the associations between parenteral amino acid and lipid intakes and blood spot amino acid concentrations, clinical outcomes and neurodevelopment. The cohort comprised 382 babies born in six New Zealand hospitals of whom 342 survived to 28 days. Nutritional intake data in the first week and newborn metabolic screening data on days 1, 5, 14, and 28 were retrieved, and 294 children were assessed for neurodevelopmental outcome at 2 years’ corrected age. Results: Blood spot amino acid concentrations were positively associated with amino acid intake (p < 0.005). Higher amino acid intakes were associated with increased odds (OR), 95% confidence intervals (CIs) of bronchopulmonary dysplasia (tyrosine: OR 2.2, CI 1.2–3.9; proline: OR 2.3, CI 1.3–4.0), patent ductus arteriosus and probable sepsis. No significant associations were found for necrotising enterocolitis. Higher lipid intakes were associated with lower odds of intraventricular haemorrhage (0.33 [0.16, 0.66]), bronchopulmonary dysplasia (0.31 [0.13, 0.73]) and retinopathy of prematurity (0.29 [0.12, 0.72]). Unlike short-term outcomes, neurodevelopment did not differ according to blood spot or intake quartile for any amino acid in week 1. Conclusions: Parenteral nutritional intakes in the first week after birth are associated with short-term outcomes. Further research is needed to optimise the composition of amino acid solutions. Trial Registration: ACTRN12612001084875, (accessed on 10 October 2012). Full article

Newborn mass screening improves outcomes for inborn errors of metabolism (IEM); nonetheless, home-based dietary therapy imposes a substantial parental burden. In this study, we explored differences in parents’ health coping behaviors, assessed using the Coping Health Inventory for Parents (CHIP), based on the presence of dietary therapy, child age group, and diagnostic category. A 21-item, CHIP-based questionnaire was distributed via the JaSMIn registry to parents of children with IEM up to school age. Overall, 201 valid responses (56.1% response rate) were analyzed regarding the implementation and perceived usefulness of coping behaviors, stratified by child age, enrollment, diagnosis, and dietary therapy. Parents in the dietary-therapy group reported more coping behaviors than did those in the non-dietary-therapy group. Notably, parents of children aged 1–3 years (not yet in preschool) and those of children with organic acid metabolism disorders rated “daily home practice of treatments” as a highly useful coping behavior. Health-related coping behaviors among parents of children with IEM vary substantially according to child age and disease characteristics. Therefore, family support strategies should be tailored to specific developmental stages and treatment requirements. Full article

Neurodegenerative diseases (NDDs) in children represent a heterogeneous group of rare but collectively significant disorders characterized by progressive neurological decline, developmental regression, and substantial morbidity and mortality. Unlike adult-onset neurodegeneration, pediatric conditions are predominantly genetic and frequently arise from defects in fundamental cellular pathways, including lysosomal degradation, mitochondrial oxidative phosphorylation, peroxisomal lipid metabolism, and myelin maintenance. This comprehensive review synthesizes current knowledge regarding the epidemiology, molecular classification, pathophysiology, and emerging therapeutic strategies of major pediatric neurodegenerative disorders. Epidemiological data indicate a “rare-but-many” landscape, where individually uncommon diseases collectively impose a measurable population burden. Mechanistically, disease progression reflects converging processes such as toxic substrate accumulation, impaired autophagy–lysosome flux, mitochondrial bioenergetic failure, oxidative stress, neuroinflammation, and glial dysfunction. Representative groups discussed include lysosomal storage disorders, leukodystrophies, mitochondrial encephalopathies, peroxisomal disorders, and other monogenic neurodegenerative syndromes. Advances in next-generation sequencing, metabolic profiling, and neuroimaging have substantially improved diagnostic accuracy and enabled earlier detection, including through newborn screening programs. Therapeutic paradigms are shifting from primarily supportive care toward mechanism-based interventions, including enzyme replacement therapy, hematopoietic stem cell transplantation, substrate reduction strategies, and gene therapy approaches. Early molecular diagnosis is increasingly recognized as critical for optimizing outcomes, particularly in disorders amenable to presymptomatic intervention. Continued integration of genomic medicine, standardized epidemiologic surveillance, and translational research will be essential to refine disease classification, improve prognostication, and expand access to targeted therapies. Collectively, pediatric neurodegenerative diseases exemplify the intersection of developmental neurobiology and inherited metabolic dysfunction, underscoring the need for multidisciplinary, precision-based clinical strategies. Full article

(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only between different disease types but also between individual patients with the same condition. In the Roma community, we analyzed the most frequent rare genetic disorders related to the founder effect. (2) Methods: This retrospective study, conducted between January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis 7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA mutation, predominantly affecting males (n = 17). The disorder is severe, with most patients dying before one year of age, and is characterized by inspiratory stridor, axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males, three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age of 8.8 months, and most children did not survive beyond three years. Common features included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying the same MFSD8 mutation. Symptoms typically began with psychomotor regression between ages 3 and 4, along with intellectual disability and seizures, which were more frequent in males. The mean age at diagnosis was 4.5 years, and eight children died before age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry were identified, predominantly females, with a mean age of 9.95 years and the oldest patient aged 25. Four children died due to severe metabolic crises. Common findings included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy, and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high morbidity and mortality, with no targeted therapies currently available. Their increased prevalence in the Roma population reflects founder effects and high consanguinity. Prenatal and newborn screening, along with voluntary carrier testing for couples, is essential for proactive health management. Full article

Background: Arginase 1 deficiency (ARG1-D) is an ultra-rare urea cycle disorder characterized by hyperargininemia and progressive neurological impairment, including spasticity, loss of motor function, and reduced quality of life. Conventional management based on dietary protein restriction and ammonia scavengers rarely achieves adequate metabolic control or prevents neurological deterioration. Pegzilarginase, a recombinant human arginase 1 enzyme, is the first disease-modifying therapy for ARG1-D. Methods: We report the first Italian real-world experience with pegzilarginase in three pediatric patients with genetically confirmed ARG1-D enrolled in the phase 3 PEACE trial. Clinical, biochemical, functional, nutritional and quality-of-life data were retrospectively collected over a long-term follow-up (2003–2025). Outcomes were evaluated across three phases: treatment initiation (Start), a 13-month treatment interruption due to trial closure (Stop), and therapy re-initiation through an early access program (Restart). Results: Pegzilarginase rapidly normalized plasma arginine levels and was associated with improvements in motor function, spasticity, walking endurance, dietary protein tolerance, bone mineral density, and quality of life. During treatment interruption, all patients experienced biochemical worsening and clinical deterioration, including increased spasticity, reduced mobility, and emotional distress. Re-initiation of pegzilarginase restored metabolic control and led to progressive neurological and functional recovery, including partial reversal of long-standing motor deficits. Conclusions: This real-world experience supports pegzilarginase as a disease-modifying therapy for ARG1-D. Sustained normalization of plasma arginine, rather than subthreshold biochemical control, correlates with functional and neurological improvement and may partially reverse non-lesional metabolic brain injury. Early initiation of pegzilarginase, including in newborn-screened patients, may further modify the natural history of ARG1-D. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

COASY-related disorders (CRDs) are a spectrum of autosomal recessive conditions caused by the dysfunction of CoA synthase, an enzyme responsible for the final steps of CoA synthesis. Clinical manifestations of CRDs are highly variable, ranging from perinatal lethal pontocerebellar hypoplasia to childhood-onset neurodegenerative brain iron accumulation, which is often recognized after clinical regression. Recent reports have described a few individuals with CRD who screened positive for carnitine palmitoyltransferase-I deficiency by newborn screening (NBS). However, heterogeneous clinical presentations, conflicting biochemical/molecular sequencing of CPT1A, and a lack of metabolic characterization have led to lengthy, costly diagnostic journeys. To address some of these aspects, this investigation retrospectively evaluated NBS acylcarnitine patterns in five CRD cases using Collaborative Laboratory Integrated Reports (CLIR). A total of 25 metabolites/ratios were identified to deviate significantly from reference ranges and were primarily composed of elevated free carnitine and reduced long-chain acylcarnitine levels. While low acylcarnitine concentrations are often not reported due to a lack of lower reference cutoffs, ratios involving these metabolites relative to short-chain acylcarnitines could aid in identifying CRD cases via NBS. When comparing this pattern to CPT-Ia cases, we confirmed a nearly identical acylcarnitine pattern between these, and thus support the need to consider CRD in cases with NBS results suggestive of CPT-Ia. This study is the first case series to characterize NBS patterns in patients with CRD and highlights the unique opportunity for early detection, particularly in cases that are neonatally asymptomatic and have unremarkable confirmatory biochemical results. Full article